Horizon Scanning Technology Summary Temozolomide

Horizon Scanning
Technology Summary
(Temodal) for
advanced metastatic
April 2007
This technology summary is based on
information available at the time of research
and a limited literature search. It is not intended
to be a definitive statement on the safety, efficacy or
effectiveness of the health technology covered
and should not be used for commercial purposes.
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Temozolomide (Temodal®) for advanced metastatic melanoma
Target group
Palliative treatment for patients with advanced (stage IV) metastatic melanoma.
Technology description
Temozolomide (TMZ, Temodal, Temodar, CCRG 81045) is an oral cytotoxic alkylating
agent which inhibits DNA replication in tumour cells, and is the lead in a class of
compounds called imidazotetrazines. It is an analogue of the standard chemotherapy
agent dacarbazine. Temozolomide is in phase III development for the palliative treatment
of advanced metastatic melanoma, using in trials an administration regime of 150 mg/m2
given orally once daily on days 1-7, 15-21 and 29-35 per six week cycle. It is already
approved for different types of brain cancer (including glioblastoma multiforme and
anaplastic astrocytoma) in Europe and North America.
Innovation and/or advantages
Advanced melanoma is currently incurable, and new palliative treatments that offer
improved tolerability and/or ease of use may be desirable. Temozolomide’s oral
formulation will enable out-patient treatment, and may offer significant quality of life
benefits over current options.
Schering-Plough Ltd.
Place of use
Home care e.g. home dialysis
Secondary care e.g. general, nonspecialist hospital
General public e.g. over the
Community or residential care e.g.
district nurses, physio
; Tertiary care e.g. highly specialist
services or hospital
Primary care e.g. used by GPs or
practice nurses
Emergency care e.g. paramedic
services, trauma care
Availability, launch or marketing dates, and licensing plans:
Temozolomide for stage IV metastatic melanoma is currently in clinical trials in Europe
and pre-registration in the USA.
NHS or Government priority area:
Cardiovascular disease
; Cancer
Older people
Long term neurological conditions
Public health
Mental health
Renal disease
Relevant guidance
NICE Cancer Service Guidance: improving outcomes for people with skin tumours
including melanoma, 2006.1
NICE Cancer Service Guidance: improving supportive and palliative care for adults
with cancer, 2004.2
Scottish Intercollegiate Guidelines Network (SIGN): National clinical guideline on
cutaneous melanoma, 20033 (updated 2004): commented that for stage IV disease,
temozolomide had equivalent efficacy and better central nervous system penetration
than dacarbazine.
April 2007
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British Association of Dermatologists and the Melanoma Study Group: UK
Guidelines for the management of cutaneous melanoma, 2002.4
Canadian clinical practice guideline (for the Program in Evidence-Based Care and
Cancer Care Ontario): temozolomide for the treatment of metastatic melanoma,
Clinical need and burden of disease
There were 7,363 new cases of malignant melanoma registered in England in 2004, and
1,622 deaths in England and Wales in 20056. The prognosis for patients with advanced
(stage IV) disease is extremely poor, with a median survival time of approximately 6-9
months,7 and a 5-year survival rate of around 5-6%.8,9 Experts estimated the potential UK
target group for temozolomide at 1,400-1,600 patients per year. The company estimates
an eligible patients population of around 1,700 patients per year in the UK.
Existing comparators and treatments
Single-agent chemotherapy with dacarbazine (DTIC), an alkylating agent
administered intravenously.
A 2007 Cochrane review10 found that cytotoxic alternatives to DTIC, including
temozolomide, cisplatin and carboplatin, vinca alkaloids, taxanes and nitrosoureas, had
not been shown to improve on standard chemotherapy with DTIC. Combination
chemotherapies had also failed to demonstrate any significant benefit, except for a small
increase in response rates.11 Chemoimmunotherapy (e.g. DTIC combined with
interleukin-2 or interferon) was not found to prolong survival compared to chemotherapy
alone, and a short-term increase in clinical response was associated with a higher rate of
serious adverse events.
Efficacy and safety
Trial name
Extended schedule, TMZ vs DTIC in
stage IV metastatic melanoma (EORTC
European Organisation for Research and
Treatment (EORTC), Schering-Plough
In progress - enrolment to be completed
in May 2007.
Phase III randomised open label study.
Phase III randomised open-label study.
Arm A: oral TMZ 200 mg/m2 per day
Arm A: oral TMZ 150 mg/m2 once daily
for 5 days every 28 days, repeated in the on days 1-7, 15-21, and 29-35.
absence of disease progression or
Treatment repeats every 42 days. Each 6
toxicity (n=156).
week period=1 cycle; 3 cycles over 4.5
Arm B: 30-minute intravenous infusion
of DTIC 250 mg/m2 once per day for 5
Arm B: DTIC 1,000 mg/m2
days every 21 days (n=149).
intravenously on day 1, and repeated
Up to 12 cycles of treatment (doses every 21 days (=1 cycle); up to 6 cycles
reduced in the event of grade 3 or 4 over 4.5 months.
Treatments A and B continue in the
absence of disease progression or
unacceptable toxicity.
Participants in N=305 patients with surgically incurable N=880 patients with advanced (stage IV)
April 2007
Temozolomide (TMZ) vs dacarbazine
(DTIC) in advanced metastatic
malignant melanoma (195-018)
Schering-Plough Ltd.
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or unresectable metastatic melanoma.
Until death.
Overall survival.
Progression-free survival (PFS), healthrelated quality of life (HQoL), response
rates, pharmacokinetics, safety and
Analysis by intention-to-treat.
Median PFS time was significantly
longer in the TMZ group (1.9 months)
than the DTIC group (1.5 months);
hazard ratio 1.37 (p=0.012, 95% CI
Median overall survival time. TMZ was
equivalent to DTIC: 7.7 months for the
TMZ group and 6.4 months for DTIC,
with a hazard ratio of 1.18 (95% CI
0.92-1.52; p=0.20).
Response rates to the 2 drugs were
similar: TMZ 13.5% versus DTIC
Quality of life. At 12 weeks, HQoL
scores favoured TMZ for physical and
global functioning (both at p<0.05).
Safety. No major difference was
observed, and both treatments were
malignant melanoma,
Until death.
Duration of survival.
Progression-free survival, objective
response in patients with measurable
disease, duration of response, safety and
Estimated cost and cost impact
The cost of treatment with temozolomide for this indication is not yet publicly known.
DTIC per 42 days (2 x 21 day cycles) costs £110.92, with additional intravenous
administration costs.
Potential or intended impact – speculative
; Reduced morbidity
Quicker or more accurate
; Reduced mortality or increased
Earlier identification of disease
; Improved quality of life for
patients and/or carers
Increased use e.g. length of stay,
Service reorganisation required
out-patient visits
; Decreased use: reduced out-patient treatment.
Staff or training required
; Increased unit cost compared to
Increased costs: capital
investment needed
New costs:
April 2007
Increased costs: more patients
coming for treatment
; Savings: oral formulation
(intended to replace current inpatient intravenous treatment)
National Horizon Scanning Centre
News on emerging technologies in healthcare
NICE Guidance on Cancer Services. Improving outcomes for people with skin tumours including melanoma,
the manual. National Collaborating Centre for cancer, February 2006.
NICE Guidance on Cancer Services. Improving supportive and palliative care for adults with cancer, March
Scottish Intercollegiate Guidelines Network (SIGN): Cutaneous melanoma – a national clinical guideline. No.
72, published July 2003, updated February 2004.
Roberts DLL, Anstey AV, Barlow RJ et al. On behalf of the British Association of Dermatologists and the
Melanoma Study Group. UK guildelines for the management of cutaneous melanoma. Br J Dermatol 2002;
146: 7-127.
Quirt I, Verma S, Petrella K, et al. Temozolomide for the treatment of metastatic melanoma: a clinical practice
guideline for the Program in Evidence-Based Care and Cancer Care Ontario, March 2006.
Office of National Statistics (ONS): 2004 incidence data and 2005 mortality data for ICD code C43. Available
at www.statistics.gov.uk/
Balch CM, Soong S-J, Gershenwald JE et al. Prognostic factors analysis of 17,600 melanoma patients:
validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19 (16):
Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in
the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1) 2000; 15:158-166.
Lee ML, Tomsu K & Von Eschen KB. Duration of survival for disseminated malignant melanoma: results of a
meta-analysis. Melanoma Research 2000; 10(1): 81-92.
Sasse AD, Sasse EC, Clark LG et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant
melanoma. Cochrane Database of Systematic Reviews 2007, Issue 1, Art No. CD005413. DOI
Huncharek M, Caubet JF & McGarry R. Single-agent DTIC versus combination therapy with or without
immunotherapy in metastatic melanoma: a meta-analysis of 3,273 patients from 20 randomised trials.
Melanoma Research. 2001; 11(1): 75-81.
The National Horizon Scanning Centre is a constituent of the NHS National
Institute for Health Research and is managed under contract from the
Department of Health's R&D Division.
The views expressed in NHSC publications are those of the author(s). They are not
necessarily shared by the Department of Health and should not be taken
as representing Government policy.
The National Horizon Scanning Centre,
Department of Public Health and Epidemiology
University of Birmingham, Edgbaston, Birmingham, B15 2TT, England
Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269
April 2007