Horizon Scanning Centre September 2013

Liposomal cisplatin (Lipoplatin) in combination with fluorouracil for head and neck cancer

SUMMARY NIHR HSC ID: 7480

Liposomal cisplatin is intended to be used in combination with fluorouracil as first and subsequent line therapy for the treatment of metastatic or relapsed squamous cell cancer of the head and neck. If licensed, it would provide an This briefing is additional treatment option for this patient group. Liposomal cisplatin is a new based on formulation of cisplatin that targets and fuses with human tumour cells information allowing for the specific delivery of the cytotoxic drug directly into cancer cells. available at the time

of research and a Approximately 85% of head and neck cancers occur in people over 50 years limited literature of age, although recent evidence suggests incidence is increasing amongst search. It is not younger people. Around 60% of patients present with locally advanced intended to be a disease and the majority of these develop local and/or regional recurrences. definitive statement The 5-year survival rate is 39% and 51% for men and women, respectively. on the safety, efficacy or Treatment options vary according to the specific site of the cancer. Currently effectiveness of the existing treatments do not have a major impact on the disease and most health technology patients are referred for palliative care. Liposomal cisplatin has completed covered and should two phase III clinical trials comparing its effect on haematotoxicity, not be used for nephrotoxicity and pharmacokinetics against treatment with cisplatin. commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Head and neck cancer: metastatic or relapsed; squamous cell - first and subsequent lines; in combination with fluorouracil (5-FU).

TECHNOLOGY

DESCRIPTION

Liposomal cisplatin (Lipoplatin) is a new formulation of cisplatin that targets and fuses with human tumour cells allowing for the specific delivery of the cytotoxic drug directly into cancer cells. This approach reduces the toxicity of cisplatin and helps evade the immune system. Liposomal cisplatin is intended to be used for the treatment of head and neck cancer and in clinical trials was administered by 4 hour intravenous (IV) infusion at 100mg/m2 on days 1, 8 and 15 of a 21 day cycle, in combination with 5-FU administered by continuous infusion at 1,000mg/m2 on days 1-5 of a 21 day cycle1.

Liposomal cisplatin is in phase III clinical trials for non-small cell lung cancer, ovarian cancer and pancreatic cancer, and in phase II trials for bladder cancer and gastric cancer.

INNOVATION and/or ADVANTAGES

If licensed, cisplatin liposomal will provide an additional treatment option for this patient group.

DEVELOPER

Regulon.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Head and neck cancer can occur in over 30 specific sites, and whilst incidence is low for individual sites, collectively they pose a large healthcare burden2. Most head and neck cancers arise from the surface layers of the upper aerodigestive tract, incorporating the lips, mouth (oral cavity), tonsils and throat (nasopharynx, oropharynx, larynx and pharynx)2. Other less common sites include the salivary glands, jaw, eye, paranasal sinuses and middle ear2. Over 90% of head and neck cancers are squamous cell carcinomas originating in the epithelial layer of the oral cavity, pharynx and larynx3,4,5. Epidermal growth factor receptor (EGFR) is overexpressed in approximately 80% of head and neck squamous cell carcinomas (HNSCCs) and is associated with poor survival6. The major risk factors for HNSCC include tobacco smoking and alcohol consumption, and the role of the human papillomavirus (HPV) is increasingly recognised as a risk factor7.

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NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: Improving Outcomes: A Strategy for Cancer (2011).

CLINICAL NEED and BURDEN OF DISEASE

The incidence of head and neck cancer is estimated to be 0.022% and 0.009% for males and females respectively, equating to approximately 8,000 cases in England each year8. Incidence increases with age, with around 85% of head and neck cancers occurring in people over 50 years of age9. However, evidence suggests the incidence of head and neck cancers is increasing amongst younger people of both sexes9 and this may be related to the rising incidence of HPV infection in this population10. Approximately 60% of patients present with locally advanced disease at diagnosis and the majority of these develop local and/or regional recurrences, with approximately 20-30% developing distant metastases11. Head and neck cancer is more common in men than women12 and 5-year survival is higher in women (51%) than men (39%)4. In 2011-12, there were 31,762 hospital admissions for head and neck cancer in England (ICD10 C00-C14; C30-C32; C73), accounting for 34,462 finished consultant episodes and 136,889 bed days and in 2010, 3,781 deaths were registered in England and Wales13.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance • NICE technology appraisal. Cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck (TA172). June 200914. • NICE technology appraisal. Cetuximab for the treatment of locally advanced squamous cell cancer of the head and neck (TA145). June 200815. • NICE cancer service guidance. Head and neck (CSGHN). November 200416.

Other Guidance • European Society for Medical Oncology. Nasopharyngeal cancer: EHNS-ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. 201217. • ENT UK. Head and Neck Cancer: multidisciplinary management guidelines. 20117. • European Society for Medical Oncology. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. 20104. • American Society of Clinical Oncology. Clinical practice guideline for the use of larynx- preservation strategies in the treatment of laryngeal cancer. 200618. • Scottish Intercollegiate Guidelines Network. Diagnosis and management of head and neck cancer (90). 20069. • NHS Clinical Knowledge Summary. Head/neck cancer – suspected. 200519.

EXISTING COMPARATORS and TREATMENTS

Treatment options vary according to the specific site of the HNSCC. Smoking and alcohol cessation interventions can help in treatment and overall outcome but may not have an effect on established tumours10. Treatment options for HNSCC are summarised below4,5,7,9,10,14,15,19,20:

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Primary treatment options may include: • Surgery – may be used in cases where the tumour is sufficiently localised to permit complete resection. Restorative surgery and/or dentistry may be required in some cases. • Radiotherapy – either alone or as adjunct to surgery. • Chemotherapy – (e.g. methotrexate, docetaxel, cisplatin or carboplatin and 5-FU) to enhance the effect of radiotherapy, or as neoadjunctive chemotherapy.

Treatment options for locally advanced disease may include: • Surgery – in combination with chemoradiation. • Biological therapies – cetuximab may be used in combination with radiotherapy for patients with locally advanced squamous cell carcinoma of the head and neck whose Karnofsky performance is 90% or greater and for whom all forms of platinum-based chemoradiotherapy are contraindicated. • Re-irradiation. • Photodynamic therapy (PDT) with tempoporfin.

Treatment options in recurrent or metastatic disease may include: • Salvage surgery. • Palliative chemo- or radiotherapy

EFFICACY and SAFETY

Trial Liposomal cisplatin vs cisplatin, both in combination with 5-FU; phase III. Sponsor Regulon. Status Ongoing. Source of Publication1, abstract21,22. information Location Germany. Design Randomised, active-controlled. Participants n=250 (planned); aged 18-75 years; HNSCC; primary metastatic or relapsed/progressive disease.

Schedule Randomised to liposomal cisplatin, 100mg/m2, 4 hour continuous infusion on days 1, 8 and 15; or cisplatin, 100mg/m2; both in combination with 5-FU, 1,000mg/m2, continuous infusion days 1-5; both arms every 21 days for 6 cycles.

Follow-up Active treatment period up to 18 weeks;

Primary Haematotoxicity; nephrotoxicity. outcome/s Secondary Not reported. outcome/s Key results Interim results for n=46, for liposomal cisplatin and cisplatin respectively (%): progressive disease, 24.0, 14.3; stable disease, 64.0, 50.0; partial remission, 19.0, 38.8. Adverse For liposomal cisplatin and cisplatin respectively (%): grade IV leukopenia, 0.0, 22.2; effects (AEs) grade III anaemia, 16.0, 9.5; grade I and II neuropathy, 27.0, 67.0; neuropathy, 4.0 (grade IV), 19.0 (grade III); grade III or IV mucositis, 8.0, 33.3; grade II renal toxicity, 40.0, 28.6; grade III renal toxicity, 0.0, 23.8.

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ESTIMATED COST and IMPACT

COST

The cost of liposomal cisplatin is not yet known. Cetuximab administered at 250mg/m2 IV once weekly costs £890.50 for a 28 day course23,a.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services: reduced infusion time

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identified: Not clear whether comparator represents current UK practice, docetaxel is frequently used in patients with a good performance status.

REFERENCES

1 Jehn CF, Boulikas T, Kourvetaris A et al. First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). Anticancer Research 2008;28:3961-3964. 2 National Institute for Health and Clinical Excellence. Improving outcomes in head and neck cancers – the manual. London: NICE; November 2004. 3 Macmillan Cancer Support. Head and neck cancers. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Headneck/Aboutheadneckcancers/ Headneckcancers.aspx Accessed 20 August 2013. 4 Grégoire V, Lefebvre JL, Licitra L et al. Squamous cell carcinoma of the head and neck: EHNS- ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(5):v184-v186. 5 National Institute for Health and Clinical Excellence. Costing statement: Cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck. London: NICE; June 2009.

a Based on an average body surface area of 1.88m2.

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6 Temam S, Kawaguchi H, El-Naggar AK et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. Journal of the American Society of Clinical Oncology 2007; 25(16):2164-2170. 7 Roland NJ, Paleri V (eds). Head and Neck Cancer: multidisciplinary management guidelines. 4th edition. London: ENT UK; 2011 8 National Institute for Health and Clinical Excellence. Cetuximab for the treatment of locally advanced squamouse cell cancer of the head and neck. Costing template and report. NICE; London: June 2008. 9 Scottish Intercollegiate Guidelines Network. Diagnosis and management of head and neck cancer. National clinical guideline 90. Edinburgh: SIGN; October 2006. 10 National Institute for Health Research Horizon Scanning Centre. Afatinib for locally advanced, recurrent or metastatic head and neck squamous cell carcinoma – second line. March 2013. www.hsc.nihr.ac.uk 11 Vermorken JB and Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Annals of Oncology 2010; 21(7): vii252–vii261. 12 Macmillan Cancer Care. Risk factors and causes of head and neck cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Headneck/Aboutheadneckcancers/ Causes.aspx Accessed 22 August 2013. 13 Office for National Statistics. Mortality statistics: deaths registered in England and Wales (series DR), 2010. www.ons.gov.uk 14 National Institute for Health and Clinical Excellence. Cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck. Technology appraisal TA172. NICE; London: June 2009. 15 National Institute for Health and Clinical Excellence. Cetuximab for the treatment of locally advanced squamous cell cancer of the head and neck. Technology appraisal TA145. NICE; London: August 2008. 16 National Institute for Health and Clinical Excellence. Improving outcomes in head and neck cancers – the manual. Cancer service guidance CSGHN. NICE; London: November 2004. 17 Chan ATC, Gregoire V, Lefebvre JL et al. Nasopharyngeal cancer: EHNS-ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(7):vii83- vii85. 18 Pfister DG, Laurie SA, Weinstein GS et al. ASCO: clinical practice guideline for the use of larynx- preservation strategies in the treatment of laryngeal cancer. Journal of Clinical Oncology 2006;24(22):3693-3704. 19 NHS Clinical Knowledge Summaries. Head/neck cancer – suspected. http://cks.nice.org.uk/headneck-cancer-suspected#!topicsummary Accessed 22 August 2013. 20 Tan IB, Dolivet G, Ceruse P et al. Temoporfin-mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicentre study. Head and Neck. 2010;2(12):1597. 21 Jehn CF, Boulikas T, Kourvetaris A et al. Pharmacokinetics of liposomal cisplatin (lipoplatin) in combination with 5-FU in patients with advanced head and neck cancer: first results of a phase III study. Anticancer Research 2007;27(1A):471-475. 22 Jehn CF, Siebmann G, Pecher K et al. First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). Journal of Clinical Oncology 2007;25(18S):6040. 23 British Medical Association and Royal Pharmaceutical Soceity of Great Britain. British National Formulary. BNF 65. London: BMJ Group and RPS Publishing, March 2013.

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