Strahlenschutzkommission Geschäftsstelle der Strahlenschutzkommission Postfach 12 06 29 D-53048 Bonn http://www.ssk.de + 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