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Combination Effects of Radiotherapy / Drug Treatments for Cancer Recommendation by the German Commission on Radiological Protection with scientific Background

Adopted at the 264th session of the SSK on 21 October 2013 Combination Effects of Radiotherapy / Drug Treatments for Cancer 2

The German original of this English translation was published in 2013 by the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety under the title:

Kombinationswirkungen Strahlentherapie/medikamentöse Tumortherapie Empfehlung der Strahlenschutzkommission mit wissenschaftlicher Begründung

This translation is for informational purposes only, and is not a substitute for the official statement. The original version of the statement, published on www.ssk.de, is the only definitive and official version. Combination Effects of Radiotherapy / Drug Treatments for Cancer 3

Contents

Preface ...... 8 Recommendation ...... 9 Scientific background of the recommendation ...... 11 1 Introduction ...... 11 2 Drug licensing and pharmacovigilance ...... 11 2.1 Various procedures lead to licensing for the German market ...... 11 2.2 Central European authorisation procedure for anti-cancer drugs ...... 12 2.3 Limitations of the data available at the time of marketing authorisation ...... 13 2.4 Pharmacovigilance obligations of the authorisation holder ...... 14 2.5 Spontaneous reporting system as an important means of gaining knowledge ...... 15 2.6 References ...... 15 3 Comments on the theory of combination effects ...... 16 4 Classic cytostatic drugs ...... 18 4.1 Anthracyclines ...... 18 4.1.1 Use ...... 18 4.1.2 The data situation in combination with radiotherapy ...... 19 4.1.2.1 Effect ...... 19 4.1.2.2 Toxicity ...... 19 4.1.3 Summary ...... 20 4.2 Taxanes ...... 20 4.2.1 Use ...... 20 4.2.2 The data situation in combination with radiotherapy ...... 22 4.2.2.1 Effect ...... 22 4.2.2.2 Toxicity ...... 22 4.2.3 Summary ...... 23 4.3 Platinum derivatives: cisplatin, carboplatin, oxaliplatin ...... 24 4.3.1 Use ...... 24 4.3.2 The data situation in combination with radiotherapy ...... 24 4.3.2.1 Effect ...... 24 4.3.2.2 Toxicity ...... 25 4.3.3 Summary ...... 25 4.4 Antimetabolites ...... 25 4.4.1 Use ...... 25 4.4.2 The data situation in combination with radiotherapy ...... 28 4.4.2.1 Effect ...... 28 Combination Effects of Radiotherapy / Drug Treatments for Cancer 4

4.4.2.2 Toxicity ...... 28 4.4.3 Summary ...... 28 4.5 Topoisomerase inhibitors...... 29 4.5.1 Use ...... 29 4.5.2 The data situation in combination with radiotherapy ...... 30 4.5.2.1 Effect ...... 30 4.5.2.2 Toxicity ...... 30 4.5.3 Summary ...... 30 4.6 Alkylating agents ...... 31 4.6.1 Use ...... 31 4.6.2 The data situation in combination with radiotherapy ...... 32 4.6.2.1 Effect ...... 32 4.6.2.2 Toxicity ...... 32 4.6.3 Summary ...... 32 4.6.4 Individual substances ...... 32 4.6.4.1 Lomustine (CCNU) ...... 32 4.6.4.2 Carmustine (BCNU) ...... 33 4.6.4.3 Procarbazine and dacarbazine ...... 33 4.6.4.4 Busulfan, chlorambucil, bendamustine and melphalan ...... 34 4.6.4.5 Cyclophosphamide, ifosfamide and trofosfamide ...... 36 4.6.4.6 Treosulfan ...... 39 4.6.4.7 Thiotepa ...... 39 4.6.4.8 Temozolomide ...... 40 4.6.4.9 Mitomycin C ...... 40 5 Antibodies ...... 42 5.1 Anti-EGFR antibodies: cetuximab, panitumumab and nimotuzumab ...... 42 5.1.1 Uses of cetuximab ...... 42 5.1.2 The data situation in combination with radiotherapy for cetuximab ...... 42 5.1.2.1 Effect ...... 42 5.1.2.2 Toxicity ...... 42 5.1.2.3 Further aspects ...... 43 5.1.3 Uses of panitumumab ...... 43 5.1.4 The data situation in combination with radiotherapy for panitumumab ...... 43 5.1.4.1 Effect ...... 43 5.1.4.2 Toxicity ...... 43 5.1.4.3 Nimotuzumab ...... 43 5.2 Anti-EGFR HER2/neu antibody: trastuzumab ...... 44 5.2.1 Use ...... 44 Combination Effects of Radiotherapy / Drug Treatments for Cancer 5

5.2.2 Effect ...... 45 5.2.3 Toxicity in combination with radiotherapy ...... 45 5.3 Anti-VEGF antibody: bevacizumab ...... 45 5.3.1 Use ...... 45 5.3.2 Toxicity in combination with radiotherapy ...... 46 5.4 Anti-CD20 antibody: rituximab ...... 47 5.4.1 Use ...... 47 5.4.2 Toxicity in combination with radiotherapy ...... 48 5.5 Summary ...... 48 6 Small molecules ...... 48 6.1 Tyrosine kinase inhibitors: gefitinib, erlotinib, lapatinib, sunitinib, sorafenib48 6.1.1 Use ...... 48 6.1.2 The data situation in combination with radiotherapy ...... 49 6.1.2.1 Effect ...... 49 6.1.2.2 Toxicity ...... 50 6.1.3 Summary ...... 51 6.2 Tyrosine kinase inhibitor: imatinib ...... 52 6.2.1 Use ...... 52 6.2.2 The data situation in combination with radiotherapy ...... 52 6.2.2.1 Effect ...... 52 6.2.2.2 Toxicity ...... 53 6.2.3 Summary ...... 54 6.3 mTOR inhibitors: temsirolimus, everolimus ...... 54 6.3.1 Use ...... 54 6.3.2 The data situation in combination with radiotherapy ...... 55 6.3.2.1 Effect ...... 55 6.3.2.2 Toxicity ...... 55 6.3.3 Summary ...... 55 6.4 Proteasome inhibitors ...... 55 6.4.1 Use ...... 55 6.4.2 The data situation in combination with radiotherapy ...... 56 6.4.2.1 Effect ...... 56 6.4.2.2 Toxicity ...... 56 6.4.3 Summary ...... 56 7 Growth factors ...... 57 7.1 Erythropoietin ...... 57 7.1.1 Use ...... 57 Combination Effects of Radiotherapy / Drug Treatments for Cancer 6

7.1.2 The data situation in combination with radiotherapy ...... 57 7.1.2.1 Effect ...... 57 7.1.2.2 Toxicity ...... 57 7.1.3 Summary ...... 57 7.2 G-CSF and GM-CSF ...... 57 7.2.1 Use ...... 57 7.2.2 The data situation in combination with radiotherapy ...... 58 7.2.2.1 Effect ...... 58 7.2.2.2 Toxicity ...... 58 7.2.3 Summary ...... 59 7.3 Keratinocyte growth factors ...... 59 7.3.1 Use ...... 59 7.3.2 The data situation in combination with radiotherapy ...... 59 7.3.2.1 Effect ...... 59 7.3.2.2 Toxicity ...... 59 7.3.3 Summary ...... 60 7.4 Thrombocyte growth factors ...... 60 7.4.1 Use ...... 60 7.4.2 The data situation in combination with radiotherapy ...... 60 7.4.2.1 Effect ...... 60 7.4.2.2 Toxicity ...... 60 8 Free-radical scavengers (e. g. selenium) ...... 61 8.1 Use ...... 61 8.2 The data situation in combination with radiotherapy ...... 61 8.2.1 Effect ...... 61 8.2.2 Toxicity ...... 61 8.2.3 Summary ...... 61 9 Miscellaneous ...... 61 9.1 Thalidomide ...... 61 9.1.1 Use ...... 61 9.1.2 The data situation in combination with radiotherapy ...... 62 9.1.2.1 Effect ...... 62 9.1.2.2 Toxicity ...... 62 9.1.3 Summary ...... 63 9.2 Lenalidomide ...... 63 9.2.1 Use ...... 63 9.2.2 The data situation in combination with radiotherapy ...... 63 9.2.2.1 Effect ...... 63 Combination Effects of Radiotherapy / Drug Treatments for Cancer 7

9.2.2.2 Toxicity ...... 63 9.2.3 Summary ...... 63 9.3 PARP inhibitors: olaparib and BSI 201 ...... 63 9.3.1 Use ...... 63 9.3.2 The data situation in combination with radiotherapy ...... 64 9.3.2.1 Effect ...... 64 9.3.2.2 Toxicity ...... 64 9.3.3 Summary ...... 64 10 Special considerations in connection with nuclear medicine therapies ... 65 10.1 Radioiodine therapy for thyroid disorders ...... 65 10.2 Therapy with 131I-metaiodobenzylguanidine (mIBG) for tumours of the neuroectoderm and its derivatives ...... 66 10.3 Treatment with 90Y-/177Lu-DOTA-D-Phe1-Tyr3-octreotide (DOTATOC), 90Y-/177Lu-DOTA-D-Phe1-Tyr3-octreotate (DOTATATE) or other somatostatin analogues for tumours of the neuroectoderm and its derivatives ...... 67 10.4 Selective internal radiation therapy (SIRT) with Y-90 microspheres for malignant liver tumours ...... 67 References ...... 71 Abbreviations ...... 104 Annex A Tables – Interaction potential of drug treatments for cancer and radiation ...... 107 Annex B Structural recommendations ...... 112 Combination Effects of Radiotherapy / Drug Treatments for Cancer 8

Preface

Great progress is being made in the treatment of cancer and leukaemia. A major reason for this is the frequent combining of radiotherapy and drug treatments. However, such combining of therapeutic measures can sometimes lead to highly undesirable side effects. This is becoming an increasing problem. The German Commission on Radiological Protection (SSK) was therefore commissioned by the Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) to ‘draw up recommendations to ensure that when administering radiotherapy, and hence when establishing the indication that justifies it, all information about accompanying chemotherapy (before, during and after the radiotherapy) is taken into account’. A working group was set up and produced a draft of the required recommendation. The members of the working group were:  Claus Belka (Klinikum Großhadern, Munich)  Andreas Bockisch (Universitätsklinikum Essen)  Peter Brossart (Universitätsklinik Bonn)  Wilfried Budach (Universitätsklinik Düsseldorf)  Michael Flentje (Universitätsklinik Würzburg)  Ulrike Hermes (Federal Institute for Drugs and Medical Devices, Bonn)  Mechthild Krause (Universitätsklinikum Dresden)  Wolfgang-Ulrich Müller (Universitätsklinikum Essen), chair of the working group  Claus Rödel (Universitätsklinik Frankfurt)  Brigitte Stöver (Charité Berlin)  Frederik Wenz (Universitätsklinikum Mannheim). The editorial deadline was 21 March 2013; literature published after this date has therefore not been considered. While preparing the recommendation we became aware that DEGRO, the German Society for Radiation Oncology, was working on S2e guidelines on this subject, although with a somewhat different aim in mind. The SSK working group therefore invited a member of the DEGRO working group to review whether there were differences in the opinions of the two groups. It transpired that there were no noteworthy discrepancies. DEGRO’s guidelines on supportive measures in radiation oncology are expected to be published towards the end of 2014.1 Bonn, July 2014 Prof. Wolfgang-U. Müller Chair of the German Commission on Radiological Protection

1 According to the Chair of the DEGRO working group, the guidelines are likely to be published under: German Guideline Programme in Oncology (DEGRO, AWMF): S2e-Leitlinie Supportive Maßnahmen in der Radio- onkologie, long version 2014, AWMF register number: 052-014, http://leitlinienprogramm- onkologie.de/Leitlinien.7.0.html [as at: July 2014] Combination Effects of Radiotherapy / Drug Treatments for Cancer 9

Recommendation

It has long been known that in certain cases there are interactions between ionising radiation and drug treatments for cancer. These interactions may result in the occurrence of effects that are either smaller or larger than would be expected from addition of the individual effects. Such interactions are always linked to very specific conditions which include but are not limited to:  the level of the radiation dose  the radiation quality  the type and mode of action of the substance  the level of concentration of the substance  the sequence of administration  the endpoint studied (cell death, mutation, transformation …). If unexpectedly large changes in effects are observed after exposure to a combination of radiation and drug treatments for cancer, one must ask whether these changes are in fact the result of an interaction between the two agents or based merely on addition of the individual effects. This issue is explored in more detail at the start of the scientific substantiation. The possibility of adverse interactions arising from the combined use of radiotherapy and drug treatments for cancer is becoming increasingly relevant. One of the main reasons for this is that such uses are occurring ever more frequently, especially in palliative therapy situations in which an extensive systemic tumour burden means that interruption of drug treatment during symptomatic or palliative local radiotherapy would be accompanied by a major risk of progression. There is growing concern that this might induce greater side effects, possibly even resulting in a fatal outcome. The German Commission on Radiological Protection (SSK) was therefore commissioned to draw up recommendations to ensure that when administering radiotherapy and hence when establishing the indication that justifies it, all information about accompanying drug treatment (before, during and after the radiotherapy) is taken into account. In order to make the significance of the issue clear, the SSK has presented, in the scientific substantiation accompanying this recommendation, the current state of knowledge by setting out some important examples of drugs that are or have been used in cancer treatment before, during or after a course of radiotherapy. For some groups of substances no unexpected side effects that might be attributable to combined usage have yet been observed. To varying degrees, however, other groups of substances have the potential to cause serious side effects as a result of being combined with ionising radiation. A table of these substances will be found in the scientific substantiation. When the possibility of combined treatment with radiation and oncological drugs arises, radiation oncologists and doctors practising in other areas of oncology should inform each other in advance about their intended treatment measures. This should occur even if the measures are not implemented concurrently. Informative doctors’ letters are undoubtedly an important aid in this regard. During the licensing process drugs used in cancer treatment are not usually explicitly reviewed with regard to their interaction with ionising radiation. Published reports on adverse interactions are not normally available, at least during the early stages of clinical use. Combination Effects of Radiotherapy / Drug Treatments for Cancer 10

Unexpected side effects must be reported immediately to the competent federal authority (the Drug Commission of the German Medical Association (AkdÄ), the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI)). Doctors responsible for aftercare must also be alert to the possibility of unexpected side effects (i. e. entirely new side effects or side effects that are unexpectedly frequent or severe) and report them. The recommendations of the SSK are therefore as follows:  Oncological drugs that are very likely to be used in combination with ionising radiation should be reviewed during the licensing process to establish whether there are any indications that an augmentation or reduction of effect occurs. If such indications are found, a warning to this effect must be included in the SPC.  Combined treatment with radiotherapy and oncological drugs should be administered on the basis of scientifically validated schemata or within clinical trials. This is particularly important in the case of concurrent use.  Where new substances are used or existing substances are used in different treatment regimens, the clinician must monitor each case carefully and must be required to maintain appropriate documentation. There is currently a particular lack of information on interactions associated with sequential treatment, such as recall phenomena.  Mandatory communication pathways such as tumour boards should be set up to ensure an exchange of patient-related information between radiation oncologists and other doctors engaged in oncological work.  There is an urgent need to initiate studies and/or set up a central competence and documentation network. This requires the establishment of an agency with radiation protection expertise (e. g. at the Federal Office for Radiation Protection, BfS) that utilises existing competences and networks.  Doctors involved in cancer treatment or aftercare should be regularly reminded by the yet- to-be-created expert agency through suitable publication channels that they have a professional obligation to report unexpected side effects associated with drug treatment for cancer/radiotherapy to the competent authority immediately.  These reports of interactions between radiotherapy and drug-based cancer treatments must be systematically evaluated by the above-mentioned agency. The SSK recommends initiating and putting out to tender an R&D project with the aim of founding a consortium of radiotherapy clinics for standardised, prospective recording of unwanted combination effects (KONSEUK network – KONsortialverbund aus Strahlen- kliniken zur standardisierten, prospektiven Erfassung Unerwünschter Kombinations- wirkungen). Combination Effects of Radiotherapy / Drug Treatments for Cancer 11

Scientific background of the recommendation

1 Introduction

Interactions between ionising radiation and cancer treatment drugs pose particular problems and have high risk potential. Contributing factors are the administration of different treatments by different clinicians, the comorbidities of individual patients, and overreporting and underreporting of unintended combinations. The intensification of many treatments, multimorbidity and the diversification of particular drug-based treatments increase the significance of these interactions. Assessing the overall extent of the problem requires a prospective approach. The aim of this scientific substantiation is to illustrate by means of suitable examples the issues that arise from combined use of ionising radiation and drugs in cancer treatment. It cannot attempt to summarise all the available information on the subject, particularly with regard to specific drugs, and does not set out to do so. The focus is on information obtained from cell biology; where available, the findings of clinical trials are taken into account. The many anecdotal reports have been largely left aside, although they may indeed constitute warning signs. Any final assessment, however, must be based on extensive analysis: without this there is a risk that a few cases of unexpectedly severe side effects – which may be related to other case-specific factors – may result in a valuable treatment regimen that is well tolerated by the vast majority of patients not being used. This scientific substantiation considers only the issues that arise in adult oncology. In children’s oncology there are of course many parallels, but there are also some refinements that are beyond the scope of this overview.

2 Drug licensing and pharmacovigilance

In Germany, drug safety was brought to the forefront of public attention in the early 1960s by the issue of thalidomide, which was marketed in Germany as Contergan. In response to this scandal, the country’s drug legislation was updated in 1976: registration of unevaluated drugs was replaced by a requirement for a risk-benefit analysis prior to marketing. The German law on medicinal products (Arzneimittelgesetz, AMG) and European regulations created rules for drug licensing and pharmacovigilance; these were subsequently refined with the aim of ensuring a high level of safety in connection with the use of drugs (Friese et al. 2007). Under the AMG, finished medicinal products must be licensed. Before marketing authorisation is granted, the licensing authority must review the evidence of efficacy, safety and appropriate pharmaceutical quality.

2.1 Various procedures lead to licensing for the German market

Various legally defined procedures can lead to licensing for the German pharmaceutical market: national authorisation, the mutual recognition procedure, the decentralised procedure and central authorisation. While national authorisation applies only to the German market, central authorisations are valid in all EU member states, Norway and Iceland. In the case of mutual recognition procedures and decentralised procedures the applicant can specify the EU member states in which the medicinal product will be marketed (European Parliament 2001: Directive 2001/83/EC; European Parliament 2004: Regulation (EC) No. 726/2004). Combination Effects of Radiotherapy / Drug Treatments for Cancer 12

As a basis for authorisation a distinction is made between a full or stand-alone application and an abridged application. Authorisation of a new active substance usually requires a full application, involving submission of complete documentation evidencing pharmaceutical quality, efficacy and safety. Authorisation of medicinal products containing existing active substances is normally based on an abridged application. The applicant makes reference to the toxicological and clinical documentation and thus to the existing risk-benefit profile of a medicinal product that has already been authorised, e. g. in a generic application, and provides evidence only of pharmaceutical quality. Special forms are bibliographic and hybrid applications in which published literature forms part of the documentation and the active substance is well-established for medical use in connection with the indication in question. The scope of the authorisation dossier – as an expression of the pre-clinical and clinical development programme – is thus different for full and for abridged applications (European Parliament 2003: Directive 2003/63/EC). For new active substances, applications for authorisation must be accompanied by full documentation of pre-clinical development, covering in particular pharmacology, pharmacokinetics and toxicology. Toxicology includes genotoxicity, carcinogenicity, reproductive toxicity and in some cases local toxicity. Interaction with radiation does not form part of the standard development programme. In the development of drugs intended for the treatment of late-stage cancers for which very few alternative options are available, the pre-clinical development programme can be reduced. Where cytotoxicity is known to exist, the requirement for studies of genotoxicity, carcinogenicity and reproductive toxicity can be waived (EMA 2010: ICH Topic S9). Full documentation of clinical development includes data on biopharmaceutical development, clinical pharmacology, efficacy, safety and the risk-benefit assessment. Phase I to III clinical trials provide evidence of efficacy and safety for the indication applied for. The safety profile from the clinical trials and the pre-clinical data together provide the basis for assessment of the risk or safety of new medicinal products. The safety profile from the clinical trials involves analysis of adverse events, serious adverse events, possible links between adverse events and the drug being investigated, and measures to prevent, mitigate and treat adverse events. Assessment of this risk in relation to the benefit of the drug on the basis of the efficacy demonstrated in the clinical trials forms the basis for authorisation decisions.

2.2 Central European authorisation procedure for anti-cancer drugs

Since 2005 drugs containing new active substances for the treatment of cancer can only receive authorisation for the European – and hence also the German – market via central authorisation procedures (European Parliament 2004: Regulation (EC) No. 726/2004). Prior to 2005 the central authorisation procedure was mandatory only for drugs produced using biotechnology; for new chemically manufactured active substances, national authorisation and the mutual recognition procedure could be used as alternatives to the central authorisation procedure. The central authorisation procedures are the responsibility of the European Medicines Agency (EMA) and national authorities. Before the authorisation is approved by the EMA’s Committee for Medicinal Products for Human Use (CHMP), which comprises representatives of all the EU states plus Norway and Iceland, the authorisation dossier is evaluated by two rapporteurs and their assessment teams from the national authorisation authorities. Combination Effects of Radiotherapy / Drug Treatments for Cancer 13

A similar procedure applies to expansion of the use of authorised medicinal products. As in the case of a new authorisation, clinical documentation must be submitted demonstrating a positive risk-benefit balance for the new indication. The introduction of additional indications after marketing authorisation occurs frequently in oncology. For example, the indications for the drug Taxotere®, which contains docetaxel, have been extended more than ten times since the drug was authorised in 1995.

2.3 Limitations of the data available at the time of marketing authorisation

When new active substances are first licensed, the extent of clinical experience of them is naturally limited. With indications for which there is a medical need for additional treatment options – as is usually the case with cancers – authorisation is frequently granted on the basis of limited development programmes so that treatment can be made available to patients rapidly. For example, authorisation may be based on just one registration trial that confirms the hypotheses from the results of the early clinical trials. For rare diseases – which include many oncological and haematological disorders – restricted development programmes are often the only option. As a result of the necessary selection of patients for early trials by means of inclusion and exclusion criteria, and because of the need to consider the safety of trial patients, safety data for particular patient groups – for example, patients with excretory disorders and patients undergoing drug-based and non-drug-based adjunctive treatment, such as radiotherapy – is still very limited. While efficacy can be relatively well established in trials of limited scope, far less information is available about risk. Because of the limited data and the small number of trial patients, rare side effects may sometimes not be identified. In addition, in oncological trials, causal attribution of adverse events to the trial treatment is often difficult. The reasons for this include the high frequency of adverse events, the difficulty of distinguishing side effects from disease symptoms and the often extensive concomitant medication taken by patients. The clinical authorisation dossier relates to the claimed indications – i. e. the quantity of data relating to other indications or to combination with other drug-based or non-drug-based treatments such as radiotherapy is usually very limited. Only a few development programmes for new areas of use that have been authorised in recent years have examined multimodal concepts that include radiotherapy. For example, in the treatment of glioblastoma and tumours of the head and neck:  Temozolomide (Temodal®) is authorised for ‘adults with newly diagnosed glioblastoma multiforme ... Temodal is used first with radiotherapy and then on its own’ (EPAR Temodal 2012).  Cetuximab (Erbitux®) is authorised for the treatment of patients with ‘squamous-cell cancers of the head and neck. In locally advanced cancer ... Erbitux is given in combination with radiotherapy’ (EPAR Erbitux 2012).  Docetaxel (Taxotere®) is used to treat ‘head and neck cancer in patients whose cancer is locally advanced. Taxotere is used with cisplatin and 5-fluorouracil.’ Induction chemotherapy is followed by radiotherapy as part of the multimodal concept (EPAR Taxotere 2012). When the authorisations for the specified indications were extended, safety data for the combination or multimodal treatment was available for a few hundred patients. Because radiotherapy is a form of treatment used with palliative intent in many cancers, the licensing authority, too, considers it necessary to collect more data on the safety of new Combination Effects of Radiotherapy / Drug Treatments for Cancer 14 medicinal products in combination with radiotherapy. The European guidelines on the development of antineoplastic substances, which came into force on 1 July 2013, refer to the importance of gathering safety information in connection with radiotherapy: ‘As radiation therapy is a standard treatment option in malignant tumours, it is foreseeable that patients will be receiving radiation therapy, e. g. for symptom palliation, concomitantly with or in a time frame close to administration of the medicinal agent. Safety information on concomitant or sequential use of the medicinal agent with radiotherapy should be collected throughout the entire study programme, including data on “radiation recall”. Subjects requiring radiation therapy while enrolled in a trial of a novel agent or combination of agents should normally be withdrawn from study therapy. If safety and tolerability information with radiation is desired, well-designed dedicated studies should be conducted in the setting of concomitant radiation, with dosing schedules guided by preclinical toxicology studies.’ (EMA 2013: Guideline on the Evaluation of Anticancer Medicinal Products in Man) This change is designed to ensure that in future more information is collected about the safety of new oncological medicinal products combined with radiotherapy and that the information is made available sooner.

2.4 Pharmacovigilance obligations of the authorisation holder

Implementation of a suitable risk management system by the applicant has formed part of the authorisation of new medicinal products since 2005. The aim of this system is to identify the risks associated with medicinal products at an early stage, evaluate them and take steps to minimise them, thereby achieving the most favourable risk-benefit balance for the individual patient and the patient population. The core component of this system is the risk management plan (RMP). The RMP summarises identified and potential risks on the basis of the experience gained from pre-clinical and clinical trials. The risks include the absence of data for particular patient groups and the risk of off-label use. The RMP includes the catalogue of measures agreed with the licensing authority to close knowledge gaps, and other risk minimisation activities. These measures may involve, for example, additional studies and activities such as the provision of additional information for doctors and patients (e. g. training materials, treatment cards, pregnancy prevention programmes, checklists) to supplement the information on ingredients and use provided on package leaflets. In addition to routine pharmacovigilance activities such as recording the adverse effects of drugs, these special pharmacovigilance activities may be considered necessary. For example, the RMP activities for the drug Thalidomide Celgene, which received approval in 2008, include information materials, the introduction of a treatment card for the information of all doctors who provide treatment, pregnancy tests each time the drug is prescribed for a woman of childbearing age and monitoring of off-label use. In addition to the obligation on the authorisation holder to operate a pharmacovigilance system, evaluate all information scientifically, consider options for risk minimisation and prevention and take regulatory action as necessary, there is also an obligation to report suspected side effects to the competent authority – the Federal Institute for Drugs and Medical Devices (BfArM), the Paul Ehrlich Institute (PEI), the European Medicines Agency (EMA), or the licensing authorities of European member states. The authorisation holder must submit periodic safety update reports that include a scientific assessment of the risk-benefit balance on the basis of all available data (European Parliament 2001: Directive 2001/83/EC; BfArM, PEI 2012: Bulletin zur Arzneimittelsicherheit Nr. 1). Combination Effects of Radiotherapy / Drug Treatments for Cancer 15

2.5 Spontaneous reporting system as an important means of gaining knowledge

Extensive spontaneous reporting of suspected adverse drug reactions (ADRs) is important to enable prompt closure of gaps in knowledge relating to the risks of new medicinal products. Spontaneous reports are particularly useful because they are obtained from broad use in ordinary situations, thereby enabling rare side effects and side effects in contexts not covered in the clinical trials to be recorded. Cases should be reported if an adverse drug reaction is suspected. Of particular interest are all severe adverse drug reactions, ADRs to new active substances (i. e. up to five years after authorisation), previously unknown ADRs and ADRs to off-label use. Unexpectedly frequent or severe ADRs are also important when they involve the use of drugs in combination therapies – including combinations with radiotherapy. Under their professional code of conduct, doctors and pharmacists are obliged to report suspected cases of adverse drug reactions to their medicinal product to their drug commission. Reports from members of the health professions as well as direct reports from patients are fed via online portals into the data files of the German higher federal authorities (BfArM, PEI). The statutory tasks of the German higher federal authorities include recording and evaluating drug risks and initiating and coordinating necessary measures. These tasks are carried out in cooperation with other authorities, including the European Medicines Agency and the World Health Organisation. The extremely high level of networking in the exchange of information goes hand-in-hand with extensive standardisation of the information (BfArM, PEI 2010: Bulletin zur Arzneimittelsicherheit Nr. 1; BfArM, PEI 2010: Bulletin zur Arzneimittel- sicherheit No 4). Possible measures as a result of evaluation of the spontaneous reports and the authorities’ assessment of the periodic safety update reports on drugs include publication of additional risk information in the product details (new adverse drug reactions, additional warnings and contraindications), ordering of additional studies to clarify the risk, or restrictions on use, which could in some circumstances extend to revocation of an authorisation.

2.6 References

Friese et al. Friese B, Jengtsen B, Muazzam UA. Guide to Drug Regulatory Affairs. 2007 Aulendorf: Edito-Cantor-Verlag; 2007. ISBN 978-3-87193-324-0

BMJ 2012 Bundesministerium für Justiz (BMJ). Arzneimittelgesetz [Law on Medicinal Products] as promulgated on 12 December 2005 (Federal Law Gazette BGBl. I p. 3394), last amended by Art. 2 of the law of 19 October 2012 (BGBl. I p. 2192)

European Directive 2001/83/EC of the European Parliament and of the Council of 6 Parliament November 2001 on the Community code relating to medicinal products for human use

European Regulation No. 726/2004 of the EP and of the Council of 31 March 2004 laying Parliament down Community procedures for the authorisation and supervision of 2004 medicinal products for human and veterinary use and establishing a European Medicines Agency Combination Effects of Radiotherapy / Drug Treatments for Cancer 16

European Commission Directive 2003/63/EC of 25 June 2003 amending Directive Parliament 2001/83/EC of the European Parliament and of the Council on the 2003 Community code relating to medicinal products for human use

EMA 2010 European Medicines Agency (EMA). Note for Guidance on nonclinical evaluation for Anticancer Pharmaceuticals. ICH Topic S9 http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideli ne/2010/01/WC500043471.pdf last accessed 18.09.2013

EPAR European Public Assessment Report (EPAR) Temodal Temodal 2012 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medic ines/000229/human_med_001085.jsp&mid=WC0b01ac058001d124, last accessed 18.09.2013

EPAR Erbitux European Public Assessment Report (EPAR) Erbitux 2012 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medic ines/000558/human_med_000769.jsp&mid=WC0b01ac058001d124 last accessed 18.09.2013

EPAR European Public Assessment Report (EPAR) Taxotere Taxotere 2012 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medic ines/000073/human_med_001081.jsp&mid=WC0b01ac058001d124 last accessed 18.09.2013

EMA 2013 European Medicines Agency (EMA). Guideline on the Evaluation of Anticancer Medicinal Products in Man http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin e/2013/01/WC500137128.pdf last accessed 18.09.2013

BfArM, PEI BfArM, PEI Bulletin zur Arzneimittelsicherheit Nr. 1, March 2012 2012 http://www.bfarm.de/SharedDocs/1_Downloads/DE/BfArM/publ/bulletin/201 0/1-2012.pdf last accessed 12.09.2013

BfArM, PEI BfArM, PEI Bulletin zur Arzneimittelsicherheit Nr. 1, March 2010 2010 http://www.bfarm.de/SharedDocs/1_Downloads/DE/BfArM/publ/bulletin/201 0/1-2010.pdf last accessed 12.09.2013

BfArM, PEI BfArM, PEI Bulletin zur Arzneimittelsicherheit Nr. 4, December 2010 2010 http://www.bfarm.de/SharedDocs/1_Downloads/DE/BfArM/publ/bulletin/201 0/4-2010.pdf last accessed 12.09.2013

3 Comments on the theory of combination effects

As long ago as 1913, Frei realised that the shape of the dose-response relationship is a key influence on the conclusions that can be drawn from experiments involving a combination of Combination Effects of Radiotherapy / Drug Treatments for Cancer 17 two or more substances. Whenever at least one of the dose-effect curves is non-linear, it is not only the effects that must be added but also the doses (or more precisely in the case of substances: the concentrations). A comprehensive and very complex theory of this issue was developed by Loewe (especially Loewe 1928 and 1953). The views propounded there apply not only to combinations of two or more substances but also to combinations of ionising radiation and drugs. Figure 3.1, which shows a typical dose-effect curve, illustrates the problem.

Fig. 3.1: Typical dose-effect curve after exposure to ionising radiation or drugs (effect: e. g. cell survival)

It very clearly makes a considerable difference whether a dose of 0.5 or a dose of 2 of the agent depicted here is used with another agent. In the first case the dose is so far away from the steep fall of the curve that the second agent has no dramatic additional effect if it has only a small effect itself. In the second case (dose of 2), a small effect of the second agent is sufficient to elicit a dramatic effect. Upon detailed analysis, however, a number of problems emerge. For example, it is not immediately clear how a radiation dose and a substance concentration should be added. This problem was elegantly solved by means of the concept of the ‘envelope of additivity’ developed by Steel and Peckham (1979). However, a potentially insuperable difficulty arises from the fact that conclusions about possible interactions cannot be reached unless complete dose-response relationships are available for all the agents involved. In clinical trials on humans, this is not achievable. In this situation the concept of ‘therapeutic synergism’ (Mantel 1974) is more useful. This concept is concerned purely with the issue of whether the combined impact of radiation and drugs under the selected conditions is more successful than the previous most successful therapy modality. In what follows the important question is whether under the selected conditions serious side effects occur that have not previously been observed in connection with administration of either radiation or drug. When serious side effects do occur, it is of scientific interest to discover whether they are actually due to an interaction between radiation and drug or simply to the shape of the dose-response relationship. However, this question cannot be answered from observations in the clinic. In the present context, answering it is in fact of secondary importance, because the primary issue is whether any side effects occur that are not to be expected after administration of the individual agents. Nevertheless, efforts should be made to evaluate potential side effects experimentally, because a good understanding of the combined efficacy Combination Effects of Radiotherapy / Drug Treatments for Cancer 18 of drugs and radiotherapy is essential if a recommendation for or against their combined use is to be made with sufficient certainty. Below, the SSK describes the problems associated with the combined use of ionising radiation and drugs in tumour therapy on the basis of examples.

4 Classic cytostatic drugs

4.1 Anthracyclines

4.1.1 Use Anthracyclines (e. g. epirubicin, doxorubicin, mitoxantrone) are used in the treatment of breast cancer, lymphoma, sarcoma, lung cancer and gastric cancer. Approved areas of use for epirubicin are:  Breast cancer  Advanced ovarian cancer  Small-cell lung cancer  Advanced gastric cancer  Advanced soft tissue sarcoma (Pharmorubicin® SPC, version 08/2011). Approved areas of use for doxorubicin are:  Small-cell lung cancer (SCLC)  Breast cancer  Advanced ovarian cancer  Intervesical prevention of recurrence of superficial bladder cancer after transurethral resection (TUR) of the prostate in patients with a high risk of relapse  Systemic treatment of locally advanced or metastatic bladder cancer  Neoadjuvant and adjuvant therapy for osteosarcoma  Advanced soft tissue sarcoma in adults  Ewing’s sarcoma  Early-stage Hodgkin’s lymphoma (stages I-II) with a poor prognosis  Advanced Hodgkin’s lymphoma (stages III-IV)  Highly malignant non-Hodgkin’s lymphoma  Inducing remission in acute lymphoblastic leukaemia (ALL)  Inducing remission in acute myeloid leukaemia (AML)  Advanced multiple myeloma  Advanced or relapsed endometrial cancer  Wilms’ tumour (in stage II for highly malignant variants, all advanced stages (III-IV))  Advanced papillary/follicular thyroid cancer Combination Effects of Radiotherapy / Drug Treatments for Cancer 19

 Anaplastic thyroid cancer  Advanced neuroblastoma  Advanced gastric cancer (Adriblastin® SPC, version 10/2009). Approved areas of use for mitoxantrone are:  Metastatic breast cancer  Non-Hodgkin’s lymphoma  Acute myeloid leukaemia in adults  Acute lymphoblastic leukaemia in adults, blast crisis in chronic myeloid leukaemia  Treatment of advanced and hormone-resistant prostate cancer in combination with low- dose oral glucocortoids, including prednisone and hydrocortisone, for pain relief in patients who no longer respond to analgesics and for whom radiotherapy is not indicated. (Novantrone® SPC, version 05/2012).

4.1.2 The data situation in combination with radiotherapy 4.1.2.1 Effect Anthracyclines directly damage the DNA and inhibit the DNA polymerase and RNA polymerase.

4.1.2.2 Toxicity Cardiac toxicity Anthracyclines by themselves are cardiotoxic. A distinction is made between acute toxicity, which is dose-independent and ranges from asymptomatic ECG changes to very rare severe acute myocarditis, and late toxicity, which is dose-dependent and leads to chronic, potentially life-threatening heart failure. An analysis of data from eight randomised studies evaluated more than 3,500 breast cancer patients, of whom more than 2,500 had received anthracycline- containing adjuvant chemotherapy (Fumoleau et al. 2006). After a median follow-up of seven years, the rate of chronic left ventricular dysfunction was 1.4%. Risk factors significantly associated with a heightened risk of cardiac toxicity were an age of 65 or more and a body mass index of 27 kg/m2 or more; the anthracycline dose (which was never higher than 628 mg/m²) and the laterality of the breast cancer and hence of the radiotherapy did not contribute significantly to the risk. The majority of diagnoses of chronic left ventricular dysfunction were made within two years. Because of the relatively short follow-up period the possibility cannot be ruled out that radiotherapy-induced cardiac toxicity, which usually occurs much later, may be exacerbated by anthracycline therapy. Similar findings are reported in a prospective Danish study, in which the rate of cardiac anthracycline-induced toxicity at a median follow-up of 15 months was 11.4% (Ryberg et al. 2008). The main risk factor for cardiotoxicity was the anthracycline dose, but contributing factors were the patient’s age, cardiovascular disorders, prior treatment with tamoxifen or aromatase inhibitors and prior mediastinal radiotherapy. For patients with such risk factors the authors quote anthracycline doses that result in a 5% cardiotoxicity rate. Considerable long-term follow-up data is available on sequential therapy for Hodgkin’s disease with anthracyclines and radiotherapy. Supra-additive toxicities are observed when mediastinal radiotherapy follows prior anthracycline-containing chemotherapy. For example, Myrehaug et al. 2008 report a heightened risk of hospitalisation for cardiac disorders in the 15 years following treatment with anthracyclines and radiotherapy (HR=2.77) Combination Effects of Radiotherapy / Drug Treatments for Cancer 20 and after mediastinal radiotherapy alone (HR=1.82), but not after anthracycline-containing chemotherapy alone. Gastrointestinal toxicity In phase I trials, anthracycline-containing polychemotherapy was administered during radiotherapy for advanced tumours of the upper gastrointestinal tract. In combination with 5- fluorouracil (5-FU) and cisplatin or irinotecan, the maximum tolerable epirubicin dose was 10 mg/m² when given weekly (Sun et al. 2011). Dose-limiting toxicities were neutropenia, dehydratation, mucositis and diarrhoea; these cannot be attributed to any one of the chemotherapy agents used. The SPCs for epirubicin and doxorubicin refer to recall phenomena, which in the case of liver toxicity may sometimes be fatal. Dose reductions are specifically recommended for patients who have had prior radiotherapy and have low bone marrow reserves. 4.1.3 Summary On account of the risk of cardiac toxicity, concurrent or sequential administration of anthracyclines during radiotherapy in the thoracic region should be avoided. Sequential therapy is an established treatment standard for some tumorous diseases (e. g. breast cancer). Here too, though, increased cardiac morbidity and mortality in the long term must be expected, so that consideration should always be given to reducing the risks to the heart as far as possible during radiotherapy. In most palliative situations, the patient’s short life expectancy means that this factor will not be of great importance. Little data is available for other organ systems; to date, however, there are no indications of other overlapping/supra-additive toxicities.

4.2 Taxanes

4.2.1 Use Taxanes (paclitaxel, docetaxel, cabizitaxel) are approved for use alone or in combination with other chemotherapy agents in the treatment of breast cancer, non-small-cell lung cancer, prostate cancer, gastric cancer and tumours of the head and neck. The approved areas of use for paclitaxel are:  Ovarian cancer  In first-line chemotherapy of ovarian cancer, Taxol® is indicated for the treatment of patients with advanced disease or a residual disease (< 1cm) after initial laparotomy, in combination with cisplatin.  In second-line chemotherapy of ovarian cancer, Taxol® is indicated for the treatment of metastatic carcinoma of the ovary after failure of standard platinum-based therapy.  Breast cancer  In the adjuvant setting, Taxol® is indicated for the treatment of patients with node- positive breast carcinoma following anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with Taxol® should be viewed as an alternative to extended AC therapy. Taxol® is indicated for the initial treatment of locally advanced or metastatic breast cancer, either in combination with an anthracycline for patients for whom anthracycline therapy is indicated, or in combination with trastuzumab if immunohistochemical scoring grades HER2 as 3+ and if anthracycline therapy is contraindicated. Combination Effects of Radiotherapy / Drug Treatments for Cancer 21

 As a single agent Taxol® is indicated for the treatment of metastatic carcinoma of the breast in patients who have failed to respond adequately to standard treatment with anthracyclines or in whom anthracycline therapy has not been appropriate.  Advanced non-small-cell lung cancer Taxol® in combination with cisplatin is indicated for the treatment of non-small-cell lung cancer (NSCLC) in patients who are not candidates for potentially curative surgical intervention and/or radiation therapy.  AIDS-related Kaposi’s sarcoma (KS) Taxol® is indicated for the treatment of patients with advanced AIDS-related Kaposi’s sarcoma (KS) after liposomal anthracycline therapy has failed. (Taxol® SPC, version 01/2009). The approved areas of use for docetaxel are:  Breast cancer  Taxotere® in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of operable, node-positive breast cancer and operable, node-negative breast cancer. For patients with operable node-negative breast cancer, adjuvant treatment should be restricted to patients eligible to receive chemotherapy according to internationally established criteria for primary therapy of early breast cancer. Taxotere® in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.  Taxotere monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent.  Taxotere® in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2 and who previously have not received chemotherapy for metastatic disease.  Taxotere® in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.  Non-small-cell lung cancer  Taxotere® is indicated for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of prior chemotherapy.  Taxotere® in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small-cell lung cancer, in patients who have not previously received chemotherapy for this condition.  Prostate cancer Taxotere® in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer.  Gastric adenocarcinoma Taxotere® in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the Combination Effects of Radiotherapy / Drug Treatments for Cancer 22

gastroesophageal junction, who have not received any prior chemotherapy for metastatic disease.  Head and neck cancer Taxotere® in combination with cisplatin and 5-fluorouracil is indicated for the induction therapy of patients with locally advanced squamous-cell carcinoma of the head and neck. (Taxotere® SPC, version 12/2011). Cabizitaxel in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer who have previously been treated with a docetaxel-containing regimen. (Jevtana® SPC, version 10/2011).

4.2.2 The data situation in combination with radiotherapy

4.2.2.1 Effect Taxanes disrupt the breakdown of the spindle apparatus; by inhibiting mitosis they prevent cell proliferation.

4.2.2.2 Toxicity A number of case reports, case series and small-scale clinical trials describe situations in which taxanes have been administered concurrently with radiotherapy to various tumour entities. A recently published study provides evidence of the efficacy of concurrent radiochemotherapy with taxanes in the neoadjuvant therapy of oesophageal cancer before surgery (van Hagen et al. 2012). While some studies report ‘good tolerability’, the following specific toxicities have been noted: Pulmonary toxicity When used alone, taxanes can cause pneumonitis. In combination with radiotherapy to the thorax, pneumonitis rates are higher than for patient groups not treated with taxanes. In a group of 139 patients who received radiochemotherapy for oesophageal cancer, pneumonitis symptoms or fibroses (grade 2 or higher) were observed within a year of therapy in 46% of patients who had not received taxanes, 62% of patients who received sequential or concurrent taxanes and 74% of patients who received both sequential and concurrent taxanes (McCurdy et al. 2010). However, a randomised study found that the rate of pulmonary complications was not significantly higher for patients who had had neoadjuvant radiochemotherapy with paclitaxel and carboplatin and subsequent surgery than for patients who had had surgery alone (van Hagen et al. 2012). However, in this study toxicities were not reported unless they were of grade 3 or higher and, in contrast to McCurdy et al. (2010), toxicities were quoted as a mixture of pulmonary infections, atelectasis, etc. with no specific focus on radiogenic toxicity, so that it is not possible to summarise the findings with regard to radiogenic toxicity. In breast cancer treatment, too, there are indications of an increased risk of pneumonitis (grade 2-3) when radiotherapy and taxanes are administered sequentially or concurrently (Taghian et al. 2001, 2005) (14% vs. 1% for taxane-containing and non-taxane-containing chemotherapy), although some contrary data has also been reported (Yu et al. 2004). With an interval of 1.5–2 months between the end of high-dose and dose-dense anthracycline- and taxane-containing chemotherapy and the start of radiotherapy, there was no increase in the rate of pneumonitis in a series of 69 patients (De Giorgi et al. 2006). In a series of 12 patients with radiation recall pneumonitis who received chemotherapy after radiotherapy for lung cancer Combination Effects of Radiotherapy / Drug Treatments for Cancer 23

(median interval between end of radiotherapy and pneumonitis 95 days, between radiotherapy and chemotherapy 42 days), eight patients had received taxane-containing chemotherapy (Ding et al. 2011). Skin toxicity When taxanes are administered concurrently with radiotherapy there is an increased risk of severe acute skin toxicity. For example, the rates of grade 3 dermatitis in a combined approach of this sort involving primary radiochemotherapy of locally recurrent breast cancer were increased by up to 57%, depending on the taxane dose (paclitaxel 90 mg/m2 or docetaxel 35 mg/m2) (Semrau et al. 2006). Toxicity in relation to head and neck cancer With concurrent radiochemotherapy with taxanes and cisplatin or carboplatin there was a high rate of infections (39% grade III) and haematological toxicity (Semrau et al. 2011). Cardiac toxicity Taxanes can amplify the cardiotoxicity of anthracyclines – a fact that is particularly relevant to chemotherapy for breast cancer (Gennari at al. 1999, Giordano et al. 2002, Magné et al. 2005, Magné et al. 2009). However, there is as yet insufficient evidence that radiogenic cardiotoxicity is amplified. In 64 patients with breast cancer, a drop in left ventricular ejection fraction was frequently observed after the conclusion of treatment but it remitted spontaneously in all cases. The effect occurred most frequently in connection with an accelerated adriamycin/docetaxel regimen, concurrent chemotherapy and radiation, left-side radiotherapy and after mastectomy (Magné et al. 2009). In a randomised study of neoadjuvant radiochemotherapy with carboplatin/paclitaxel before surgery for oesophageal cancer, no increase in the rate of cardiac complications was reported in the combined therapy arm (van Hagen et al. 2012); however, the follow-up period, with a median of 45 months, was relatively short. Other findings A relatively large number of infections occurred (grade 3: 39%) among 25 patients with squamous-cell carcinoma of the head and neck who received taxane-containing induction chemotherapy and concurrent radiochemotherapy. Other grade 3 toxicities were haematological side effects (leukopenia 30%, thrombocytopenia 4% and dermatitis (13%). When taxanes are administered concurrently with radiotherapy to the abdomen or pelvis, relatively good tolerability is reported on the whole, although cytopenia (up to 80% grade 3) and gastrointestinal toxicity have been observed (Mabuchi et al. 2009, Rochet et al. 2010).

4.2.3 Summary Concurrent administration of taxane-containing chemotherapy during radiotherapy is an established standard for neoadjuvant treatment of oesophageal cancer (van Hagen et al. 2012). In principle the combination of taxanes and radiotherapy appears tolerable; however, the increased frequency of pneumonitis that has been reported by a number of authors should be taken into account when radiotherapy is administered to the thorax. In particular, alternative regimens outside established therapy standards or clinical trials should be considered in connection with high doses of radiation to the lungs. Sequential administration of radiochemotherapy is likely to reduce the risk of pneumonitis, but not to the level associated with radiotherapy alone. Combination Effects of Radiotherapy / Drug Treatments for Cancer 24

4.3 Platinum derivatives: cisplatin, carboplatin, oxaliplatin

4.3.1 Use Cisplatin and carboplatin are used for many solid tumours, sometimes in combination with radiotherapy. Oxaliplatin, by contrast, has only become available recently. The approved areas of use for cisplatin are:  Testicular tumours  Advanced epithelial ovarian cancer (FIGO stages IIb – IV)  Small-cell lung cancer  Advanced non-small-cell lung cancer  Advanced oesophageal cancer  Cervical cancer (in cases of local recurrence or distant metastasis)  Metastatic and locally recurrent endometrial cancer  Squamous cell carcinoma of the head and neck  Patients with inoperable locally advanced tumours who have not yet received any treatment  In cases of local recurrence or distant metastasis  Advanced bladder cancer  Adjuvant and neoadjuvant treatment of osteosarcoma (Cisplatin medac® SPC, version 02/2011). The approved areas of use for carboplatin are:  Epithelial ovarian cancer  Small-cell lung cancer  Squamous cell carcinoma of the head and neck  Cervical cancer in cases of local recurrence or distant metastasis (Carbo-cell® SPC, version 04/2011). The approved areas of use for oxaliplatin are:  As adjuvant treatment for colon cancer in stage III (Dukes’ C)  For metastatic colorectal cancer (Eloxatin® SPC, version 05/2011).

4.3.2 The data situation in combination with radiotherapy 4.3.2.1 Effect Platinum derivatives act like a bifunctional alkylating agent by crosslinking DNA strands. Links are formed within a DNA strand (intrastrand crosslinks) and between adjacent DNA strands (interstrand crosslinks). Cisplatin also inhibits DNA repair and teleromase activity. Combination Effects of Radiotherapy / Drug Treatments for Cancer 25

4.3.2.2 Toxicity Cisplatin is nephrotoxic and ototoxic and causes polyneuropathy; its bone marrow toxicity, however, is relatively low. Carboplatin is more toxic to the bone marrow but has minimal organ toxicity. Oxaliplatin is associated with bone marrow toxicity and diarrhoea and frequently causes pronounced polyneuropathy. In combination with radiotherapy these substances were tested in a number of randomised studies of head and neck tumours (Pignon et al. 2007), oesophageal cancer (Wong and Malthaner 2006), lung tumours (O'Rourke et al. 2010) and cervical cancer (CCCMAC 2010) and survival advantages were found, especially for the combination with cisplatin. Oxaliplatin was studied in combination with 5-FU and radiotherapy for rectal cancer. High rates of full pathological remission were found when the drug was used pre-operatively (Aschele et al. 2011, Roedel et al. 2011). Studies in vitro and in animal models have shown that oxaliplatin has a moderate radiosensitising effect, especially on the tumour (Hermann et al. 2008, Muggia and Glatstein 1979). In the majority of studies the clinical data indicate that the acute side effects of radiotherapy are amplified, especially around irradiated mucous membranes; grade 3-4 mucous membrane toxicity is usually increased by 10%–20% (Aschele et al. 2011, CCCMAC 2010, O'Rourke et al. 2010, Pignon et al. 2007, Roedel et al. 2011, Wong and Malthaner 2006). In only a few studies were the typical late toxicities of radiotherapy significantly increased; nevertheless, the average of all studies indicates that slightly increased late toxicity must be expected. Significantly increased toxicity is likely when irradiation of the inner ear is combined with concurrent administration of cisplatin (Hitchcock et al. 2009). According to data from animal experiments, this also applies to the kidneys; these studies indicate that the sequential administration of cisplatin after radiotherapy should also be regarded as problematic (Stewart et al. 1987, 1988).

4.3.3 Summary Overall the interactions between radiotherapy and platinum derivatives have been well studied and especially in relation to late toxicity – apart from the quoted exceptions in experienced hands – they can be largely regarded as non-critical.

4.4 Antimetabolites

4.4.1 Use Because the number of antimetabolites is very large, only a selection of the most frequently used drugs can be listed here. The approved areas of use for the pyrimidine analogue 5-fluorouracil (5-FU) are:  Advanced or metastatic colorectal cancer  Adjuvant chemotherapy of stage III colon cancer (T1-4 N1-2) after curative resection of the primary tumour  Adjuvant chemotherapy of stage II rectal cancer (T3-4) and stage III rectal cancer (T1-4 N1-2) after curative resection of the primary tumour  Advanced gastric cancer  Advanced pancreatic cancer  Advanced oesophageal cancer  Advanced and/or metastatic breast cancer Combination Effects of Radiotherapy / Drug Treatments for Cancer 26

 Adjuvant therapy of primary invasive breast cancer  Squamous cell carcinoma of the head and neck  Patients with inoperable locally advanced tumours who have not yet received any treatment  In cases of local recurrence or distant metastasis (Neofluor® SPC, version 01/2011). Capecitabine is a relatively new, orally administered agent that is converted into active 5-FU in the body. The approved areas of use are:  Xeloda® is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon cancer.  Xeloda® is indicated for the treatment of metastatic colorectal cancer.  Xeloda® is indicated for first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.  Xeloda® is indicated in combination with docetaxel for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.  Xeloda® is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline- containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. (Xeloda® SPC, version 06/2011). Although not officially approved, concurrent radiotherapy with 5-FU is a clinical standard in neoadjuvant or adjuvant treatment of rectal cancer, treatment of oesophageal cancer and adjuvant treatment of advanced head and neck cancer, because the combined therapy produces an improvement in tumour cure rates by comparison with radiotherapy alone. Capecitabine is now used relatively frequently in this context. The approved areas of use for the pyrimidine analogue gemcitabine are:  Gemcitabine is indicated in combination with cisplatin for the treatment of locally advanced or metastatic bladder cancer.  Gemcitabine is indicated for the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.  Gemcitabine is indicated in combination with cisplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).  Gemcitabine monotherapy can be considered for older patients or patients of performance status 2.  Gemcitabine is indicated in combination with carboplatin for the treatment of locally advanced or metastatic epithelial ovarian cancer in patients with a recurrence after a recurrence-free period of at least six months following platinum-based first-line therapy.  Gemcitabine is indicated in combination with paclitaxel for the treatment of patients with inoperable, locally recurrent or metastatic breast cancer who have experienced a Combination Effects of Radiotherapy / Drug Treatments for Cancer 27

recurrence after adjuvant/neoadjuvant chemotherapy. The preceding chemotherapy should have included an anthracycline unless this was clinically contraindicated. (Gemzar® SPC, version 07/2011). Although not officially approved, in clinical practice gemcitabine is also used concurrently with radiotherapy in the treatment of advanced pancreatic cancer and bladder cancer. The approved areas of use for the antifolate methotrexate are:  Malignant trophoblastic tumours  As monochemotherapy for low-risk patients  In combination with other cytostatic drugs for high-risk patients  Breast cancer In combination with other cytostatic drugs for adjuvant treatment after resection of the tumour or mastectomy and for palliative treatment of advanced disease  Cancers of the head and neck For palliative monotherapy in the metastatic stage or during recurrence  Acute lymphoblastic leukaemia (ALL) Methotrexate at a low dose is used to treat acute lymphoblastic leukaemia in children and adults as part of complex therapy protocols in combination with other cytostatic drugs for remission maintenance (administered systemically) and for prophylaxis and treatment of meningeal leukaemia (administered intrathecally).  Primary central nervous system non-Hodgkin’s lymphoma prior to radiotherapy  Acute lymphoblastic leukaemia (ALL) Methotrexate at a high dose is used in combination with other cytostatic drugs to treat acute lymphoblastic leukaemia in children and adults. (Methotrexate Lederle® solution 25 mg SPC, version 09/2010). In clinical practice the substance is also used for intrathecal treatment of meningeal carcinomatosis. Purine analogues are usually used to treat haematological disorders. The approved areas of use for fludarabine are: Treatment of B-cell chronic lymphocytic leukaemia (CLL) in patients with adequate bone marrow reserves. First-line treatment with Fludara® should only be initiated in patients with advanced disease, i. e. Rai stages III/IV (Binet stage C) or Rai stages I/II (Binet stage A/B) where the patient has disease-related symptoms or evidence of progressive disease. (Fludara® SPC, version 03/2011). Some antimetabolites (e. g. the purine analogue azathioprine or the antifolate methotrexate) are also used as immunosuppressants in the treatment of non-oncological diseases. Combination Effects of Radiotherapy / Drug Treatments for Cancer 28

4.4.2 The data situation in combination with radiotherapy 4.4.2.1 Effect Antimetabolites are incorporated into the DNA or RNA as false building blocks, or they prevent incorporation of the correct building blocks. They thus interfere with cell division. Many antimetabolites have been shown to inhibit proliferation. When used concurrently with radiotherapy, the pyrimidine analogues 5-FU and gemcitabine can improve local tumour control.

4.4.2.2 Toxicity 5-FU and capecitabine increase the risk of nausea, vomiting, diarrhoea, severe inflammation of the mucous membranes, ulceration, gastrointestinal bleeding and bone marrow depression. The SPCs also mention hand-foot syndrome, fatigue, cardiotoxicity, thrombosis/embolism and impaired renal function in patients with pre-existing renal disease. Gemcitabine causes bone marrow depression, dyspnoea, gastrointestinal symptoms, allergic skin rashes, mild proteinuria, haematuria, oedema, raised transaminases, flu-like symptoms, hair loss and occasionally bronchospasm and interstitial pneumonitis. Because of the radio- sensitising effect of gemcitabine, the SPC recommends that treatment with the drug is not commenced until the acute effects of radiotherapy have resolved or at least a week has passed since radiation. Concurrent radiotherapy and treatment with 5-FU, capecitabine or gemcitabine can produce an increase in mucous membrane reactions, which can be life-threatening if the irradiated volume is large. Increased haemotoxicity is likely if a large proportion of the bone marrow is irradiated. A number of randomised studies have provided data on this issue (Budach et al. 2005, 2006, Cooper et al. 2004, Peters et al. 2000, Rose et al. 1999, Thomas 1999). The incidence of leukoencephalopathy in children was found to rise when methotrexate and cranial irradiation were administered concurrently or in quick succession. The effect is more marked when methotrexate is administered systemically rather than intrathecally (Evans 1981). In a randomised study involving high-dose methotrexate and subsequent whole-brain radio- therapy for adults with CNS lymphoma, there was no significant improvement in overall survival after combined therapy. Combined therapy significantly increased the level of neurotoxicity (Thiel et al. 2010). Concurrent administration of radiotherapy and methotrexate may increase the risk of necrosis of soft tissue or bone.

4.4.3 Summary Concurrent use of 5-FU, capecitabine or gemcitabine during radiotherapy with curative intent should be carried out in accordance with applicable guidelines or in clinical trials. Other antimetabolites should not be used concurrently with radiotherapy with curative intent except in clinical trials. When the aims are palliative, concurrent administration is often possible, but it should be avoided if large areas of mucous membrane (especially in the abdomen and pelvis) are irradiated. Methotrexate should not be administered concurrently with radiotherapy to the central nervous system, and extreme care is called for when the two are used in quick succession. Combination Effects of Radiotherapy / Drug Treatments for Cancer 29

4.5 Topoisomerase inhibitors

4.5.1 Use The approved areas of use for topotecan (Hycamtin®) are:  Topotecan monotherapy is indicated for the treatment of:  Patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy  Patients with relapsed small-cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate  Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with the combination. (Hycamtin® SPC, version 10/2010). The approved areas of use for irinotecan (Campto®) are:  Campto® is used in combination with 5-fluorouracil and folinic acid for treatment of metastatic cancer of the colon or rectum in adult patients who have not received prior chemotherapy in whom the disease is at an advanced stage.  Campto® is used as monotherapy in adult patients who have not responded to prior treatment with a regimen containing 5-fluorouracil.  Campto® is used in combination with cetuximab in adults with KRAS wild-type EGFR (epidermal growth factor receptor)-expressing metastatic colorectal cancer who have not received prior treatment for metastatic disease or who have not responded to prior chemotherapy with irinotecan.  Campto® is indicated in combination with bevacizumab, 5-fluorouracil and folinic acid for first-line treatment of patients with metastatic carcinoma of the colon or rectum.  Campto® is indicated in combination with capecitabine with or without bevacizumab as first-line treatment for patients with metastatic colorectal cancer. (Campto® SPC, version 08/2011). Etoposide (Etopophos®) is approved in combination with other cytostatic drugs or as monotherapy for acute myeloid leukaemia, Hodgkin’s disease, advanced non-Hodgkin’s lymphoma, small-cell lung cancer and germinal cell tumours and as a reserve regimen for a number of other cancers such as choriocarcinoma. The approved areas of use for etoposide are: Vepesid K® 100 mg/K® 50 mg is indicated in combination with other antineoplastic agents for treatment of the following malignant neoplasms:  Palliative treatment of advanced small-cell lung cancer  Palliative treatment of advanced non-small-cell lung cancer  Reinduction treatment for Hodgkin’s disease after failure of standard treatments (incomplete response to treatment or recurrence of the disease)  Intermediate-grade and high-grade non-Hodgkin's lymphoma after failure of standard treatments (incomplete response to treatment or recurrence of the disease) Combination Effects of Radiotherapy / Drug Treatments for Cancer 30

 In mono- and polychemotherapy Vepesid K® 100 mg/K 50 mg is indicated for treatment of acute myeloid leukaemia in patients for whom intensive myeloablative therapy is not appropriate. In monotherapy Vepesid K® 100 mg/K® 50 mg is indicated for  Treatment of recurrent or refractory testicular cancer  Palliative systemic treatment of advanced ovarian cancer after failure of platinum-based standard treatments (Vepesid K® SPC, version 08/2008).

4.5.2 The data situation in combination with radiotherapy

4.5.2.1 Effect Topoisomerase I and II are enzymes that temporarily cleave the DNA and thus alter the topology of the DNA molecules. They convert supercoiled DNA into a relaxed form, thereby creating the conditions for DNA replication and transcription. Inhibition results in irreversible DNA breaks, spontaneous crosslinking and radiosensitivity and induces apoptosis (Pommier 2006).

4.5.2.2 Toxicity The following remarks relate to recent studies (2010) and to toxicity following radiotherapy/radiochemotherapy involving topoisomerase inhibitors as a single agent or in combination with cisplatin, the fluoropyrimidine derivative S-1 or capecitabine. A phase I trial examined the daily use of irinotecan as a radiation sensitiser in patients with locally advanced, non-resectable pancreatic cancer. The maximum tolerated dose was 18 mg/m2/day; dose-limiting toxicities were diarrhoea, anorexia and dehydration (de la Fouchardière et al. 2010). A phase II study of 43 patients with locally advanced rectal cancer investigated the efficacy and safety of neoadjuvant radiochemotherapy with irinotecan (40 mg/m2, weekly in weeks 1 to 5) and S-1 (70 mg/m2, daily). Complete pathological regression occurred in 21% of the patients. Three patients experienced grade 3 diarrhoea, one had grade 3 sepsis and two had septic shock. Haematological toxicity of grades 3-4 was observed in five patients (Shin et al. 2010). Another phase II study found grade 3 leukopenia, neutropenia and infection when irinotecan and capecitabine were used in combination to treat advanced rectal cancer (Hong et al. 2011). Dose-limiting toxicities for the combination of irinotecan (35 mg/m2/week), cisplatin (20 mg/m2/week) and radiotherapy in patients with locally advanced cervical cancer were grade 3-4 diarrhoea, abdominal pain and febrile neutropenia (Fabbro et al. 2010).

4.5.3 Summary Overall the studies show that, despite increased toxicity (grade 3-4 diarrhoea and grade 3-4 leukopenia/neutropenia), the combination of topoisomerase inhibitors and radiochemo- therapy is feasible and effective and has a survival benefit. However, because of the increased toxicity spectrum its use outside clinically controlled trials cannot currently be recommended. Combination Effects of Radiotherapy / Drug Treatments for Cancer 31

4.6 Alkylating agents

Alkylating agents are among the cytostatic drugs with the longest history of clinical use. In clinical terms the most important alkylating agents include: Nitrosourea compounds  carmustine (BCNU)  lomustine (CCNU)  semustine (MeCCNU)*  mimustine (ACNU)*  fotemustine*  streptozotocin*. Nitrogen mustard compounds  busulfan  bendamustine  chlorambucil  cyclophosphamide  ifosfamide  melphalan  treosulfan  trofosfamide. Tetrezines  dacarbazine  mitozolomide*  temozolomide. Aziridines  thiotepa  mitomycin C  AZQ (diaziquone)*. Non-classical alkylating agents - procarbazine - hexamethylmelamine* - adozelesin*. * = not currently available as a drug in Germany. These substances are therefore not addressed in the text.

4.6.1 Use Alkylating agents are widely used in the treatment of both haematological cancers and almost all solid tumours. Special areas of use are referred to under the individual agents. Combination Effects of Radiotherapy / Drug Treatments for Cancer 32

4.6.2 The data situation in combination with radiotherapy 4.6.2.1 Effect Alkylating agents attack almost all biological molecules. They can cause complex damage to the DNA and can even change its tertiary structure. During DNA repair some of the damage is converted first into single-strand and double-strand breaks. Alkylating agents are thus largely cell-cycle non-specific, even though cell death occurs mainly during DNA replication. At clinically applicable dosages the DNA damage is by no means at saturation level. Alkylating agents are therefore the type of drug most frequently used for high-dose chemotherapy. They are in principle effective at all stages of the cell cycle. With the exception of temozolomide, all the agents have been in use for some time. Their mechanism of action is therefore not described again in connection with the individual substances. 4.6.2.2 Toxicity The prime toxicity of all alkylating agents is bone marrow suppression. Some substances, especially at high dose, are also associated with organ-specific toxicities; these are discussed in connection with the individual substances.

4.6.3 Summary Experimental and clinical data indicate that the combining of alkylating agents with radiotherapy tends to produce an additive effect and toxicity rather than a genuine radiosensitising effect (see also the individual substances).

4.6.4 Individual substances 4.6.4.1 Lomustine (CCNU) Use The approved areas of use for lomustine (CCNU) are:  Palliative treatment of brain tumours and brain metastases of other tumours  For advanced Hodgkin’s disease, when established chemotherapy regimens are no longer effective  For malignant skin tumours (metastatic, malignant melanoma)  For small-cell lung cancer (Cecenu® SPC, version 07/2007). However, the nitrosourea lomustine is rarely used as the first-choice treatment for the above indications. Toxicity The main issue is the bone marrow toxicity of the drug. Lomustine in combination with concurrent radiotherapy has been studied almost exclusively in the context of brain tumours. No evidence of interaction with radiotherapy has been found (Cairncross et al. 2006, Eyre et al. 1993). Lomustine and radiotherapy have been used sequentially to treat Hodgkin’s disease. Here, too, there was no evidence of interaction with radiotherapy (Cisei et al. 2011, Proctor et al. 2010). Summary There is no evidence of interaction with radiotherapy. Combination Effects of Radiotherapy / Drug Treatments for Cancer 33

4.6.4.2 Carmustine (BCNU) Use The approved areas of use for carmustine (BCNU) are:  Carmubris® is indicated as an adjunct to surgery and radiation or in combination with other drugs for the following neoplasms:  Brain tumours: glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymona, metastatic brain tumours  Multiple myeloma: in combination with other cytostatic drugs and an adrenal cortex hormone, especially prednisone  Malignant tumours of the lymphatic system: Hodgkin’s disease, lymphosarcoma, reticulum cell sarcoma, in combination with other drugs and after failure of primary therapy  Malignant gastrointestinal tumours: only for advanced disease, when other means of inhibiting cell growth have failed (Carmubris® SPC, version 07/2010).  Gliadel® implants are indicated for treatment of patients with newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiotherapy.  Gliadel® implants are used to treat patients for whom there is histological evidence of recurrent glioblastoma multiforme and for whom surgery is indicated (Gliadel® SPC, version 02/2008).  Local treatment during neurosurgical interventions for brain tumours. Toxicity Bone marrow toxicity. When administered locally in the brain also local tissue damage with neurological dysfunction, impaired wound healing and local infections. There is currently no evidence of interaction with radiotherapy; it should be noted in this regard that the combination of carmustine and concurrent radiation has been studied almost exclusively in connection with the brain (Curran et al. 1992, Walker et al. 1980). Carmustine has been used for high-dose chemotherapy for Hodgkin’s disease and non-Hodgkin’s lymphoma; a significant proportion of the patients had received local radiotherapy prior to the high-dose chemotherapy (Arakelyan et al. 2008, Kaiser et al. 2002). There are no reports of unexpected complications in the previously irradiated regions. Summary There is no evidence of interactions with concurrent or prior radiotherapy.

4.6.4.3 Procarbazine and dacarbazine Use Both drugs are used as standard treatment for Hodgkin’s disease. The approved areas of use for dacarbazine (DTIC) are:  DTIC is indicated for the treatment of metastatic malignant melanoma.  Other situations in which DTIC is used as a component of combination chemotherapy are:  Advanced (Hodgkin’s disease) Combination Effects of Radiotherapy / Drug Treatments for Cancer 34

 Advanced soft tissue sarcoma (except mesothelioma, Karposi’s sarcoma) in adults (DTIC® 100 mg SPC, version 06/2002). The approved area of use for procarbazine is Hodgkin’s disease (combination chemotherapy) (Natulan® SPC, version 03/2005). Toxicity With both drugs haemotoxicity is the main issue. Allergic reactions and neurotoxicities are described. After procarbazine interstitial pneumonia has also been observed. In the primary area of use (Hodgkin’s/non-Hodgkin’s lymphoma) the substances in combination with other cytostatic agents are not used on a planned basis concurrently with full-dose local radiotherapy. For Hodgkin’s disease and some non-Hodgkin’s lymphomas local radiotherapy with doses of between 20 Gy and a maximum of 50 Gy (5 x 2 Gy/week) is usually used after poly- chemotherapy containing procarbazine or dacarbazine (Bonadonna et al. 2004, Engert et al. 2007, 2010, Fermé et al. 2007). The acute and late side effects of these sequential treatments have been very well documented in clinical trials. The acute side effects of radiotherapy that occur do not differ from those of radiotherapy alone. In the trials there is also no clear evidence of any increase in deterministic late side effects caused by the alkylating agents. However, there is evidence that the rate of second malignancies is increased, including when radiotherapy and chemotherapy are administered sequentially (Mauch et al. 1996, Swerdlow et al. 2011). There is no clinical information on the exact proportion of alkylating agents in these trials. Summary Procarbazine in combination with nitrosoureas was also used concurrently with radiotherapy for gliomas (Shapiro et al. 1989). There was no evidence of unexpected toxicities in these trials.

4.6.4.4 Busulfan, chlorambucil, bendamustine and melphalan Use These drugs are used almost exclusively to treat haematological cancers. The approved areas of use for busulfan are:  Chronic myeloid leukaemia (CML) Palliative treatment in the chronic phase of the disease after failure of primary therapy (usually with hydroxyurea)  Conditioning before a haematopoietic stem cell transplant Myleran is indicated as conditioning treatment before haematopoietic stem cell transplantation in patients for whom the combination of high-dose busulfan and cyclophosphamide is considered to be the best treatment option. (Myleran® SPC, version 04/2005). The approved areas of use for chlorambucil are:  Chronic lymphocytic leukaemia (CLL)  Low-grade malignant non-Hodgkin’s lymphoma  Waldenström's macroglobulinemia (Leukeran® SPC, version 12/2003). The approved areas of use for bendamustine are: Combination Effects of Radiotherapy / Drug Treatments for Cancer 35

 Primary treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludaribine combination therapy is contraindicated.  Monotherapy of indolent non-Hodgkin’s lymphoma in patients with progression during or within six months of treatment with rituximab or a regimen containing rituximab  Primary treatment of multiple myeloma (stage II under the Durie-Salmon system with progression or stage III) in combination with prednisone for patients over the age of 65 who are unsuitable for an autologous stem cell transplant (HDT/ASCT) and who had clinical neuropathy at the time of diagnosis, so that treatment with thalidomide or bortezomib is contraindicated. (Levact® SPC, version 12/2010). The approved areas of use for melphalan are:  Multiple myeloma (plasmacytoma)  Advanced ovarian cancer after failure of standard treatment (Alkeran®, 2 mg tablets SPC, version 04/12). Toxicity With both drugs haemotoxicity is the main issue. In multiple myeloma, in particular, but occasionally also in the other diseases mentioned, additional palliative radiotherapy is indicated during ongoing chemotherapy, e. g. if the disease is in the bones or if there are large lymph node packets. In this situation the radiotherapy is typically administered in doses of between 20 Gy and 40 Gy, in 2-3 individual doses. Although virtually no formal studies of the issue have been conducted, it is widespread clinical practice to maintain that the chemotherapy must not be interrupted for the radiotherapy. There is no published evidence of any major increase in the acute or late side effects of radiotherapy in this situation. When large areas are irradiated, however, the likelihood of an increase in the haematological toxicity of the alkylating agents must be borne in mind. Busulfan and melphalan are also used for high-dose chemotherapy. When used in combination with total body irradiation it must be assumed that the pneumonitis rate will be higher than for radiotherapy or chemotherapy alone; in particular, an unexpectedly high pneumonitis rate has been reported for the combination of melphalan and total body irradiation (Abraham et al. 1999). This treatment must only be carried out at specialised centres. After high-dose treatment with these substances some cases of myelopathy with paraplegia have been reported in connection with subsequent or prior palliative irradiation of affected vertebrae in Ewing’s sarcoma (Seddon et al. 2005). The radiation doses used were below the typical tolerance doses of the spinal cord. The German Society for Paediatric Oncology and Haematology (GPOH) reported on its experience in this connection (Bölling et al. 2009) and was unable to identify any comparable observations; however, the follow-up period was restricted. Summary Overall the evidence shows that no significant increase in the acute and late side effects of radiotherapy is to be expected from standard doses of melphalan and busulfan. The same is likely to be true for chlorambucil and bendamustine, but at present there is little experience of the use of these drugs in combination with radiotherapy. High-dose treatment with busulfan or melphalan should be approached with caution, especially where the lungs are involved and possibly also in connection with the spinal cord. Combination Effects of Radiotherapy / Drug Treatments for Cancer 36

4.6.4.5 Cyclophosphamide, ifosfamide and trofosfamide Use These drugs are used to treat haematological cancers and a variety of solid tumorous diseases; cyclophosphamide is also used to treat some autoimmune disorders. The approved areas of use for cyclophosphamide are:  Inducing remission and consolidating treatment in acute lymphoblastic leukaemia (ALL)  Inducing remission in Hodgkin’s disease  Non-Hodgkin’s lymphoma (also as monotherapy, depending on histological type and the stage of the disease)  Chronic lymphocytic leukaemia (CLL) after failure of standard treatment (chlorambucil/prednisone)  Inducing remission in plasmacytoma (also in combination with prednisone)  Adjuvant treatment of breast cancer after resection of the tumour or mastectomy  Palliative treatment of advanced breast cancer  Advanced ovarian cancer  Small-cell lung cancer  Ewing’s sarcoma  Neuroblastoma  Rhabdomyosarcoma in children  Osteosarcoma  Conditioning before an allogenic bone marrow transplant Notes on conditioning before an allogenic bone marrow transplant: Establishment of the indications for a bone marrow transplant and hence for prior conditioning with Endoxan® depends on a complex set of factors and must be taken on a case-by-case basis. The main factors are the stage of the disease, prognosis (risk group), type and success of previous treatments of the underlying disease, the patient’s age and general state of health, and the availability of a suitable bone marrow donor.  For severe aplastic anaemia as monotherapy or in combination with anti-thrombocyte globulin  For acute myeloid and acute lymphoblastic leukaemia in combination with total body irradiation or busulfan  For chronic myeloid leukaemia in combination with total body irradiation or busulfan  Dangerous autoimmune disorders: severe, progressive forms of lupus nephritis and Wegener's granulomatosis. The approved areas of use for ifosfamide are:  Testicular cancer For combination chemotherapy in patients with advanced tumours at stages II-IV according to the TNM classification system (seminoma and non-seminoma) that respond inadequately or not at all to initial chemotherapy Combination Effects of Radiotherapy / Drug Treatments for Cancer 37

 Cervical cancer Palliative cisplatin/ifosfamide combination chemotherapy (alone, without other combination components) for cervical cancer at FIGO stage IVB (if curative treatment by means of surgery or radiotherapy is not possible) as an alternative to palliative radiotherapy  Breast cancer For palliative treatment of advanced, refractory or recurrent breast cancer  Non-small-cell lung cancer For single-agent or combination chemotherapy of patients with inoperable or metastatic tumours  Small-cell lung cancer  For combination chemotherapy of soft tissue sarcoma (inc. osteosarcoma and rhabdomyosarcoma)  For single-agent or combination chemotherapy of rhabdomyosarcoma or osteosarcoma after failure of standard treatment  For single-agent or combination chemotherapy of other soft tissue sarcomas after failure of surgery and radiotherapy  Ewing’s sarcoma For combination chemotherapy after failure of cytostatic primary treatment  Non-Hodgkin’s lymphoma  For combination chemotherapy of patients with highly malignant non-Hodgkin’s lymphoma who respond inadequately or not at all to the initial therapy  For combination therapy of patients with recurrent tumours  Hodgkin’s disease For treatment of patients with primary progressive Hodgkin’s disease and early recurrence (duration of complete remission less than one year) after failure of primary treatment with chemotherapy or radiochemotherapy – in the context of a recognised combination chemotherapy regimen, such as the MINE protocol. (Holoxan® SPC, version 11/2008). The approved area of use for trofosfamide is treatment of non-Hodgkin’s lymphoma after failure of standard treatment (Ixoten® SPC, version 11/2004). Toxicity In addition to significant haemotoxicity, when cyclophosphamide and ifosfamide are administered intravenously there is also marked toxicity in the area of the lower urinary tract, which manifests clinically as haemorrhagic cystitis. This side effect can be largely prevented by simultaneous administration of mesna (sodium 2-sulfanylethanesulfonate). In rare cases, interstitial pneumonitis and hepatic veno-occlusive disease have been observed and classed as serious. In experimental tumours (breast cancer, soft tissue sarcoma) cyclophosphamide and ifosfamide in combination with radiotherapy display additive to slightly synergistic effects (Budach et al. Combination Effects of Radiotherapy / Drug Treatments for Cancer 38

1998, von der Maase 1986). In the murine model, side effects on most normal tissues were increased only slightly or not at all by the combination; however, this does not apply to the lungs and bladder. After the maximum tolerated dose of cyclophosphamide, mouse lungs could cope only with a radiation dose that was reduced by a factor of up to 1.8. Similar observations were made for the bladder, although mesna was possibly not used optimally in the experiments. Cyclophosphamide enhances the effect of radiotherapy on tumours and normal tissues with the exception of the lungs only when the two treatments are administered concurrently or close together – roughly during the period for which cyclophosphamide remains detectable in the animal. In the lungs, by contrast, the above-mentioned effects still occurred when the cyclophosphamide was administered between one month before and three months after the radiotherapy, although they were somewhat less marked than when the treatments were administered concurrently (dose modification factors: 1.1 to 1.4) (von der Maase 1986, von der Maase et al. 1986). No comparable studies of ifosfamide have been conducted. Clinically the use of cyclophosphamide and radiotherapy for breast cancer and small-cell lung cancer has been predominantly sequential, although in some cases it has been concurrent. A comparison of the cosmetic results after breast-conserving surgery and subsequent radiotherapy with and without sequential chemotherapy with CMF or CAF showed that results were either no worse or only slightly worse when the chemotherapy was used (Hickey et al. 2006). However, an increase in subcutaneous fibrosis was noted in patients who had undergone mastectomy followed by radiotherapy and sequential CMF treatment (Bentzen et al. 1989). The proportion of cyclophosphamide used is not clear. Simultaneous use of cyclophosphamide, mitoxantrone and 5-fluorouracil results in an increase in acute skin reactions (Toledano et al. 2006). According to some authors, CMF and CAF adversely affect the cosmetic outcomes to a significant extent; in the experience of other authors, however, the effect is only slight (Abner et al. 1991, Markiewicz et al. 1996). Whether CMF and CAF increase the rate of radiogenic pneumonitis is disputed. Lind et al. (2002) reported a trend towards an increased pneumonitis risk in patients who had received high-dose chemotherapy with alkylating agents, especially when the lymphatic drainage system was irradiated at the same time. Ifosfamide is used clinically in combination with sequential radiotherapy for soft tissue sarcoma. There is no evidence of interaction with radiotherapy. The limited clinical data on the concurrent use of ifosfamide and radiotherapy that is available (Eckert et al. 2010, Quantin et al. 1997, Wong et al. 2006) contains no evidence of unexpected side effects. There is a discrepancy between the published data and SPCs, which mention an enhanced reaction to irradiation in isolated cases. Cyclophosphamide is also used with other agents, some of them alkylating ones (especially melphalan), in combination with total body irradiation (10 Gy to 14 Gy) for conditioning before a planned bone marrow transplant. There is an increased risk of pneumonitis when cyclophosphamide is used at high dose, especially when this is combined with total body irradiation (Kelsey et al. 2011). Summary The overall risk of enhanced acute or late side effects of radiotherapy when cyclo- phosphamide/ifosfamide and radiotherapy are used sequentially can be classed as low. Little experience of concurrent use of cyclophosphamide/ifosfamide and radiotherapy has been reported. When irradiation of the female breast is combined with cyclophosphamide, a slight increase in acute and late side effects must be expected. Data from experiments on animals indicates that simultaneous use of cyclophosphamide/ifosfamide and radiotherapy results in an increased risk of side effects when the bladder is irradiated; in the case of cyclophosphamide Combination Effects of Radiotherapy / Drug Treatments for Cancer 39 there is also an increased risk when the lungs are the target of irradiation. Because trofosfamide itself has no cytostatic potency and is only converted to the active substance ifosfamide in the body, trofosfamide and ifosfamide can be regarded as equivalent in terms of their interaction with radiotherapy.

4.6.4.6 Treosulfan Use Palliative treatment of advanced ovarian cancer after failure of platinum-based standard treatment. The approved area of use is: Ovastat® 1000 (5000) mg is indicated alone or in combination with other antineoplastic agents in the palliative treatment of epithelial ovarian cancer at FIGO stages II-IV (Ovastat® SPC, version 2008). Toxicity Like all alkylating agents, treosulfan causes bone marrow toxicity. There is no clinical data on treosulfan in combination with radiotherapy. In the experimental model, treosulfan in combination with total body irradiation in rats caused unexpectedly high gastrointestinal toxicity; this was interpreted by the authors as a possible indication that treosulfan has a radiosensitising effect (Sender et al. 2009). Treosulfan is now rarely used in the clinical setting.

4.6.4.7 Thiotepa Use According to the SPC, Tepadina® is used in combination with other chemotherapy agents:  With or without total body irradiation (TBI) as conditioning treatment prior to allogenic or autologous haematopoietic stem cell transplantation (HSCT) for the treatment of haematological disorders in adults and children  When high-dose chemotherapy with subsequent HSCT is indicated for the treatment of solid tumours in adults and children (Tepadina® SPC, version 03/2010). Toxicity Like all alkylating agents, thiotepa causes bone marrow toxicity. Thiotepa has also been used in combination with total body irradiation on small numbers of patients (van Besien et al. 2003, Devetten et al. 2004). The same side effects were observed as when thiotepa is used in combination with other alkylating agents. Because of its unconvincing efficacy, however, this combination is now rarely used in clinical practice. High-dose treatment with thiotepa and local radiotherapy has been used to treat a range of solid tumours, with a relatively long interval between the two types of treatment. There are no reports of unexpected toxicities as a result of this regimen (Stemmer et al. 2001). According to the SPC, patients who have previously received radiotherapy are at higher risk of veno-occlusive hepatic disease. Earlier irradiation of the brain or craniospinal radiotherapy can promote severe toxic reactions (e. g. encephalopathy). Combination Effects of Radiotherapy / Drug Treatments for Cancer 40

4.6.4.8 Temozolomide Use The approved areas of use for Temodal are:  The treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment  The treatment of children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. (Temodal® SPC, version 06/2012). Toxicity Use of temozolomide is associated with moderate bone marrow toxicity, especially thrombocytopenia, while other toxicities are low. The combination of radiotherapy and temozolomide has been used almost exclusively for concurrent and sequential treatment of brain tumours. For patients with glioblastoma the combination treatment has been shown to result in a survival benefit by comparison with radiotherapy alone (Stupp et al. 2005). Experimental (Chakravarti et al. 2006) and clinical data (Stupp et al. 2009) indicate that the possible radiosensitising effect on the tumour of temozolomide may depend on the methylation status of the MGMT gene. Patients with a methylated MGMT gene in the tumour benefit somewhat more from the combination therapy than patients with a non-methylated MGMT gene in the tumour. There are no reports of unexpected acute side effects as a result of the combination treatment. However, there are reports of unexpectedly high brain necrosis rates in the parts of the brain subjected to high-dose irradiation. In some cases this is hard to distinguish from an early recurrence of the tumour; this has given rise to the concept of pseudoprogression. Some of the changes that were classed as necrosis on the basis of magnetic resonance imaging criteria regress spontaneously; in consequence it is unclear whether the risk of brain necrosis is actually significantly increased as a result of combination treatment with Temodal (Brandes et al. 2008, Yaman et al. 2010).

4.6.4.9 Mitomycin C Use Mitomycin C is used in palliative tumour therapy.  When administered intravenously it is effective in monochemotherapy or combined cytostatic chemotherapy for the following metastatic tumours:  Advanced colorectal cancer  Advanced hepatocellular carcinoma  Advanced stomach cancer  Advanced and/or metastatic breast cancer  Advanced oesophageal cancer  Advanced cervical cancer  Non-small-cell lung cancer  Advanced pancreatic cancer  Advanced head and neck cancers Combination Effects of Radiotherapy / Drug Treatments for Cancer 41

 Intravesical administration for prevention of recurrence of superficial bladder cancer after transurethral resection (Mitomedac® SPC, version 06/2012). Effect As well as having the typical properties of an alkylating agent, mitomycin is a bioreductive agent that is cytotoxic to hypoxic tumour cells and has a radiosensitising effect on some tumour cell lines (Bremner et al. 1990, Holden et al. 1990, Keohane et al. 1990). Toxicity The main issue is bone marrow toxicity. After high cumulative doses, haemolytic-uraemic syndrome, pulmonary hypertension and veno-occlusive disorders of the lungs and liver have also been observed. The effect of radiotherapy on various normal tissues with or without simultaneous or very close administration of mitomycin C has been studied in animal experiments. The radiation response was most enhanced in the lungs (up to 1.7 times), followed by the bowel (up to 1.2 times) and the skin (up to 1.1 times). By contrast, no radiosensitising effects on the kidneys and bladder were observed (von der Maase 1984 a and b, von der Maase et al. 1986). Clinically mitomycin C is used in combination with concurrent radiotherapy for squamous-cell cancers of the head and neck (Budach et al. 2005), cancer of the anus (Bartelink et al. 1997, Flam et al. 1996, UKCCCR 1996), the cervix (Lorvidhaya et al. 2003, Roberts et al. 2000), the vulva (Han et al. 2000, Tans et al. 2011) and lung cancer (Furuse et al. 1999). There is clear evidence from randomised studies that this treatment has advantages over radiotherapy alone for tumours of the head and neck (Budach et al. 2005), the anus (Bartelink et al. 1997, Flam et al. 1996, UKCCR 1996) and the cervix uteri (Lorvidhaya et al. 2003, Roberts et al. 2000). For lung cancer, concurrent radiochemotherapy was superior to sequential therapy. In addition to the expected bone marrow toxicity, the studies found that acute toxicities to the skin and mucous membranes were significantly increased by comparison with radiotherapy alone at the same dose. However, there was no significant increase in the rate of serious late complications in the individual studies, although the mean of all studies shows a slightly increased rate of late consequences. According to pre-clinical data, concurrent administration of mitomycin C and irradiation of the lungs would be expected to result in higher pneumonitis rates. Clinically, however, there was no evidence of an increased pneumonitis rate when mitomycin C at a moderate dose (8 mg/m² days 1 + 29) was administered in combination with sequential radiotherapy, also at a moderate dose (56 Gy at 5 x 2 Gy per week) (Furuse et al. 1999). By contrast, Ohe et al. (2001), in a multivariate analysis of 1,799 lung cancer patients treated with various radiochemotherapy regimens, found a higher risk of pneumonitis and lung fibrosis when radiotherapy was administered with the triple combination of mitomycin/cisplatin/ vindesine than when it was used with the double combination of cisplatin/vindesine. Summary There was no evidence of unexpected interactions with radiotherapy in the standard indications mentioned when mitomycin C was administered concurrently with radiotherapy. There may be an increased risk of pneumonitis and lung fibrosis when mitomycin C is used in combination with high-volume, higher-dose irradiation of the lungs. Combination Effects of Radiotherapy / Drug Treatments for Cancer 42

5 Antibodies

5.1 Anti-EGFR antibodies: cetuximab, panitumumab and nimotuzumab

5.1.1 Uses of cetuximab Cetuximab is a monoclonal antibody that blocks activation of the epidermal growth factor receptor (EGFR). The approved areas of use are:  Treatment of patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer  in combination with irinotecan-based chemotherapy  in first-line treatment in combination with Folfox®  as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan  In addition cetuximab is indicated for the treatment of patients with squamous-cell cancer of the head and neck  in combination with radiation therapy for locally advanced disease  in combination with platinum-based chemotherapy for recurrent and/or metastatic disease (Erbitux® SPC, 08/2012). The registration trials have been published (Bonner et al. 2006, Cunningham et al. 2004, Vermorken et al. 2008).

5.1.2 The data situation in combination with radiotherapy for cetuximab 5.1.2.1 Effect A number of experimental studies and a major clinical trial have shown that the combination of radiotherapy and cetuximab results in an optimised impact on the tumour, especially for squamous-cell cancers (Bonner et al. 2010, Dittmann et al. 2005, Huang and Harari 2000).

5.1.2.2 Toxicity There are various reports of increased skin toxicity associated with the combination of cetuximab and radiotherapy (Berger and Belka 2008, Billan et al. 2008, Bölke et al. 2008, Budach et al. 2007, Giro et al. 2009, Koutcher et al. 2009, Pryor et al. 2009, Studer et al. 2011). In the first publication relating to the combined use, an increased rate of an acneiform exanthema was observed in the verum group; however, no influence on the occurrence of radiation dermatitis was described. The subsequent publications, most of which consist of collected case studies, refer to the issue of enhanced skin toxicity with grade 4 skin damage, in particular in the head and neck region. In other studies of the use of cetuximab in combination with radiotherapy in the thoracic region (Hallqvist et al. 2011, Hughes et al. 2008), these problems are not described. Likewise, the use of cetuximab in combination with radiotherapy to the pelvis has not led to any reports of an increase in the rate of skin reactions. Combination Effects of Radiotherapy / Drug Treatments for Cancer 43

To date no relevant influence has been observed on the remaining side effect spectrum of radiotherapy, such as mucous membranes, connective tissue, the peripheral nervous system and the CNS (Hasselbalch et al. 2010, Horisberger et al. 2009, Safran et al. 2008).

5.1.2.3 Further aspects When cetuximab is combined with radiotherapy, it should be borne in mind that in individual prospective series, involving for example colorectal cancer, combining cetuximab with radiochemotherapy resulted in lower pathologic complete response rates. However, the significance of this observation for local tumour control is unclear. However, when cetuximab is combined with radiotherapy consideration should be given to the fact that the treatment may affect the cell cycle distribution and alter the vulnerability of cells (Weiss et al. 2010).

5.1.3 Uses of panitumumab Panitumumab, like cetuximab, is a monoclonal antibody that targets the EGF receptor. The approved areas of use are:  The treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC)  in first-line therapy in combination with Folfox®  in second-line therapy in combination with Folfiri® for patients who have received first- line fluoropyrimidine-based chemotherapy (excluding irinotecan)  as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan- containing chemotherapy regimens (Vectibix® SPC 06/2012). The approval trial for monotherapy has been published (Giusti et al. 2008).

5.1.4 The data situation in combination with radiotherapy for panitumumab For panitumumab in combination with radiotherapy, a single phase I dose-finding study is available in addition to pre-clinical data.

5.1.4.1 Effect The pre-clinical data (Kruser et al. 2008) shows that panitumumab augments the radiation response in the same way as cetuximab.

5.1.4.2 Toxicity The available phase I study (Wirth et al. 2010) does not describe any specific toxicities associated with the addition of panitumumab to radiotherapy of the head and neck in patients who were also receiving paclitaxel and carboplatin. There are no other studies of the use of panitumumab in combination with radiotherapy.

5.1.4.3 Nimotuzumab Like cetuximab and panitumumab, nimotuzumab is a therapeutic antibody that targets the EGFR. It is not licensed. A single study has been conducted of the use of the antibody in combination with radiotherapy to the head and neck. The authors state that no increased skin toxicity was observed (Rodríguez et al. 2010). Combination Effects of Radiotherapy / Drug Treatments for Cancer 44

5.2 Anti-EGFR HER2/neu antibody: trastuzumab

5.2.1 Use Trastuzumab is a therapeutic humanised monoclonal antibody that targets the epidermal growth factor receptor HER2/neu. The approved areas of use are:  Metastatic breast cancer (MBC) Herceptin® is indicated for treatment of patients with HER2-positive metastatic breast cancer:  as monotherapy for the treatment of patients who have received at least two chemotherapy regimens for their metastatic disease. Prior chemotherapy must have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments. Hormone-receptor-positive patients must also have failed hormonal therapy, unless patients are unsuitable for these treatments.  in combination with paclitaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable.  in combination with docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.  in combination with an aromatase inhibitor for treatment of post-menopausal patients with hormone-receptor-positive metastatic breast cancer, not previously treated with trastuzumab.  Early breast cancer (EBC) Herceptin® is indicated for the treatment of patients with HER2-positive early breast cancer:  following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable);  following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel;  in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin;  in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy, for locally advanced (including inflammatory) breast cancer or tumours > 2 cm in diameter. Herceptin® should only be used in patients with metastatic or early breast cancer whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay.  Metastatic gastric cancer (MGC) Herceptin® in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or the gastroesophageal junction in patients who have not received prior anti- cancer treatment for their metastatic disease. Herceptin® should only be used in patients with metastatic gastric cancer (MGC) whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory SISH or Combination Effects of Radiotherapy / Drug Treatments for Cancer 45

FISH result, or by an IHC 3+. Accurate and validated assay methods should be used (Bang et al. 2010, Piccart-Gebhart et al. 2005, Slamon et al. 2001). (Herceptin® SPC, version February 2012).

5.2.2 Effect In connection with the use of Herceptin® it has been shown that the concurrent use of Herceptin for HER2-positive cancers potentially increases the pathologic complete response rate (Horton et al. 2010).

5.2.3 Toxicity in combination with radiotherapy According to the SPC, severe pulmonary events have been reported with the use of trastuzumab. Prior and concurrent radiotherapy could increase the risk of interstitial lung disease. Trastuzumab alone (without being combined with radiotherapy) is occasionally cardiotoxic (de Azambuja et al. 2009, Chien and Rugo 2010, Ewer and Ewer 2010). On the basis of the cardiotoxicity of trastuzumab when administered alone, there are concerns that the drug’s cardiotoxicity could be increased by concurrent radiotherapy, especially in cases of breast cancer involving parasternal lymph node drainage. A number of studies have explored this issue – the largest is based on an analysis of the NCCTG trial N9831 (Halyard et al. 2009). The use of trastuzumab was randomised between the chemotherapy arms. Radiotherapy never extended to the internal mammary nodes. There were no differences in the incidence of skin reactions, pneumonitis or the number of patients with cardiac side effects. Another specific study investigated whether administration of trastuzumab concurrently with irradiation of the internal mammary chain increases the incidence of side effects (Shaffer et al. 2009). No increased cardiotoxicity was observed in this small retrospective analysis. The findings were backed up by an analysis of a French multicentric study (Belkacémi et al. 2008); here, too, the authors found no clear increase in the incidence of side effects when Herceptin was used concurrently with radiotherapy. However, the follow-up periods were very short.

5.3 Anti-VEGF antibody: bevacizumab

5.3.1 Use Bevacizumab is a humanised monoclonal antibody that targets the vascular endothelial growth factor (VEGF). The approved areas of use are:  Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of patients with metastatic carcinoma of the colon or rectum.  Bevacizumab in combination with paclitaxel is indicated for first-line treatment of patients with metastatic breast cancer.  Bevacizumab in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Avastin® in combination with capecitabine. Combination Effects of Radiotherapy / Drug Treatments for Cancer 46

 Bevacizumab in addition to platinum-based chemotherapy is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small- cell lung cancer other than predominantly squamous cell histology.  Bevacizumab in combination with interferon alfa-2a is indicated for first-line treatment of patients with advanced and/or metastatic renal-cell cancer.  Bevacizumab in combination with carboplatin and paclitaxel is used for the front-line treatment of patients with advanced (FIGO stages IIIB, IIIC and IV) epithelial ovarian, fallopian-tube, or primary peritoneal cancer.  Bevacizumab in combination with carboplatin and gemcitabine is used for treatment of patients with recurrent epithelian-ovarian, fallopian-tube or primary peritoneal cancer. (Avastin® SPC, version 07/2013). In the USA, bevacizumab is licensed for treatment of recurrent glioblastoma (Vredenburgh et al. 2007). The EMA (European Medicines Agency) has not authorised this use.

5.3.2 Toxicity in combination with radiotherapy Various studies refer to the use of bevacizumab in combination with radiotherapy protocols. For example, Lordick (Lordick et al. 2006) notes an increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation. In a study of the use of bevacizumab with concurrent capecitabine and radiation for patients with locally advanced pancreatic cancer, an increased rate of bleeding and ulceration was found, especially in patients in whom the tumour had invaded the duodenal mucosa (Crane et al. 2006, 2009). After exclusion of these patients, no further problems of this sort were observed. More data is available on the sequential use of bevacizumab following radiotherapy to the abdomen. The effect of prior irradiation on the incidence of gastrointestinal perforation in patients treated with bevacizumab was analysed in a large prospective study (Kabbinvar et al. 2012) of nearly 2,000 patients. Multivariate analysis showed that prior irradiation of the abdomen up to six months before administration of bevacizumab is a significant risk factor for gastrointestinal perforation: in the previously irradiated cohort (n=262) gastrointestinal perforation occurred in 3.4% of patients, while in the non-irradiated cohort 1.7% of patients were affected by this complication (HR=2.6, p=0.03). For patients who received radiotherapy more than six months previously the multivariate analysis showed a trend towards an elevated risk (HR=3.45, p=0.16 n.s.). A phase II trial of neoadjuvant bevacizumab, capecitabine and radiotherapy for locally advanced rectal cancer found an increased rate of wound dehiscences, anastamostic complications and impaired wound healing (Crane et al. 2010). Some studies consider the combination of radiotherapy and bevacizumab – in some cases with subsequent surgery – for cancer of the pancreas to be ‘feasible’ (Small et al. 2011). In other studies, case reports and summaries refer clearly to the risk of post-operative complications and late wound dehiscences when antiangiogenic substances (bevacizumab) are used in the neoadjuvant situation for rectal cancer (Bège et al. 2009, Deshaies et al. 2010, Dipetrillo et al. 2012), However, the literature is not consistent on this point (Koukourakis et al. 2009, 2011, Willett et al. 2009). These authors do not report any increase in surgical complication rates, although similar procedures were involved. Combination Effects of Radiotherapy / Drug Treatments for Cancer 47

When radiotherapy to the thorax was used in combination with bevacizumab during treatment for lung cancer, fistula formation was observed. Two trials were closed early for this reason (both described in Spigel et al. 2010). In case reports (Goodgame et al. 2008, Gore et al. 2009), too, there are references to fistula formation associated with radiotherapy to the thorax and administration of bevacizumab. Skin and lung toxicity associated with the use of bevacizumab combined with radiotherapy was analysed in a collective of patients receiving radiotherapy for breast cancer. No relevant increase in the incidence of side effects was found (Goyal et al. 2011). However, a phase I study of definitive radiotherapy for lung cancer after induction chemotherapy (cisplatin doublet) was terminated on account of the high rate of pneumonitis (4 out of 6 patients) (Lind et al. 2012). Various studies have investigated the combination of radiotherapy and bevacizumab alone or in combination with temozolomide to treat cancers of the brain. No intracerebral haemorrhaging was observed, but there were isolated instances of wound dehiscences around the surgical access routes (Gutin et al. 2009, Lai et al. 2008, Niyazi et al. 2012). A case series makes reference to the possibility of increased late consequences associated with bevacizumab use and irradiation of the brain (Kelly et al. 2011). Leaving aside potentially increased side effects, there are indications that bevacizumab could be a treatment option for radiogenic brain necrosis (Furuse et al. 2011, Liu et al. 2009, Wong et al. 2008).

5.4 Anti-CD20 antibody: rituximab

5.4.1 Use Rituximab is a therapeutic monoclonal antibody that targets the CD20 antigen. Rituximab was initially developed as a targeted agent for the treatment of CD20-positive lymphomas. Rituximab is usually administered in the context of a chemotherapy regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). The approved areas of use are:  Non-Hodgkin’s lymphoma (NHL)  MabThera® is indicated for the treatment of previously untreated patients with stage III- IV follicular lymphoma in combination with chemotherapy.  MabThera® maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.  MabThera® monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.  MabThera® is indicated for the treatment of patients with CD20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with CHOP chemotherapy.  Chronic lymphocytic leukaemia (CLL)  MabThera® in combination with chemotherapy is indicated for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukaemia. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera® or patients refractory to previous MabThera® plus chemotherapy.  Rheumatoid arthritis Combination Effects of Radiotherapy / Drug Treatments for Cancer 48

MabThera® in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying antirheumatic drugs (DMARDs) including one or more tumour-necrosis-factor(TNF)-inhibitor therapies. (MabThera® SPC, version 06/2012). For rheumatoid arthritis rituximab is used as a reserve medication after failure of basic drugs and TNF-α inhibitors.

5.4.2 Toxicity in combination with radiotherapy Because of the radiotherapy of primary/bulk regions specified in many protocols, use of rituximab and radiotherapy in combination or in close temporal proximity is to be expected and is associated with clear benefits (Phan et al. 2010, Wirth 2007, Yahalom 2010). There are no reports of any noteworthy toxicities attributable to the combination treatment. In all studies the side effects that occurred have been attributable to the single effect (Pfreundschuh et al. 2006, 2008).

5.5 Summary

It is not possible to make any general recommendation regarding the use of antibodies in combination with radiotherapy. The findings of a number of studies are contradictory and for some antibodies very few studies have been published. If cetuximab is used, an increase in the incidence of skin reactions must be expected, especially if radiotherapy targets the head and neck. Nevertheless, primary radiotherapy in combination with cetuximab is an established and effective regimen for patients with squamous-cell carcinoma of the head and neck, with an effect roughly comparable to that of radiochemotherapy. Use for this indication is therefore evidence-based. A combination of radiation and bevacizumab appears to be problematic in terms of intestinal damage. The uncritical use of antibodies in combination with ionising radiation must be avoided.

6 Small molecules

6.1 Tyrosine kinase inhibitors: gefitinib, erlotinib, lapatinib, sunitinib, sorafenib

6.1.1 Use The approved areas of use for gefitinib are:  treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer with activating mutations of epidermal-growth-factor-receptor tyrosine kinase. The approved areas of use for erlotinib are:  Non-small-cell lung cancer (NSCLC)  Tarceva® is indicated for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR-activating mutations.  Tarceva® is also indicated as monotherapy for maintenance treatment in patients with locally advanced or metastatic NSCLC with stable disease after four cycles of standard platinum-based first-line chemotherapy. Combination Effects of Radiotherapy / Drug Treatments for Cancer 49

 Tarceva® is also indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.  Pancreatic cancer Tarceva® in combination with gemcitabine is indicated for the treatment of patients with metastatic pancreatic cancer. (Tarceva® SPC, version 06/2012). The approved areas of use for the ErbB2 TK inhibitor lapatinib are:  treatment of patients with breast cancer whose tumours overexpress HER2 (ErbB2).  in combination with capecitabine for patients with advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting.  in combination with an aromatase inhibitor for post-menopausal women with hormone- receptor-positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor. (Tyverb® SPC, version 08/2012). The approved areas of use for the multikinase inhibitor sunitinib are:  Gastrointestinal stromal tumour (GIST) Sutent® is indicated for the treatment of unresectable and/or metastatic malignant GIST after failure of imatinib-mesilate treatment due to resistance or intolerance.  Metastatic renal cell carcinoma (MRCC) Sutent® is indicated for the treatment of advanced/metastatic renal cell carcinoma in adults.  Pancreatic neuroendocrine tumours (pNET) Sutent® is indicated for the treatment of unresectable or metastatic, well differentiated pNET with disease progression in adults. (Sutent® SPC, version 03/2012). The approved areas of use for sorafenib are:  Treatment of hepatocellular carcinoma.  Treatment of patients with advanced renal cell carcinoma who have failed prior interferon- alpha or interleukin-2 based therapy or are considered unsuitable for such therapy. (Nexavar® SPC, version 06/2012

6.1.2 The data situation in combination with radiotherapy 6.1.2.1 Effect Tyrosine kinase inhibitors are small molecules that pass through the cell membrane and inhibit intracellular tyrosine kinases of various growth factor receptors. At present no tyrosine kinase inhibitor is licensed for concurrent use with radiotherapy. Pre-clinical and early clinical trials indicate that tyrosine kinase inhibitors have the potential to inhibit proliferation, but the effects vary widely between individuals. In addition, radiosensitising effects have been observed in vitro. Combination Effects of Radiotherapy / Drug Treatments for Cancer 50

6.1.2.2 Toxicity The available data on the toxicity of concurrent treatment comes from case reports or small patient series and can be summarised as follows: Gefitinib, erlotinib, lapatinib: When these substances are used alone the main side effects are nausea, diarrhoea and skin reactions. There is limited data on the use of these drugs in combination with radiotherapy. In a randomised phase II trial involving patients with squamous-cell carcinoma of the head and neck who received cisplatin and radiotherapy with or without erlotinib, there was a significantly increased rate of grade 3 rash in the patients who received erlotinib but acute toxicities were otherwise comparable in the two treatment arms. There was no evidence of any improved effect on the patients’ tumours (Martins et al. 2013). In principle overlapping and hence possibly potentiating toxicity must be expected, especially when the abdomen is irradiated. One case report describes fatal diarrhoea after a combination of erlotinib (150 mg/d) and abdominal radiotherapy at 2 x 8 Gy (1x per week) (Silvano et al. 2008). By contrast, no dose-limiting toxicity was observed in phase I trials in which patients with pancreatic cancer received erlotinib, albeit at a low dose (50 mg/d or 100 mg/d) and radiochemotherapy (Raftery et al. 2013; Robertson et al. 2012). In a phase II trial of 100 mg/d erlotinib and radiochemotherapy for cancer of the pancreas the authors conclude that the treatment is definitely feasible. However, the toxicity rates were striking: grade 2 toxicities occurred in 50% of patients, grade 3 toxicities in 15% and grade 4 toxicities in 2%; treatment was interrupted in 15% of cases and discontinued in 17%. Discontinuation was on account of severe abdominal pain (2x), fistula formation (1x), rash (1x), diarrhoea (1x), neutropenia (1x), severe nausea (1x) and gastrointestinal complications (4x, including ischaemia, enterocutaneous fistula, gastritis, uncontrollable vomiting). Significantly less data is available in connection with lapatinib. There is a danger of increased renal toxicity when lapatinib is used in combination with (radio)chemotherapy. A phase I dose- finding study of lapatinib in combination with induction chemotherapy (docetaxel/cisplatin/5- FU) prior to radiochemotherapy for patients with squamous-cell carcinoma of the head and neck was halted after four dose-limiting renal toxicities occurred in the lowest lapatinib dose groups (Lalami et al. 2012). By contrast, in a randomised phase II study (66 patients) in which patients with squamous-cell carcinoma of the head and neck received a combination of primary cisplatin radiochemotherapy and lapatinib or a placebo, increased toxicity was observed in the lapatinib arm in the form of diarrhoea, skin toxicities and two grade 4 cardiac events, but there was no increase in renal toxicity (Harrington et al. 2013). It is known that EGFR is also expressed in blood vessels. In patients with brain metastasis, increased intracerebral haemorrhage was reported after treatment with EGFR TK inhibitors; however, there is no evidence that radiotherapy increases the incidence of haemorrhage (Yan et al. 2010). In a phase II study of combined whole-brain irradiation (2.5 Gy to 37.5 Gy) and erlotinib therapy (150 mg/d for 1 week), no grade 4 toxicities occurred (Welsh et al. 2013). By contrast, a phase III study that was terminated prematurely because of poor recruitment investigated the effects of a combination of whole-brain radiation and stereotactic radiation with temozolomide or erlotinib in patients with non-small-cell lung cancer who had 1-3 brain metastases: the time before relapse occurred was significantly shorter for both combination therapies than for radiotherapy alone. Although the authors state that this difference is not attributable to the greater toxicity of the combination therapy, toxicity was significantly higher in the combination therapy arms (grade 3-5 49% in the radiotherapy + erlotinib arm vs. 11% in the radiotherapy arm). The grade 4-5 toxicities (7% in the combination with erlotinib) involved Combination Effects of Radiotherapy / Drug Treatments for Cancer 51 brain necrosis and myocardial infarction/apoplexy and did not occur when radiotherapy was used alone (Sperduto et al 2013). The erlotinib SPC refers to the possible influence of prior radiotherapy on the occurrence of interstitial lung disease when erlotinib is used. There are case reports that describe both this and radiation recall pneumonitis. Sunitinib/sorafenib: When these substances are used alone the main adverse effects are diarrhoea, hypertonia, hand-foot syndrome, fatigue, haemorrhage and haemotoxicity. The SPC mentions the possibility of recall radiation dermatitis. There are also references in case reports to recall pneumonitis associated with sequential radiation and sunitinib therapy. Because of the single toxicities, overlapping/potentiating toxicity is possible when the drugs are used concurrently with radiotherapy to the abdomen. One case report describes a fatal perforation of the small intestine a week after palliative radiotherapy of 1 x 8 Gy (lumbar vertebrae L1-L3); the treatment with sorafenib had been halted two days before the radiotherapy until three days after it (Peters et al. 2008). In a phase I study of concurrent radiotherapy (40 Gy) and sunitinib for patients with metastases in various locations, dose-limiting toxicities in the form of thrombocytopenia and lymphocytopenia were observed in patients who had undergone prior chemotherapy and/or irradiation of large areas of the liver. The authors conclude that sunitinib enhances radiogenic haemotoxicity and that irradiation of large parts of the liver may result in greater haemotoxicity as a result of slower breakdown of sunitinib. They recommend that sunitinib is not used concurrently with irradiation of a hepatic volume of more than 6 cm³. For the remaining patients it was recommended that the dose be reduced from 50 mg/m²/d to 37.5 mg/m²/d for phase II studies. It should be noted that in this study the dose limits for healthy tissue were kept very low (e. g. max. 30 Gy in the spinal cord, max. 40 Gy in the rectum) (Kao et al. 2009). In a phase II study of combined radiotherapy (50 Gy) and sunitinib (37.5 mg/d) for patients with oligometastases the metastases responded well to the treatment, while toxicities occurred in 28% of patients, mainly in the form of haematological toxicities, bleeding and metabolic disorders. One patient suffered fatal gastrointestinal bleeding (Tong et al. 2012).In a phase II study of combined radiotherapy and sunitinib for patients with small-cell lung cancer that was relapsed or refractory after prior chemotherapy, the tumour response rate was very low and toxicity was very high. The sunitinib treatment had to be interrupted or halted for 75% of patients. The side effects were mainly haematological, but asthenia and cardiac toxicities also occurred (Han et al. 2013). An increase in the incidence of intracerebral haemorrhage was noted in patients with brain metastases treated with sunitinib or sorafenib. There was no evidence that radiotherapy enhanced the effect. In some studies the presence of brain metastases is an exclusion criterion for sunitinib use (Pouessel and Culine 2008). One case report describes a fatal bronchial fistula after treatment with sunitinib in a patient who had previously received mediastinal radiation (Basille et al. 2010). In this case a connection with the radiotherapy can neither be proved nor excluded. Fistula formation is also known to occur after treatment with sunitinib alone (Hur et al. 2008).

6.1.3 Summary Simultaneous radiotherapy and treatment with tyrosine kinase inhibitors with curative intent should be used only within clinical trials. When the intent is palliative and interruption of systemic therapy during radiotherapy cannot be justified because of the risk of systemic progression, the treatments will in some cases be administered concurrently. However, according to the current state of knowledge this is associated with a high toxicity risk (including the risk of fatal complications) when radiotherapy targets the abdomen or if there is a risk of bleeding. Extreme caution is also called for in connection with irradiation of the brain and thorax. Combination Effects of Radiotherapy / Drug Treatments for Cancer 52

6.2 Tyrosine kinase inhibitor: imatinib

6.2.1 Use Imatinib inhibits a range of tyrosine kinases and thus has correspondingly varying applications. The approved areas of use are: Treatment of  adult and paediatric patients with newly diagnosed Philadelphia-chromosome (bcr-abl)- positive (Ph+) chronic myeloid leukaemia (CML) for whom bone-marrow transplantation is not considered as the first line of treatment  adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon- alpha therapy, or in accelerated phase or blast crisis  adult and paediatric patients with newly diagnosed Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy  adult patients with relapsed or refractory Ph+ ALL as monotherapy  adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements  adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRa re-arrangement  adult patients with c-kit (CD 117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST)  adult patients who are at significant risk of relapse following resection of c-kit (CD117)- positive GIST (adjuvant treatment). Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.  adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery (Glivec® clinical data sheet, version 02/2012).

6.2.2 The data situation in combination with radiotherapy 6.2.2.1 Effect Imatinib is a tyrosine kinase inhibitor that blocks BCR-ABL, PDGFR (platelet derived growth factor receptor) alpha and beta and c-kit. The first and very successful clinical use of imatinib was in the treatment of CML, which usually involves expression of the BCR-ABL gene that arises from reciprocal translocation. Imatinib is also effective in other haematological disorders with BCR-ABL expression and is licensed for treatment of them. Only later was it discovered that imatinib also inhibits the tyrosine kinases of c-kit and PDGFR. The majority of GISTs (gastrointestinal stromal tumours) have an activating c-kit mutation that plays a major part in the growth of these tumours. Treatment with imatinib has therefore proved effective in both the metastatic and the adjuvant situation. Imatinib is also effective in some patients with dermatofibrosarcoma protuberans since this sarcoma is often associated with overproduction of PDGF as a result of translocation and this overproduction stimulates growth via autocrine and paracrine activities involving the PDGFR. Combination Effects of Radiotherapy / Drug Treatments for Cancer 53

6.2.2.2 Toxicity Imatinib is usually well tolerated. The most frequent side effects of treatment (reported in more than 10% of patients) in both indications were slight nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and erythema. Superficial oedema occurred in all trials, mainly in the form of periorbital oedema or oedema of the lower limbs. Leukocytopenia and thrombocytopenia are observed almost exclusively when the drug is used to treat leukaemia. Mutations and overexpression of c-kit and PDGFR also occur frequently in some other tumorous diseases without essential involvement of the metabolic pathways that are blocked by imatinib; as a result, no significant rate of remission has been reported in these cases (Candelaria et al. 2009, Dy et al. 2005, Hotte et al. 2005, Huh et al. 2010, Wen et al. 2006). The effects of combined treatment with imatinib and other therapies including ionising radiation have been investigated in experimental and clinical trials involving a range of cancers. In in- vitro tests, imatinib sensitised BCR-ABL-positive leukaemia cells to ionising radiation (Topaly et al. 2002). This effect may be due to the fact that imatinib partially inhibits DNA repair in BCR-ABL-positive cells (Majsterek et al. 2006). Varying results have been obtained in connection with solid tumours. In the majority of the tumour cell lines studied in vitro and in the mouse model the effect of radiotherapy was moderately enhanced (Choudhury et al. 2009, Holdhoff et al. 2005, Oertel et al. 2006, Podtcheko et al. 2006, Ranza et al. 2009, Weigel et al. 2010, Yerushalmi et al. 2007). In some tumour cell lines no effect was found (Holdhoff et al. 2005) and in one squamous-cell cancer line imatinib was observed to have an antagonistic effect (Bartkowiak et al. 2007). In one study imatinib was only radiosensitising when PDGFR beta was overexpressed (Holdhoff et al. 2005); another study (Choudhury et al. 2009) postulates downregulation of RAD51, a protein essential for homologous recombination and DNA repair, as a radiosensitising mechanism in solid tumours. Imatinib slows the proliferation of fibroblasts in vitro (Li et al. 2006) and there is speculation that it could reduce radiotherapy-induced fibrosis. Two groups working with the murine model have shown independently that after whole-lung irradiation with a single dose of 18-20 Gy, subsequent therapy with imatinib extends the animals’ survival and reduces lung fibrosis (Abdollahi et al. 2005, Li et al. 2009, Thomas et al. 2010). Very few clinical trials have investigated the combination of imatinib and radiotherapy. Imatinib was used in combination with hydroxyurea for recurrent gliomas after prior radiotherapy in three case series each involving 30-40 patients and as sole therapy in a case series of 112 patients. Efficacy was moderate. There were no unexpected side effects attributable to interaction between radiotherapy and subsequent treatment with imatinib (Desjardins et al. 2007, Dresemann 2005, Raymond et al. 2008, Reardon et al. 2005). Treatment with imatinib was also tolerated without unexpected side effects by 27 patients with prostate cancer with evidence of biochemical relapse after prior radiotherapy (Bajaj et al. 2007). Only one published clinical trial has investigated the concurrent use of imatinib and radiotherapy. In this phase I trial imatinib was used in combination with conventional doses of radiotherapy (55.8 Gy in 31 fractions) to treat 24 children with newly diagnosed brainstem tumours. The maximum tolerated dose of imatinib was 465 mg/m² without anticonvulsant drugs and 800 mg/m² or higher with anticonvulsant drugs. There was a higher rate of intratumoral haemorrhage (in some cases subclinical) than in retrospective comparison groups. Otherwise no unexpected toxicities were observed (Pollack et al. 2007). In addition, two case reports relating to the use of imatinib in combination with concurrent radiotherapy for gastrointestinal stromal tumours (GIST) have been published (Boruban et al. 2007, Ciresa et al. 2009). Both cases involved standard radiotherapy treatment (50.4 Gy in 28 fractions / 54 Gy in 27 fractions). In the report by Ciresa et al. (2009) the patient, who had a Combination Effects of Radiotherapy / Drug Treatments for Cancer 54

GIST of the rectum, subsequently underwent surgery and a complete pathological response was achieved. In the other case, involving a metastatic patient, complete remission was achieved in the radiotherapy region and lasted for more than four years; non-irradiated regions went into only partial remission. In both cases no unexpected side effects of the combination treatment were observed.

6.2.3 Summary From the effect mechanisms and the limited clinical data available it can be assumed that sequential administration of imatinib and radiotherapy is unlikely to be associated with any increased risk of side effects. There is insufficient data on the concurrent use of imatinib and radiotherapy for a valid judgement to be formed. From the data currently available there is no evidence of an increased risk of side effects.

6.3 mTOR inhibitors: temsirolimus, everolimus

6.3.1 Use Everolimus and temsirolimus are approved for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Temsirolimus is also approved for the treatment of recurrent and/or refractory mantle cell lymphoma. The approved areas of use for everolimus are:  Hormone-receptor-positive advanced breast cancer Afinitor® is indicated for the treatment of hormone-receptor-positive, HER2/neu-negative advanced breast cancer, in combination with Exemestane®, in post-menopausal women without symptomatic visceral disease after recurrence or progression following a non- steroidal aromatase inhibitor.  Neuroendocrine tumours of pancreatic origin Afinitor® is indicated for the treatment of unresectable or metastatic, well or moderately differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease.  Renal-cell carcinoma Afinitor® is indicated for the treatment of patients with advanced renal-cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy. (Afinitor® SPC, version 07/2012).  Votubia® is indicated for the treatment of patients from the age of 3 with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery. (Votubia® SPC, version 07/2012). The approved areas of use for temsirolimus are:  first-line treatment of adult patients with advanced renal-cell carcinoma (RCC) who have at least three of six prognostic risk factors  treatment of adult patients with relapsed and/or refractory mantle cell lymphoma (MCL) (Torisel® SPC, version 09/2011) Combination Effects of Radiotherapy / Drug Treatments for Cancer 55

6.3.2 The data situation in combination with radiotherapy 6.3.2.1 Effect mTOR is an intracellular serine/threonine kinase that plays a key part in various signal transduction pathways in cancer and is an important regulator of tumour growth. Inhibition of mTOR can block cell growth and proliferation as well as cell metabolism and angiogenesis. While mTOR inhibitors have been shown to have antiproliferative effects, there is no evidence that combining them with radiation has higher curative potential.

6.3.2.2 Toxicity When the substances are used alone, the main side effects are fatigue, obstipation, anorexia, venous thrombosis, hyponatremia, diarrhoea, haemotoxicity, mucositis, nausea, rash, dehydration, infections (pneumonia), hypophosphatemia, hypercholesterolemia, hyperglycaemia, hyperlipidemia, diabetes mellitus and pneumonitis, renal failure, gastrointestinal perforation and psychiatric side effects. Non-infectious pneumonitis and impaired wound healing are regarded as class effects of rapamycin derivatives. Cerebral bleeding has also been reported. There is very little data on the combination of mTOR inhibitors and radiation, so that we have little more than hints for the side effect profile of this combination. A combination of temsirolimus and topotecan was used in a clinical phase I study of recurrent gynaecologic malignancies in the pelvis. Myelosuppression was a dose-limiting toxicity; doses of 1 mg/m² topotecan combined with 25 mg temsirolimus were well tolerated by patients who had not previously received radiation. Because haemotoxicity occurred at an early stage, it was not possible to establish a meaningful dose regimen for patients who had undergone prior radiotherapy (Temkin et al. 2010). In a phase I study in which glioblastoma patients received everolimus concurrently with temozolomide radiochemotherapy, escalation up to 10 mg/d was possible. However, dose-limiting toxicities occurred in two of the six patients. The main side effects observed were gait disturbances, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, earache, headache and mucositis. Increased tumour vessel thrombosis was observed in a pre-clinical study (Weppler et al. 2007). It is unclear whether vessels outside the tumour are similarly affected. Until further clinical data is available it must be assumed that, as with antiangiogenic substances, combined treatment with mTOR inhibitors and radiation can result in an increase in wound healing complications, bleeding and thrombosis.

6.3.3 Summary The data situation is currently too weak to enable valid recommendations to be made. However, in the light of current knowledge concurrent treatment with mTOR inhibitors and radiotherapy cannot be recommended if large areas of the bone marrow are irradiated.

6.4 Proteasome inhibitors

6.4.1 Use The approved areas of use for the proteasome inhibitor bortezomib (Velcade®) are:  Velcade® as monotherapy is indicated for the treatment of patients with progressive multiple myeloma who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation. Combination Effects of Radiotherapy / Drug Treatments for Cancer 56

 Velcade® in combination with melphalan and prednisone is indicated for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplantation. (Velcade® SPC, version 08/2012).

6.4.2 The data situation in combination with radiotherapy 6.4.2.1 Effect Proteasomes are large protein complexes (two subunits, molecular weight 1,700 kDa) present in eukaryote cells that are responsible for proteolysis of many proteins that have been tagged for degradation by polyubiquitination. Because of its key role in regulating the activity of enzymes, transcription factors (e. g. NF-B) and proteins that control the cell cycle (cyclins, CDK inhibitors) in the tumour cell, the proteasome is one of the structures that may be targeted in cancer therapy. Possible mechanisms by means of which this can be effected are inhibition of tumour growth, inhibition of angiogenesis or enhancement of apoptosis. Cell-biology studies have found the addition of bortezomib to have a radiosensitising effect on cancer cells in the colon, prostate, oesophagus and head and neck. Mechanically this is based on an increase in apoptosis mediated by NF-B, downregulation of the anti-apoptotic protein Bcl-2 and/or activation of the P38 mitogen activated protein (MAP) kinase pathways (Goktas et al. 2010, Lioni et al. 2008, O'Neil et al. 2010).

6.4.2.2 Toxicity Several studies of bortezomib in combination with radiotherapy are available. In a phase I study of patients with glioblastoma, no dose-limiting toxicities (grade 4-5) occurred when bortezomib (0.7 mg/m2, 1.0 mg/m2 and 1.3 mg/m2) was used in combination with temozolomide (75 mg/m2) and radiotherapy. The most frequent toxicities were grade 1 and 2 stomatitis and erythema (Kubicek et al. 2009). O’Neil investigated the combination of bortezomib, 5-FU and 50.4 Gy of radiation for patients with locally advanced or metastatic rectal cancer. The dose- limiting toxicity in this study was diarrhoea, which occurred at a bortezomib dose of 1 mg/m2 (O'Neil et al. 2010). In patients with advanced or recurrent head and neck tumours, the maximum tolerable dose of bortezomib administered in combination with cisplatin-based RCT (cisplatin at 30 mg/m2) was 1.0 mg/m2 for patients who had undergone prior radiotherapy and 1.3 mg/m2 for those who had not. The grade 3 and 4 toxicities observed were thrombocytopenia and neutropenia. A case report published in 2008 described the treatment of two patients with extramedullary plasmacytomas who received a combination of bortezomib, dexamethasone and radiation. The authors report improvement ranging from 75% remission to full remission. Grade 3 peripheral neuropathy is mentioned as a side effect (Varettoni et al. 2008). Interstitial lung disorders have occasionally been reported. A recent phase I study of the tolerability of bortezomib and simultaneous palliative radiation for a variety of advanced tumours (12 patients with cancer of the prostate, head/neck, lungs, kidneys, breast and colon) resulted in no dose-limiting toxicity when a weekly dose of 1.6 mg/m2 was administered (Lioni et al. 2008, Pugh et al. 2010).

6.4.3 Summary The data so far published shows that bortezomib in combination with radio(chemo)therapy is well tolerated, with no unexpected increase in the level or type of toxicity. Combination Effects of Radiotherapy / Drug Treatments for Cancer 57

7 Growth factors

7.1 Erythropoietin

7.1.1 Use Epoetin alpha (ERYPO®), Epoetin beta (NeoRecormon®) and Epoetin zeta (SILAPO®) are approved for the treatment of anaemia associated with renal failure, for reduction of transfusion requirements in patients being treated for solid tumours and to increase the yield of autologous blood. For example, the approved areas of use for NeoRecormon® are:  Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adult and paediatric patients.  Treatment of symptomatic anaemia in adult patients with non-myeloid malignancies receiving chemotherapy.  Increasing the yield of autologous blood from patients in a pre-donation programme.

7.1.2 The data situation in combination with radiotherapy 7.1.2.1 Effect The growth factor erythropoietin is a glycoprotein hormone that is essential for erythrocyte formation during haematopoesis.

7.1.2.2 Toxicity In two large phase II trials involving 351 patients with head and neck tumours scheduled for radiotherapy and 939 patients with metastatic breast cancer who were treated with first-line chemotherapy and recombinant epoetin, relapse-free survival and overall survival were lower in the epoetin group than in the placebo group (Henke et al. 2003, Leyland-Jones et al. 2005). A possible explanation of this finding is that erythropoietin receptors stimulate the growth of tumour cells (Henke et al. 2006). In addition, a recent meta-analysis of 53 studies involving almost 14,000 patients shows an increase in mortality (factor 1.17, 95% CI 1.06-1.30) and a reduction in the overall survival (factor 1.06, 95% CI 1.00-1.12) of tumour patients after administration of erythropoiesis-stimulating agents (Bohlius et al. 2009). In addition, there is a significant increase in the risk of venous thromboembolism after EPO therapy of patients with solid tumours (Bennett et al. 2008).

7.1.3 Summary Treatment of tumour patients with erythropoiesis-stimulating agents increased mortality during the active study period and reduced overall survival. Therefore the use of epoetin in combination with radiotherapy or radiochemotherapy cannot be recommended. Exceptions can be made in the case of purely palliative or symptomatic therapy.

7.2 G-CSF and GM-CSF

7.2.1 Use The G-CSFs (granulocyte colony-stimulating factors) lenograstim (Granocyte®), filgrastim (Neupogen®) and pegfilgrastim (Neulasta®) are approved for the following indications: Reduction in the duration of neutropenia in patients with non-myeloid malignancies and mobilisation of peripheral blood stem cells (PBSC). Sargramostim (Leukine®) is authorised for Combination Effects of Radiotherapy / Drug Treatments for Cancer 58 reduction in the duration of neutropenia in the US market only. In addition, Leukine® is approved in the USA for four other indications: myeloid reconstitution after autologous or allogeneic bone marrow transplantation (BMT), myeloid reconstitution after PBSC transplantation, and cases of transplantation failure or engraftment delay.

7.2.2 The data situation in combination with radiotherapy 7.2.2.1 Effect The granulocyte colony-stimulating factor is a peptide hormone that stimulates the survival and proliferation of immature precursor cells in the haematopoietic system and determined progenitor cells for neutrophil granulocytes (CFU-GM), while GM-CSF stimulates the production of granulocytes and macrophages. In addition, both growth factors are considered to be essential for wound healing, mainly through activation of neutrophil granulocytes, monocytes and macrophages, migration of endothelial cells and modulation of the fibroblast phenotype (Bussolino et al. 1989).

7.2.2.2 Toxicity 2 An early phase III study investigated the use of GM-CSF (250 µg/m ) to reduce haemotoxicity and morbidity after radiochemotherapy for non-small-cell lung cancer. There was a significant increase in the frequency of thrombocytopenia, non-haematologic toxicities and toxic deaths (Bunn et al. 1995). In addition, irradiation of large areas combined with concurrent administration of G-CSF reduced CD34-positive progenitor cells and bone marrow recovery capacity (Pape et al. 2006). According to guidelines published by the American Society of Clinical Oncology (ASCO) in 2006 (Smith et al. 2006), concurrent administration of G- CSF/GM-CSF and radiochemotherapy should therefore be avoided, especially in patients receiving radiotherapy to the mediastinum. The German leukaemia competence network (http://www.kompetenznetz- leukaemie.de/content/aerzte/therapie/supportive_therapie/empfehlungen/g_csf___gm_csf/inde x_ger.html) therefore concludes that there is no evidence that the use of G-CSF/GM-CSF has any benefits for patients who already have febrile neutropenia and recommends that the substances be administered mainly prophylactically immediately after completion of haematotoxic chemotherapy (where the risk of neutropenia-related febrile complications is > 40%). More recent data on the concurrent use of G-CSF and thoracic radiochemotherapy confirms the increased risk of thrombopenia but did not find increased rates of pneumonitis (Sheikh et al. 2011). Whether the toxicity risks are outweighed by the long-term outcome of full-dose therapy is currently being investigated in a randomised phase III study (CONVERT). At present the use of these drugs with radiotherapy alone can be considered for patients who are at risk of having their therapy delayed on account of protracted neutropenia. Phase I/II studies have investigated the reduction of radiation-induced mucositis through administration of GM-CSF after radiotherapy. In an earlier study of GM-CSF (150-300 µg) for patients with squamous-cell cancers of the head and neck, GM-CSF and sucralfate produced no significant change in the grade of mucositis, pain levels and survival by comparison with sucralfate alone. The most frequent toxicities were skin reactions at the injection site, fever and bone pain (Makkonen et al. 2000). By contrast, a later study found that patients given 100 µg GM-CSF subcutaneously per day developed less grade 2 mucositis and dysphagia (Patni et al. 2005). In a double-blind placebo-controlled prospective phase III study of 121 patients from 36 institutions who had head and neck cancer (Radiation Therapy Oncology Group 9901) there Combination Effects of Radiotherapy / Drug Treatments for Cancer 59 was no significant improvement in mucositis scores after administration of GM-CSF (250 µg/m2) rather than a placebo (Ryu et al. 2007). A recent study showed that the use of GM- SCF was well tolerated by patients with squamous-cell cancer of the head and neck undergoing combined radiochemotherapy (70 Gy, cisplatin 100 mg/m2). In this study GM-CSF reduced the level of acute side effects (grade 2 mucositis and grade 2 dysphagia). One case of erythema at the injection site was reported as a minimal side effect of the GM-CSF (Harrington et al. 2010).

7.2.3 Summary The routine use of G-CSF and GM-CSF for prophylaxis or therapy of leukopenia resulting from radiochemotherapy is not recommended, because there is still no evidence that the clinical benefit outweighs the toxicity. In particular, the high risk of severe thrombocytopenia must be borne in mind. Only in exceptional cases, therefore, should G-CSF and GM-CSF be used in combination with radiochemotherapy. The findings on the use of GM-CSF to reduce radiation-induced mucositis are contradictory and it is not possible to derive any recommendation from them. Use of GM-CSF for this purpose should therefore be confined to clinical trials.

7.3 Keratinocyte growth factors

7.3.1 Use The approved area of use of the human recombinant keratinocyte growth factor (KGF) palifermin (Kepivance®) is: to decrease the incidence, duration and severity of oral mucositis in adult patients with haematological malignancies receiving myeloablative radiochemotherapy associated with a high incidence of severe mucositis and requiring autologous-haematopoietic-stem-cell support (Kepivance SPC, version July 2012).

7.3.2 The data situation in combination with radiotherapy 7.3.2.1 Effect The KGF binds to epithelial cell surface receptors and stimulates the proliferation of keratinocytes. Differentiation of these keratinocytes and upregulation of cytoprotective mechanisms can help to reduce mucositis.

7.3.2.2 Toxicity Early experiments on animals (Farrell et al. 1998) found that recombinant KGF used in conjunction with chemo- and radiotherapy had a protective effect on intestinal mucositis, weight loss and mortality in various mouse models. In a study of the effect of palifermin on ulceration of mouse tongue epithelium after combined radiochemotherapy with cisplatin and 5- FU, the drug was found to increase mucositis tolerance and the dose needed to induce ulceration in 50% of the mice (Dörr et al. 2005, Henke et al. 2011). A phase II study of advanced squamous-cell carcinoma of the head and neck after simultaneous cisplatin/5-FU-containing radiochemotherapy found that palifermin (60 µg/weekly) reduced oral mucositis slightly during hyperfractionated (1.26 Gy to 72 Gy) radiotherapy but not during standard radiation therapy (2 Gy ED to 70 Gy). The range of adverse events was similar between treatment groups, as were tumour response and survival (Brizel et al. 2008). In more recent studies of patients with advanced head and neck cancer after postoperative and definitive radiochemotherapy, the incidence and duration of severe oral mucositis (WHO grade 3 and 4) was significantly reduced after the palifermin dose was increased (120 µg/kg / 180 µg/kg), while overall and progression- Combination Effects of Radiotherapy / Drug Treatments for Cancer 60 free survival were unaffected. Erythema, oedema and dysgeusia occurred more frequently in the palifermin group than in the placebo groups (Le et al 2011). Increased migration and proliferation of breast cancer cells was reported after administration of palifermin (Nguyen et al. 2002). By contrast, other authors have found that KGF (0.01 to 1000 ng/ml) does not affect the proliferation and in-vivo growth of human carcinoma cells in the animal model (Alderson et al. 2002). Recent cell culture trials have shown that recombinant KGF or tumour-cell-derived KGF does not induce proliferation of epithelial tumour cells (HNSCC) but does improve the radiation resistance of keratinocytes in normal tissue (Hille et al. 2010). Researchers have also demonstrated that palifermin can protect salivary glands from radiation damage by expanding the glands’ pool of stem cells (Lombaert et al. 2008).

7.3.3 Summary Despite positive results in patients with advanced head and neck tumours, the data does not permit the formation of a clear view on the use of KGF to reduce radiation-induced mucositis. A possible influence on tumour cell proliferation/migration requires further experimental clarification.

7.4 Thrombocyte growth factors

7.4.1 Use Because of its effect mechanism (competitive and selective blocking of the ATP binding site of specific tyrosine kinases), the tyrosine kinase inhibitor imatinib (Glivec®) is also used to inhibit platelet-derived growth factor receptor activity. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GIST), BCR-ABL-positive acute lymphoblastic leukaemia, dermatofibrosarcoma protuberans, special cases of myeloproliferative neoplasia and hypereosinophilic syndrome / eosinophilic leukaemia.

7.4.2 The data situation in combination with radiotherapy 7.4.2.1 Effect PDGF is a potent mitogen and chemokine for mesenchymal cells, neutrophil granulocytes and monocytes. It is considered to be a key factor in various processes including oncogenesis, angiogenesis and fibrogenesis (Li et al. 2006). The factor is expressed by endothelial cells, fibroblasts and tumour cells after ionising radiation and protects vessels from radiation-induced damage (Li et al. 2006, Nistér et al. 1988). In various models overexpression of the protein has been associated with a worse clinical prognosis (Kerbel and Folkmann 2002) and radiation resistance (Geng et al. 2001).

7.4.2.2 Toxicity The use of small molecule inhibitors to block PDGF-receptor tyrosine kinase activity is one of the clinical options for inhibiting PDGF activity. Although radiosensitisation of tumour cells and reduction of radiation-induced pulmonary fibrosis by inhibition of the PDGF receptor has been demonstrated in cell culture and in the animal model, there are currently no clinical studies of PDGF receptor inhibition using imatinib and radiation. Combination Effects of Radiotherapy / Drug Treatments for Cancer 61

8 Free-radical scavengers (e. g. selenium)

8.1 Use

Sodium selenite (Selenase®) is approved for the treatment of proven selenium deficiency that cannot be remedied nutritionally. Selenium deficiency can occur as a result of maldigestion, malabsorption, malnutrition and undernutrition. (Selenase AP® SPC, version May 2012).

8.2 The data situation in combination with radiotherapy

8.2.1 Effect Selenium is an essential trace element that functions as a free-radical scavenger in the body’s antioxidative system. It is thought to play a role in radioprotection of normal tissue, radiosensitising in malignant tumours, anti-oedematous therapy and cancer prevention (Micke et al. 2009).

8.2.2 Toxicity An early explorative study examined the impact of selenium in the treatment of radiotherapy- induced lymphoedema of the arms and endolarynx. There was a subjective reduction in oedema and a reduced need for tracheostomy (Micke et al. 2003). A recent multicentre phase II trial investigated whether selenium supplementation reduced the side effects of radiotherapy of 39 patients with cervical and uterine cancer. Patients who received Selenase® had an improved concentration of selenium in the blood and a significant reduction in grade 2 diarrhoea; there was no difference in other blood parameters and subjective quality of life (Muecke et al. 2010). The reduction in the severity of diarrhoea is most marked when the planning target volume is large (>1302 ml) (Muecke et al. 2010). In other groups, however, serum selenium levels had no effect on radiotherapy-related toxicity (Eroglu et al. 2012). 8.2.3 Summary Overall the studies – most of which have involved only small numbers of patients – find no evidence that selenium increases the toxicity of radiotherapy. It is still unclear whether selenium supplementation reduces radiation toxicity or has a radiosensitising effect on tumour cells. Because of the effect mechanism (free-radical scavenger), it is also possible that selenium reduces the effect of radiation on tumours, because the formation of free radicals is important in enhancing the cytotoxicity of radiotherapy.

9 Miscellaneous

9.1 Thalidomide

9.1.1 Use The angiogenesis inhibitor thalidomide is approved in combination with melphalan and prednisone as first-line treatment of patients with untreated multiple myeloma, aged ≥ 65 years or ineligible for high-dose chemotherapy. Combination Effects of Radiotherapy / Drug Treatments for Cancer 62

9.1.2 The data situation in combination with radiotherapy 9.1.2.1 Effect Thalidomide was originally licensed as a hypnotic under the trade name Contergan until it became clear in the early 1960s that taking thalidomide during pregnancy leads to severe abnormalities, especially phocomelia. It was not until the late 1990s that thalidomide was rediscovered as a cancer treatment on account of its antiangiogenic properties (Singhal et al. 1999). In the clinical setting thalidomide is used in the treatment of multiple myeloma; at present (November 2011) this is the only indication for which it is approved in Germany. However, the efficacy of thalidomide for a number of other oncological diseases and dermatological disorders has been and will continue to be the subject of research.

9.1.2.2 Toxicity In addition to its sedative effect, a significant side effect of thalidomide is an increased risk of thromboembolic events and peripheral polyneuropathy. According to the SPC the most frequent side effects also include haemotoxicity, obstipation, paraesthesia, dizziness, dysaesthesia, tremor and peripheral oedema. The most important clinically relevant side effects mentioned are deep vein thrombosis and pulmonary embolism, peripheral neuropathy, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, syncope, bradycardia and dizziness. Interstitial lung disease is also described as a common side effect. In-vitro studies produced no evidence that thalidomide has a radiosensitising effect on multiple myeloma and squamous-cell carcinoma cells, although it was found to have some radiosensitising effect on normal haematopoietic bone marrow (Epperly et al. 2006). Thalidomide was found to lower interstitial fluid pressure in experimental tumours in the animal model, providing indirect evidence that it could promote tumour reoxygenation (Ansiaux et al. 2005). In the rat model thalidomide injected for seven days immediately after a single dose of radiation was shown to attenuate radiogenic proctitis (Kim et al. 2008). Phase I-III trials have examined the use of thalidomide in combination with radiotherapy or radiochemotherapy in humans. The majority of this experience relates to irradiation of the CNS in combination with thalidomide. In a phase III trial, 193 patients with multiple brain metastases were randomised to receive either palliative whole-brain radiation therapy (37.5 Gy in 15 fractions) or the same radiotherapy in combination with thalidomide (200 mg/day with weekly escalation to a maximum of 1,200 mg/day to progression or a maximum of two years after radiotherapy). In the thalidomide arm only the known side effects of thalidomide occurred, and they did so at the expected frequency. There was no evidence of interaction with the radiotherapy (Knisely et al. 2008). Thalidomide in combination with concurrent radiotherapy or radiotherapy plus temozolomide was used to treat newly diagnosed and recurrent malignant gliomas. Isolated instances of intratumoral bleeding and thromboembolic complications were reported. However, the rate of these complications was no higher than that reported for treatment with thalidomide alone (Chang et al. 2004, Groves et al. 2007, Kim et al. 2010, Turner et al. 2007). Similarly, there was no evidence of an increased rate of acute or late side effects when thalidomide was administered concurrently or sequentially in combination with irradiation of pelvic tumours and bone/soft tissue metastases (Kerst et al. 2005, Yi-Shin Kuo et al. 2006). However a study of 10 patients with stage III NSCLC who received radiotherapy of 66 Gy (33 fractions) in combination with vinorelbine and thalidomide (starting dose 50 mg/day) was closed prematurely. Two of the first six patients developed thrombotic events. The thalidomide dose was reduced and four further patients were treated, of whom one developed grade 2 bradycardia and one a grade 2 rash. The study was then halted (Anscher et al. 2006). Combination Effects of Radiotherapy / Drug Treatments for Cancer 63

Because in this study, too, the only side effects that occurred were known side effects of the treatment used, it remains unclear whether irradiation of large areas of the lungs or heart is actually associated with an increased risk of side effects of thalidomide.

9.1.3 Summary Overall the combination of thalidomide in combination with concurrent or sequential radiotherapy can be largely regarded as not giving cause for concern. However, caution is called for when the radiation field includes large areas of the heart or lungs.

9.2 Lenalidomide

9.2.1 Use The angiogenesis inhibitor lenalidomide is approved in combination with dexamethasone for the treatment of multiple myeloma in patients who have received at least one prior therapy. 9.2.2 The data situation in combination with radiotherapy 9.2.2.1 Effect Lenalidomide is an analogue of thalidomide, with a very similar chemical structure. It has a similar angiogenesis-inhibiting effect to thalidomide and comparable side effects but lacks the sedative/hypnotic effect of thalidomide and is therefore better tolerated by patients. 9.2.2.2 Toxicity According to the SPC the most frequent side effects are fatigue, neutropenia, obstipation, diarrhoea, muscle cramp, anaemia, thrombocytopenia and rash. There are very few studies of the possible interactions between lenalidomide and ionising radiation. A phase I study investigated the use of radiotherapy (60 Gy / 30 fractions) in combination with escalating doses of lenalidomide for patients with newly diagnosed glioblastoma. Some patients experienced thromboembolic events, and dose-limiting toxicities that occurred were pneumonitis and transaminase elevations (Drappatz et al. 2009). The maximum tolerable dose was stated to be 15 mg/m², which is roughly equivalent to the monotherapy dose.

9.2.3 Summary From the very similar chemical structure of lenalidomide and the fact that its clinical efficacy in the treatment of multiple myeloma is similar to that of thalidomide it can be indirectly concluded that its interaction pattern with ionising radiation will also be similar. In view of the lack of valid data, however, a definitive assessment is not possible. Caution is therefore called for, especially in connection with concurrent use.

9.3 PARP inhibitors: olaparib and BSI 201

9.3.1 Use At present (January 2012) no PARP inhibitor is approved for clinical use. The findings have been published of initial clinical trials of the use of PARP inhibitors to treat metastatic breast and ovarian cancer and this could lead to approval being granted. Combination Effects of Radiotherapy / Drug Treatments for Cancer 64

9.3.2 The data situation in combination with radiotherapy 9.3.2.1 Effect PARPs (Poly(ADP-ribose) polymerases) are enzymes needed for base excision repair (BER). PARP I and PARP II are the most important enzymes in this group. BER is necessary for repair of single-strand DNA breaks. If PARP I is not present or is inhibited, single-strand DNA breaks are therefore not repaired or their repair is much delayed, giving rise to double-strand DNA breaks in the S-phase if the unrepaired single-strand breaks encounter a replication fork. Double-strand DNA breaks are repaired in the S-phase largely through homologous recombination (HR) with the help of the sister chromatid. If cells have defects in HR, double- strand breaks remain and eventually lead in various ways to cell death. BRCA1 and BRCA2 are two genes that are important for the functioning of HR; in genetically caused breast and ovarian cancer these genes are often damaged. Similarly, in many cases of sporadic triple- negative breast cancer (no receptors for oestrogen, progesterone or HER2/neu), BRCA1 or BRCA2 is not functioning. The efficacy of PARP inhibitors for cell lines and patients with BRCA1/2 mutations has been demonstrated both in vitro and in clinical phase I and II studies.

9.3.2.2 Toxicity In HR-competent cells PARP inhibitors are not usually toxic. PARP I knockout mice are viable and capable of reproduction; they have a normal life span if not exposed to DNA-damaging substances or ionising radiation. If infliction of damage to the DNA by means of ionising radiation or DNA-damaging chemotherapy agents (e. g. alkylating agents, platinum derivatives) is combined with PARP inhibition, the number of double-strand breaks that arise during the S-phase is so high that the HR is unable to cope; double-strand breaks remain and subsequently lead to cell death (for a summary see Comen and Robson 2010, Powell et al. 2010). In vitro and in the animal model it has already been shown that the effect of ionising radiation can be enhanced by a factor of 1.2–1.7 in most, but not all, of the tumour cell lines studied. This enhancement of effect has also been demonstrated in some cases in human fibroblasts, germ cells and lung cells. The available data indicates that the effect-enhancing impact of PARP inhibitors in tumour cells and normal tissue cells is largely limited to cells with a high proliferation rate (Powell et al. 2010). The clinically most advanced drugs are the PARP inhibitors olaparib and iniparib (BSI-201). Olaparib has been successfully tested as a monosubstance in patients with metastatic breast cancer with confirmed or probable BRCA1/2 mutation (Tutt et al. 2010). Iniparib was used in combination with carboplatin and gemcitabine in a randomised phase II study (n=123) of patients with metastatic triple-negative breast cancer. BSI 201 was found to have a significant survival benefit (O'Shaughnessy et al. 2011). No significant increase in toxicity was reported. However, in view of the small number of cases and the short follow-up period, it is not possible to make any valid statement about possible increases in toxicity.

9.3.3 Summary At present (December 2011) there is still a complete lack of clinical data on the combination of PARP inhibitors and ionising radiation. In view of the enhancement of effect observed in vitro in normal tissue cells as well as in tumour cells, an express warning must be issued against the uncritical use of PARP inhibitors in combination with concurrent ionising radiation. This includes the administration of relatively low doses of radiation in the palliative situation. Sequential administration of ionising radiation and PARP inhibitors is theoretically safe if it is certain that no effective concentration of the PARP inhibitor remains in the irradiated tissue. Combination Effects of Radiotherapy / Drug Treatments for Cancer 65

This assessment is indirectly supported by the fact that no unusual toxicities in previously or subsequently irradiated patients have been reported in the phase I and II trials conducted to date.

10 Special considerations in connection with nuclear medicine therapies

Nuclear medicine therapies differ significantly from all other types of radiotherapy. They are usually based on targeted exploitation of specific pathophysiological functions of the diseased tissue. The whole body is always irradiated. The target tissue of course receives significantly more intensive radiation than the rest of the body. In principle, though, the radiation exposure of all organs can be influenced. The modulation of radiation sensitivity, e. g. by drugs, can also have an impact at considerable distance from the target tissue. In general it can be stated that nuclear medicine therapy necessarily exploits the pathophysiology of the disease (hereinafter termed ‘the tumour’ for the sake of simplicity) for its therapy. The basis of therapy planning is therefore to achieve or maintain a defined state of functioning in the patient. Because nuclear medicine therapy usually utilises the pathological function of the tissue to be treated to concentrate the radiotherapy and hence to increase the focal dose, all prior therapeutic measures that treat the tumour are usually detrimental. This applies both to drugs and to percutaneous radiation. This is used to pave the way for therapy by enhancing the selective update of the radiopharmaceutical or to block non-required non- selective accumulation by means of drugs. The greater the selective accumulation of the radiopharmaceutical in the tumour, the more effective is the therapy. Because beta radiation is usually used as the therapy nuclide, it has an impact through the cross-fire effect – irrespective of the range of the beta radiation in the tissue – not only at the site of physiological accumulation but also for some millimetres around it. As soon as a nuclear medicine therapy is considered, no other therapy may be introduced or changed without the approval – or at least the knowledge – of the nuclear medicine therapist as it might interfere with the nuclear medicine therapy or render it impossible. By way of example, the most frequent radionuclide therapies and the most frequently evidenced specific influences on them are described and listed below.

10.1 Radioiodine therapy for thyroid disorders

The thyroid gland forms part of a regulatory circuit. Hormone production in healthy thyroid cells is stimulated by the pituitary gland via a thyroid-stimulating hormone (TSH). To produce thyroid hormones, the cell needs iodide, which it actively absorbs via the sodium iodide symporter. If hormone production is increased as a result of focal or disseminated functional autonomy, this results in pathologically elevated uptake of iodine and at the same time in a reduced uptake of iodine in healthy thyroid tissue. Ideally the healthy tissue should be maximally suppressed, which can sometimes be achieved through additional administration of thyroid hormones. Thyrostatic drugs can have a significant impact on iodine uptake and intrathyroidal iodide kinetics. This can jeopardise the success of treatment or result in undesirably high irradiation of the thyroid, with organ loss as a possible consequence in extreme cases. If large quantities of stable iodide are administered, e. g. in connection with the use of X-ray contrast agents (also via iodine-containing disinfectants or drugs), uptake of the radioactive therapeutic agent 131I Combination Effects of Radiotherapy / Drug Treatments for Cancer 66 will be competitively inhibited and for a period relevant irradiation of the focus of the disease in the thyroid will not be possible. These considerations apply in analogous form to goitre reduction therapy and treatment of hyperthyroidism resulting from autoimmune thyropathy (e. g. Graves’ disease). Extrathyroidal radiation exposure in the treatment of benign thyroid disorders is of subordinate importance in the present context. Significantly higher activities are used in the treatment of thyroid cancer – typically between 1 and 10 GBq and in some cases up to 20 GBq. The therapy requires maximum TSH stimulation of any thyroid cancer cells or foci that may be present or even known. Traditionally this stimulation is typically achieved by means of four weeks of thyroxine withdrawal and at least two weeks of complete thyroid hormone withdrawal. Any major exposure to iodide and any unauthorised administration of thyroid hormones are both deleterious to the concept. Alternatively, stimulation can nowadays be provided via exogenously administered recombinant human rTSH. The rTSH must be administered in accordance with the manufacturer’s instructions in the prescribed timeframe. It is not within the remit of this paper to assess the extent to which the two procedures produce an equivalent outcome. Non-target radiation exposure (i. e. exposure of areas outside the thyroid or thyroid cancer foci) must be borne in mind, especially in connection with repeated radioiodine treatment or therapies with very high single activities. The salivary glands can even be influenced functionally. Adequate hydration must be ensured. How an increase in salivation or blocking of the functioning of the salivary glands affects the salivary gland radiation dose has not been systematically investigated. Because of the complexity of the salivary gland the influences cannot be expected to be linear. Experimental indications and theoretical considerations based on them lead to the conclusion that the – unwanted – salivary gland dose that is achieved depends on the time of day at which treatment is delivered. Treatment in the evening can be assumed to lead to higher radiation exposure, in part because mechanical stimulation of the salivary glands is reduced during sleep. The radiation exposure of the bladder is affected by renal function and hydration, while that of the bowel is influenced by stool frequency. These functions can be influenced by means of drugs.

10.2 Therapy with 131I-metaiodobenzylguanidine (mIBG) for tumours of the neuroectoderm and its derivatives

Because of its structural similarity to noradrenaline, mIBG is actively accumulated and to some extent also stored by cells that have the human noradrenaline transporter on their surface. The principal such cells are pheochromocytomas, paragangliomas and neuroblastomas, and also neuroendocrine tumours (NET) or carcinoids. Various drugs can theoretically influence mIBG uptake and storage or have been found in practice to do so (Solanki et al. 1992, Wafelman et al. 1994). It can be assumed that the extent to which influence is possible depends on the number of transporters on the tumour cells and their mIBG storage capability. However, the data on quantification of the influence of drugs on mIBG storage is limited, so that it is not possible to determine generally how strongly the continued intake of a drug hinders mIBG accumulation/storage. However, it is conceivable that a drug interaction could be exploited to prolong intratumoral retention of mIBG (Wafelman et al. 1994). Again, the data situation here is limited. The main drugs that are known or expected to interact with mIBG uptake and storage Combination Effects of Radiotherapy / Drug Treatments for Cancer 67 are certain prescription antiarrhythmic agents, calcium channel blockers, neuroleptics and antidepressants. Attention should also be paid to the use of over-the-counter drugs (e. g. decongestant nose drops). It is usually recommended that the potentially interacting drugs are temporarily stopped and that the duration of the pause is linked to their half-life. However, the patient’s state of health does not always permit this. To avoid jeopardising either the patient or the efficacy of treatment, therefore, no drugs should be started or stopped without consultation with the doctor and the practitioner of nuclear medicine who are providing treatment. A detailed list of drug interactions with 131I-mIBG can be found in the procedure guidelines for 131I-mIBG therapy (Giammarile et al. 2008) of the European Association of Nuclear Medicine (EANM). The bladder’s exposure to radiation is influenced by renal function and hydration. These functions can in turn be influenced by means of drugs.

10.3 Treatment with 90Y-/177Lu-DOTA-D-Phe1-Tyr3-octreotide (DOTATOC), 90Y-/177Lu-DOTA-D-Phe1-Tyr3-octreotate (DOTATATE) or other somatostatin analogues for tumours of the neuroectoderm and its derivatives

Because of their structural similarity to somatostatin, DOTATOC/DOTATATE (and other somatostatin analogues that can be radiolabelled) are taken up and internalised by cells that have the somatostatin receptor on their surface. The cells that fall into this category are in particular neuroendocrine tumours (NET) and carcinoids, but also medullary thyroid cancers, pheochromocytomas, paragangliomas and Merkel cell tumours. There are important interactions with non-radiolabelled somatostatin analogues, which are often taken as long-term medication (e. g. octreotide acetate, lanreotide) and compete with the radioactive treatment agent for the receptor. The competition on the receptors on the tumours (target) can be expected to lead to a reduction in the bound/internalised treatment substance and the dose that can be achieved. However, it is not yet clear whether the competition on the receptors on the non- tumour tissues (non-target) results in an increase in the treatment agent available for tumour binding and can (over-)compensate for the reductive effect on the tumour tissue (Hanin et al. 2010). However, it is usually recommended that somatostatin analogues are temporarily stopped and that the duration of the pause is linked to their half-life (Kwekkeboom et al. 2009). Any starting or stopping of drugs before/during treatment should be based on consultation with the doctor and the practitioner of nuclear medicine who are providing treatment. Because the therapy agents are retained by the kidneys, supporting medication is required to reduce renal uptake/retention and the resulting radiation exposure. Amino acid solutions and/or gelatine solutions are usually used. They can reduce renal uptake/retention by 40–50%; uptake in the tumours is apparently unaffected (Rolleman et al. 2010). The radiation exposure of the kidneys and bladder is also influenced by renal function and hydration. Patients are usually hydrated prior to therapy; diuresis is if necessary accelerated by drugs.

10.4 Selective internal radiation therapy (SIRT) with Y-90 microspheres for malignant liver tumours

Patients with metastases who receive SIRT with Y-90 microspheres for malignant liver tumours have usually undergone several previous courses of chemotherapy. For patients with hepatocellular carcinoma (HCC), simultaneous or prior treatment with sorafenib is a possibility. Sorafenib is a multikinase inhibitor that targets RAF, PDGFR and VEGFR; it is licensed in Germany for treatment of hepatocellular carcinoma. Combination Effects of Radiotherapy / Drug Treatments for Cancer 68

There are as yet no studies of changes in tumour vascularisation as a result of sorafenib therapy and the effect of sorafenib on the blood-flow-dependent distribution of the microspheres in the liver and tumour and hence on the dose distribution. Some studies have produced an inconsistent picture of the interactions that can be expected between sorafenib and the effects of radiotherapy involving Y-90. In-vitro experiments on HCC cells resulted in reduced radiosensitivity after treatment with sorafenib (Li et al. 2011). Sorafenib was not observed to produce any change in radiosensitivity in cultures of colorectal cancer cells, but in xenografts there was a synergistic effect which may be attributable to the antiangiogenic effect of sorafenib (Suen et al. 2010). The timing of radiotherapy in relation to sorafenib treatment is important (Plastaras et al. 2007). There is insufficient evidence of the effect of sorafenib on normal tissue tolerance. While there is one case report of a fatal bowel perforation after palliative radiotherapy of vertebral metastasis in a patient with renal cell carcinoma (Peters et al. 2008), another report describes three patients who experienced no complications when they received radiotherapy while undergoing sorafenib therapy (Kasibhatla et al. 2007). According to another case report, there were no complications when conformal percutaneous radiotherapy was administered to a patient with hepatocellular carcinoma (HCC) concurrently with sorafenib therapy (Hsieh et al. 2009). In animal experiments the angiogenesis inhibitor bevacizumab, which is used to treat colorectal cancer, was found to influence the vascularisation and oxygenation of solid tumours and – depending on the timing of the radiation therapy – the enhancement of tumour growth delay by radiotherapy (Dings et al. 2007). In the animal model, administering a PDGFR inhibitor as well as angiogenesis inhibitors appeared to inhibit the improved tumour survival effect of PDGF induced by radiation; however, it also demonstrates the complexity of the interactions involved, in connection with both the various signalling pathways in the tumour and the interactions with radiation effects (Timke et al. 2008). A phase I study of the use of bevacizumab with fluorouracil- and hydroxyurea-based chemoradiotherapy for head and neck cancer was associated with a risk of increased toxicity (Seiwert et al. 2008). The risk of complex interactions between signal transduction inhibitors and the SIRT must therefore be taken into account. At present it remains unclear whether and to what extent these considerations are transferable to more recent signal transduction inhibitors or combinations with other chemotherapy agents. This means that at the moment it is not possible to make any recommendations about SIRT after or during treatment with sorafenib or other signal transduction inhibitors. Systematic studies are urgently needed, especially in view of the increasing clinical use of sorafenib for HCC. It must also be borne in mind that on account of its antiangiogenic effect sorafenib can influence tumour blood perfusion. The amount by which the ratio of arterial tumour perfusion to arterial perfusion of the healthy liver is changed is the same as the extent to which the ratio of target to non-target radiation dose is influenced. The antiangiogenic effect can be used positively to reduce an unacceptable hepatopulmonary shunt (usually based on an intratumoral shunt) as a result of sorafenib treatment before an SIRT to an acceptable level. Combination Effects of Radiotherapy / Drug Treatments for Cancer 69

Table 10.1 Effect of various disturbance variables on nuclear medicine therapy within the tumour (target) and outside it (non-target)

Therapy/ Target Non-target disturbance variable

Radioiodine therapy

Iodine exposure Uptake ↓ , kinetics ↑ ↔ dose ↓↓

Increased salivation ↔ Salivary gland variously ↓↑

Salivation blockade ↔ Salivary gland variously ↓↑

Thyroid inhibitors Variously ↑↓ In the event of focal autonomy, therapy may be impossible.

Thyroid hormones Uptake ↓ , kinetics ↑ dose ↓↓ May be necessary in the event of focal autonomy. In the event of thyroid cancer therapy may not be possible.

[131I]mIBG

Calcium channel blockers Uptake ↓ , dose ↓

Tricyclic antidepressants Uptake ↓ , dose ↓

Sympatheticomimetics Uptake ↓ , dose ↓

Reserpine Uptake ↓ , dose ↓

Labeltalol Uptake ↓ , dose ↓

Nifedipine Uptake ↑ , dose ↑ (Blake et al. 1988)

‘Cold’ (carrier) mIBG Uptake ↑ , dose ↑ (Taal et al. 2000)

Iodide Desired in the thyroid, salivary gland, stomach and bowel uptake ↓ , dose ↓

Sodium perchlorate Desired in the thyroid, salivary gland, stomach and bowel uptake ↓ , dose ↓ Combination Effects of Radiotherapy / Drug Treatments for Cancer 70

Therapy/ Target Non-target disturbance variable

Somatostatin receptor The literature is unclear. Amino acid infusion, dose ↓ therapy In any event it should be assumed kidney (DOTATOC/DOTATE) that a response to an anti-tumour therapy is associated with a reduction in the therapy dose.

SIRT of liver NPL Effect of signal transduction Insufficient information on effect of inhibitors such as sorafenib on signal transduction inhibitors such tumour vascularisation and hence as sorafenib on normal tissue on dose distribution is unclear. tolerances (liver, lungs, Modulation of tumour gastrointestinal organs); there is a radiosensitivity not finally clarified. real risk of serious complications. Timing of optimum administration (before/during/after SIRT) not sufficiently studied.

Combination Effects of Radiotherapy / Drug Treatments for Cancer 71

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Abbreviations

5-FU 5-fluorouracil

AC therapy anthracycline/cyclophosphamide therapy

ADR adverse drug reaction

ALL acute lymphoblastic leukaemia

AML acute myeloid leukaemia

ASCO American Society of Clinical Oncology

BCNU bis-chlorethyl nitrosourea

BER base excision repair

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (German Federal Institute for Drugs and Medical Devices)

BMT (autologous) bone marrow transplant

CAF cyclophosphamide, adriamycin and 5-fluorouracil

CCNU chlorethyl-cyclohexyl-nitrosourea

CHMP Committee for Medicinal Products for Human Use of the EMA

CHOP cyclophosphamide, doxorubicin, vincristine and prednisolone

CLL chronic lymphocytic leukaemia

CMF cyclophosphamide, methotrexate and 5-fluorouracil

CML chronic myeloid leukaemia

DFSP dermatofibrosarcoma protuberans

EANM European Association of Nuclear Medicine

EBC early breast cancer

EGF epidermal growth factor

EGFR epidermal growth factor receptor

EGFR-TK epidermal growth factor receptor tyrosine kinase

EMA European Medicines Agency

EPAR European Public Assessment Report Combination Effects of Radiotherapy / Drug Treatments for Cancer 105

FIGO International Federation of Gynecology and Obstetrics

G-CSF granulocyte colony-stimulating factor

GIST gastrointestinal stromal tumour

HCC hepatocellular carcinoma

HES hypereosinophilic syndrome

HR homologous recombination

HSCT haematopoietic stem cell transplantation

K-GF keratinocyte growth factor

MBC metastatic breast cancer

Mesna 2-mercaptoethane sulfonate Na

MGC metastatic gastric cancer

MRCC metastatic renal-cell carcinoma

NET neuroendocrine tumour

NSCLC non-small-cell lung cancer

PARP poly(ADP-ribose) polymerase

PBSC peripheral blood stem cells

PDGF platelet-derived growth factor

PEI Paul Ehrlich Institute

pNeT pancreatic neuroendocrine tumour

RCC renal cell carcinoma

recall later occurrence of a reaction when treatment is administered in a second phenomenon modality

RMP risk management plan

RT radiotherapy

SCLC small-cell lung cancer

SEGA subependymal giant cell astrocytoma

SIRT selective internal radiation therapy Combination Effects of Radiotherapy / Drug Treatments for Cancer 106

SPC summary of product characteristics

TBI total body irradiation

TSC tuberous sclerosis

TSH thyroid-stimulating hormone

TUR transurethral resection of the prostate

VEGF vascular endothelial growth factor

Combination Effects of Radiotherapy / Drug Treatments for Cancer 107

Annex A Tables – Interaction potential of drug treatments for cancer and radiation

Table A1: Low interaction potential Substance class Substance Comments Angiogenesis inhibitor Thalidomide No evidence of interaction in authorised indications. Cytostatic Cisplatin Very well studied in concurrent and sequential use in all areas of the body in a large number of studies. In the doses evaluated in the studies there was only a slight increase in the toxicity of the radiotherapy. Increased interaction potential when radiation is applied to the kidneys and the inner ear, even if use is sequential. Cytostatic Carboplatin Very well studied in concurrent and sequential use in all areas of the body in a large number of studies. In the doses evaluated in the studies, only a slight increase in the toxicity of the radiotherapy. Cytostatic Oxaliplatin Well studied in concurrent and sequential use in a number of studies of rectal cancer. In the doses evaluated in the studies, only a moderate increase in the toxicity of the radiotherapy. Cytostatic Lomustine (CCNU) Concurrent use in brain tumours has been well Carmustine (BCNU) studied with no evidence of significantly increased toxicity of radiotherapy. In sequential use in Hodgkin’s disease there is no evidence of relevant interactions. Cytostatic Procarbazine Sequential use in Hodgkin’s disease has been Dacarbazine well studied with no evidence of interactions. When used concurrently with irradiation of brain tumours, no increased toxicity was found. Cytostatic Busulfan In combination with palliative irradiation of bone Melphalan foci in concurrent and sequential use for haematological disorders involving 20–40 Gy conventionally fractionated, no increased toxicity observed. Caveat: Increased pneumonitis rate in high- dose chemotherapy with irradiation in the area of the lungs, including when used sequentially. Isolated reports of paraplegia in connection with high-dose chemotherapy in cases of subsequent or preceding irradiation of affected vertebrae. Cytostatic Bendamustine Sequential use in non-Hodgkin’s lymphoma has been studied with no evidence of interaction. Cytostatic Chlorambucil Sequential use in Hodgkin’s disease and non- Hodgkin’s lymphoma has been well studied with no evidence of significant interaction. Combination Effects of Radiotherapy / Drug Treatments for Cancer 108

Substance class Substance Comments Cytostatic Cyclophosphamide Sequential and concurrent use in breast cancer Ifosfamide and soft tissue sarcoma well studied with no Trofosfamide evidence of significant interaction. According to pre-clinical data there could be an increased risk of pneumonitis when large lung volumes are irradiated. Caveat in connection with concurrent irradiation of the urinary tract where there is known toxicity of ifosfamide and cyclophosphamide in this area. Cytostatic Thiotepa The limited clinical data on sequential use showed no evidence of a strong interaction. Studied in small series in connection with conditioning before bone marrow transplant. Toxicity in this indication similar to that for melphalan and busulfan. Cytostatic Temozolomide Well studied in concurrent and sequential use for brain tumours with no evidence of interaction. No valid clinical data for other tumour localisations. Cytostatic Mitomycin C Well studied in concurrent use in all areas of the body in a large number of studies. In the doses evaluated in the studies there was only a slight increase in the toxicity of the radiotherapy. Pre-clinical data and some clinical observations indicate a potentially increased risk of pneumonitis and lung fibrosis when there is high-dose irradiation of large lung volumes.

Table A2: Moderate interaction potential Substance class Substance Comments Taxanes Paclitaxel Established in neoadjuvant radiochemotherapy Docetaxel for oesophageal cancer. Concurrent use also Cabizitaxel justified in principle outside this indication. But: increased rates of pneumonitis and fibrosis when used concurrently with irradiation in the lung area. Recall pneumonitis when taxanes are used after the end of radiotherapy. Increased rate of grade III acute dermatitis with concurrent therapy. For radiochemotherapy to the head and neck area, a high rate of severe infections and haematological toxicity was reported.

Combination Effects of Radiotherapy / Drug Treatments for Cancer 109

Table A3: High interaction potential Substance class Substance Comments PARP inhibitor Olaparib According to pre-clinical studies, significant interaction with radiotherapy is to be expected. No clinical data yet published. PARP inhibitor On the basis of the effect mechanism, a BSI-201 significant interaction with radiotherapy is to be expected. No pre-clinical or clinical data on the interaction has yet been published. Tyrosine kinase inhibitor To date only case reports and small case series Erlotinib or early clinical trials. Interactions (up to and Tyrosine kinase inhibitor Gefitinib including lethal toxicities) seem to occur mainly Tyrosine kinase inhibitor Lapatinib gastrointestinally and possibly in blood vessels (haemorrhage); the frequency is unclear. Tyrosine kinase inhibitor Sunitinib Small trials and case reports. Mucous Tyrosine kinase inhibitor Sorafenib membrane toxicity up to and including perforations and fistula formation especially with irradiation in the gastrointestinal area, possibly also mediastinally; dose-limiting thrombocytopenia and lymphocytopenia for simultaneous radiotherapy (40 Gy) and sunitinib where parts of the liver were also exposed to radiation in a prospective phase I study. Cerebral bleeding with sunitinib/sorafenib – it is unclear whether this might be exacerbated by radiation. mTOR inhibitor Temsirolimus As yet very little data. However, what data there mTOR inhibitor Everolimus is shows noticeable bone marrow toxicity when combined with radiation, including in sequential use. For patients who had undergone prior irradiation of the pelvis, it was not possible to establish a purposeful dose regimen in a phase I trial on account of haemotoxicity. Pre-clinical data indicate risk of thrombosis. In addition, as with angiogenesis inhibitors, impaired wound healing and a risk of bleeding must be expected. Anthracycline e. g. Epirubicin Increased cardiac toxicity for mediastinal Doxorubicin radiotherapy, including when used sequentially. Mitoxantrone Increased liver toxicity for gastrointestinal radiation (also described as recall phenomenon, up to and including lethal outcome), increased haemotoxicity. Antimetabolite Methotrexate Increased neurotoxic effect of radiotherapy.

Antimetabolite Gemcitabine Combination Effects of Radiotherapy / Drug Treatments for Cancer 110

Substance class Substance Comments Antimetabolite 5-Fluorouracil, Xeloda Simultaneous radiochemotherapy has been established in a number of curative protocols, e. g. for gastrointestinal squamous cell carcinoma or adenocarcinoma, through randomised trials and is used for such indications in the clinical routine in accordance with applicable guidelines. However, for non-curative indications or non- established protocols, the high potential for interaction should be taken into account when making the treatment decision: Increase in the mucous membrane toxicity and bone marrow toxicity of radiotherapy; depending on the irradiated volume, these toxicities can be so severe as to be life-threatening. Because of the radiosensitising effect of gemcitabine, the clinical data sheet recommends that treatment with the drug is not commenced until the acute effects of radiotherapy have resolved or at least one week has passed since radiation. Antibody Bevacizumab Extremely severe side effects (fistulae and VEGF Trap haemorrhage) in the thoracic area described in combination with radiation. Severe wound healing complications described in the abdominal area, especially if treatment is administered soon after surgery. Less problematic when used in combination in the CNS area. Overall very critical use. Antibody Cetuximab When used concurrently with radiotherapy to the EGF-R head and neck, some significantly increased skin reactions reported (necrosis). When used concurrently with radiotherapy to the thorax, no problems of this sort reported. Approved for use in combination in the head and neck area; however, patients, must be closely monitored for cutaneous side effects. Combination Effects of Radiotherapy / Drug Treatments for Cancer 111

Table A4: Unknown interaction potential Substance class Substance Comments Angiogenesis inhibitor Lenalidomide Despite the probably frequent use of palliative irradiation of bone foci in multiple myeloma during ongoing therapy with lenalidomide, no reports of enhanced side effects in combination with radiotherapy have been published. Tyrosine kinase inhibitor Imatinib Pre-clinical data and the very limited clinical experience provide no indication of high interaction potential with radiotherapy. Cytostatic Treosulfan No valid clinical data on interaction with radiotherapy available. Pre-clinical data shows increased gastrointestinal toxicity in combination with total body irradiation. Combination Effects of Radiotherapy / Drug Treatments for Cancer 112

Annex B Structural recommendations

Establish a consortium of radiotherapy clinics for standardised, prospective recording of unwanted combination effects (KONSEUK network – KONsortialverbund aus Strahlenkliniken zur standardisierten, prospektiven Erfassung Unerwünschter Kombinationswirkungen). Attention is again drawn to the particular problems and high risk potential of interactions between ionising radiation and drug treatments for cancer:  Sequential use by different therapists  Comorbidities of individual patients enhance or mask interactions  This can lead to overreporting (observation of individual cases), but also to  Underreporting as a result of the insufficient experience of the doctor confronted with the complication and of small case series  Unintended combining as a result of changes that become necessary in the course of therapy. Radiation recall (the occurrence of a reaction at a later time when a second treatment modality is used) is particularly critical in this context. These points have not been and are unlikely to be investigated in prospective studies (see also the current discussion in Booth and Tannock 2013). Their significance is likely to increase with the intensification of many tumour therapies, growing multimodality and diversification, in particular of medical therapy (including immunotherapeutic drugs with a delayed or extended period of efficacy). A prospective study (cohort design) is needed to assess the real extent of the problem. To this end, it is recommended that a consortium of radiotherapy clinics with high patient volumes be established. These clinics would for two years prospectively document the treatment of all their cancer patients who receive radiotherapy for a period starting three months before radiotherapy and ending six months after radiotherapy. At the same time, they would standardise effects and side effects (e. g. CTC criteria). According to present practice and at a conservative estimate, around two-thirds of the patients would receive additional drug treatment for cancer during this period. If 8 to 10 clinics are recruited for a competence and documentation network, it should be possible to capture the data of 20,000 patients in two years. A large number of patients is required in order to arrive at valid statements, given the inevitable heterogeneity (indication, objective, tumour entity, radiation volume and intensity, type of adjunct therapy). To assist in this process, it is recommended that a central database be set up on the basis of a modified and extended ADT dataset and that appropriate evaluation methods are made available (big data mining). An R&D project should be put out to tender and project funding should be provided. As well as answering the project’s question regarding the extent of previously unrecorded interactions in everyday clinical practice, this will create a unique set of data relating to the reality of modern radiooncology treatment, which will underpin benefit/risk assessments. In addition, it will provide urgently needed preparatory work for the integration into clinical cancer recording of radiotherapy data, as far as possible from existing electronic patient files taking account of the German Radiation Protection Ordinance (StrlSchV), and for the creation of long- term registers.