Guideline 72: Cutaneous melanoma

Cutaneous melanoma
Section 8: Management of stage IV disease

The outlook for patients with distant and visceral metastatic melanoma is poor with survival time ranging from six to nine months. Survival appears to be increased in women and in those patients who have undergone surgery for metastases.²⁰⁶ Poorer survival is associated with initial metastases to the skin and brain; poor Karnovsky status; involvement of more than two primary sites;²⁰⁶ short durations of remission; visceral compared to non-visceral metastases;²⁰⁷ an ECOG status of one or less, and metastases to the lungs, gastrointestinal tract or liver.²⁰⁸ Evidence level 3

8.1 Surgery

Metastasectomy may be an option for patients with distant skin, node and visceral metastases. In subcutaneous metastases prevention of ulceration of superficial lesions is best ensured by resection when they are at a size where skin closure is possible. Surgery of single or localised metastases has been shown to improve survival.²⁰⁸ The proportion of patients suitable for metastasectomy ranges from 10 to 25%.^{206,
209, 210} Five year survival of 14-33% was described in one retrospective review for those with distant subcutaneous and lung metastases respectively. This study showed prognostic significance for Breslow thickness, number of metastases and prior disease-free interval. ²⁰⁶

Metastasectomy should be considered in patients with stage IV disease.

8.2 Chemotherapy, chemoimmunotherapy and immunotherapy

No RCTs were identified comparing systemic therapy with placebo or best-supportive care in metastatic cutaneous melanoma.²¹¹ The most commonly used agent is DTIC (dacarbazine), a single agent with an overall response rate activity of approximately 20%.²¹¹

8.2.1 SINGLE AGENT OR COMBINATION THERAPY

A meta-analysis comparing the ‘gold standard’ DTIC with combination chemotherapy, with or without immunotherapy, found a response rate to treatment of 16.9% for single agent DTIC; no statistically significant benefit for multiple drug regimens with or without DTIC compared to single agent DTIC was identified.²¹² Interferon a (IFN) combined with DTIC produced a 53% greater response rate than DTIC alone though there was no increase in survival. Evidence level 1++

One of the most popular combination regimens, the Dartmouth regimen (DTIC, cisplatin, carmustine and tamoxifen), was compared with single agent DTIC in a randomized Phase III study.²¹³ There was more toxicity with the combination regimen in that 21% versus 2% were taken off treatment due to unacceptable side effects. The response rate was higher with the combination therapy (18.5% versus 10.2%) but there were no complete responses and no survival difference between the two treatments. Evidence level 1++

The oral preparation of DTIC, temozolamide, has been shown to have equivalent efficacy and better CNS penetration.²¹⁴

Tamoxifen

Most published studies are Phase II non-randomised studies incorporating fewer than fifty patients. One review of seven Phase II and nine RCTs concluded that tamoxifen does not improve patient outcome.²¹⁵ Two RCTs published since the review also conclude against any benefit for addition of tamoxifen.^{216,
217} Evidence level 1+

Interferon alpha

An overview of trials including six published and five unpublished melanoma trials of 1,164 patients evaluated regimens with or without IFN.²¹⁸ The overall response rates for IFN containing regimens was 24% compared with 17% without IFN. Analysis of five trials where the survival data were reported demonstrated a pooled odds ratio for improved survival of 0.69 but heterogeneity of patient groups may have led to the non-significant result.²¹⁸ Evidence level 1+

Multiple drug regimens and DTIC-based chemoimmunotherapy combinations increase response rates but improved rates do not correlate with better survival. Evidence level 1+

Interleukin 2

Interleukin 2 (IL2) has been given intravenously or subcutaneously as a single agent or in combination with IFN and chemotherapy. Although durable responses are occasionally seen, the data do not support its routine use outwith a clinical trial.²¹⁹

Dacarbazine (DTIC) is the standard single agent of choice in stage IV melanoma.

Multiple drug regimens including those with tamoxifen and interferon a do not improve survival compared to single agent DTIC and are not recommended outside of clinical trials.

Patients should be evaluated before every cycle of chemotherapy and treatment discontinued if there is poor tolerance or lack of benefit after three cycles.

Patients with metastatic melanoma should be treated within a clinical trial wherever possible and be offered palliative care.

8.3 Radiotherapy

8.3.1 RADIOSENSITIVITY

There is evidence that melanoma cells in vitro have a spectrum of radiosensitivity and that melanoma should not be considered a uniformly radioresistant disease.²²⁰ Experimental studies have suggested that atypical, large radiotherapy fraction sizes may be more efficacious than standard treatments but at present there are no randomised trials to support the use of large fraction sizes routinely.^{220,
221}Evidence level 4,3

8.3.2 BONE METASTASES

Studies looking at the treatment of bone metastases usually include only a small percentage of patients with melanoma. Recommendations have been extrapolated from the data available from studies of bone metastases from various tumour types. When using single fractions to palliate pain from bone metastases, an 8 Gy fraction is effective and provides superior pain relief to lower doses.²²² There does not appear to be an advantage to using 20 Gy in four fractions over an 8 Gy single fraction.²²³ Some patients may benefit from higher dose, fractionated regimens, although this has not been fully established.²²⁴ Evidence level 2+,2++,4

Single dose radiotherapy of a least 8 Gy is an effective treatment for bone metastases.

All patients with painful bone metastases should be offered radiotherapy.

8.3.3 SPINAL CORD COMPRESSION

There is no clear evidence to support or refute the use of radiotherapy (in combination with other treatments) to alleviate the pain and neurological deficit associated with spinal cord compression caused by metastatic melanoma.^{225,
226} Evidence level 3,4

The value of surgical intervention in such patients has been established.²²⁶ Patients with symptoms of spinal cord compression should be referred urgently to an appropriate surgeon.²²⁷ Evidence level 3,4

All patients with spinal cord compression should be referred urgently for surgical intervention and/or palliative radiotherapy.

8.3.4 BRAIN METASTASES

Although central nervous system (CNS) involvement by melanoma is a common finding at autopsy, brain metastases are diagnosed in only approximately 10% of patients before death.²²⁸ For cerebral metastases from all tumour types, good performance status, favourable response to corticosteroid treatment, and the absence of systemic disease are statistically significant predictive factors for a better survival.²²⁹ Evidence level 4,2+

Postoperative radiotherapy has been used as adjuvant treatment following the resection of CNS disease. However, no survival benefit of postoperative radiotherapy has been demonstrated.^{230,
228} Radiotherapy without surgery, combined with corticosteroids appears to palliate the symptoms of some patients with inoperable cerebral metastases from melanoma but again there is no evidence of a survival benefit.^{220,
230, 231} Radiosurgery (stereotactic radiotherapy) has been used to treat inoperable patients who are fit enough to undergo this procedure, and the results may be equivalent to radiotherapy alone.²³² Radiosurgery remains an experimental technique in the treatment of this disease. Evidence level 3

Patients with good performance status, favourable response to corticosteroid treatment, the absence of systemic disease and who harbour favourable CNS disease should be considered for surgical resection of their CNS disease.

If surgery is not possible, whole brain radiotherapy combined with corticosteroids may help palliate neurological symptoms.

8.4 Specialist palliative care

The General Medical Council has stated that basic palliative care skills are required by every member of the medical profession.²³³ The Clinical Standards Board for Scotland (CSBS) has agreed standards for the provision of both basic and specialist palliative care.²³⁴ Specialist palliative care is an integral component of the care of patients with advanced malignancy, required at varying times during their illness. SIGN guideline no. 44 (Control of pain in patients with cancer) covers the evidence base for pain control in all cancers.²³⁵

Patients who develop metastatic melanoma require input from a number of agencies both within and outwith the health service. They may need rehabilitative, functional, social and/or financial support services, most of which are available in specialist palliative care settings, as well as in primary care and cancer centres. The evaluation of the effectiveness of specialist palliative care involves assessment of the different dimensions of care provided, such as pain and other symptom control, psychological care, care of the family and carers, rehabilitation and terminal care.

Three RCTs were identified that included all carcinomas, which, in the context of palliative care, are reasonable to relate to patients with melanoma.^{236,
237, 238} The first two studies looked at the effect of coordinating all services available within the NHS, local authorities and the voluntary sector via the addition of nurse coordinators. A total of 203 cancer patients expected to live for less than one year were randomly assigned to either the intervention or the routine services group. Patients assigned to the intervention group spent fewer days in hospital, required fewer home visits and their family were less likely to feel angry about their relative’s death.^{236,
237} The third RCT used place of death as the outcome measure in a study of 434 patients with incurable malignant disease.²³⁸ The intervention group had inpatient and outpatient hospital services provided by the palliative medicine unit, the unit served as a link to community services, predefined guidelines maintained communication between services and community staff took part in an educational programme. Significantly more intervention group patients died at home and spent less time in nursing homes in their last months of life. Evidence level 1+

A systematic review of the effectiveness of specialist palliative care teams identified 18 studies, including five randomised controlled trials. Specialist palliative care teams were associated with more time spent at home by patients, satisfaction of patients and their carers, symptom control, a reduction in the number of inpatient hospital days, a reduction in overall cost, and with the patient dying where they wished. Evidence level 1+

Patients with advanced melanoma require a coordinated multiprofessional approach with input from a specialist palliative care team.

Patients with poorly controlled symptoms should be referred to specialist palliative care at any point in the cancer journey.