Westmead Institute for Cancer Research
University of Sydney at Westmead Millennium Institute
Westmead Hospital, NSW
Despite major advances in the treatment of many solid tumours, metastatic melanoma remains stubbornly resistant to therapeutic attack with systemic agents. Much of the resistance of melanoma to immunotherapy and cytotoxic treatment is due to an impressive array of molecular defences that derive ultimately from the essential molecular structure of the melanocyte and its biological requirement for defence against apoptosis. Patients with metastatic disease should be cared for by a multidisciplinary team with a coordinating clinical nurse consultant playing a central role. In selected patients observation remains the best initial management. All eligible patients should be entered on clinical trials of new treatments. Standard systemic therapy consists of chemotherapy with dacarbazine, but response rates are less than 10% in recent Phase III trials. The Ras-RAF signalling pathways are commonly constitutively activated in melanoma and newly tested inhibitors of these, like sorefenib, may sensitise melanoma cells to cytotoxic attack. Considerable hope is also provided by recent Phase II trials with immunotoxins. These provide novel opportunities for targeted therapy in the treatment of melanoma.
Despite continuous research endeavours in chemotherapy, immunotherapy and biological therapy, there is no cure for disseminated melanoma and only rarely do systemic treatments appear to modify the natural history of the disease. Advanced melanoma is a tumour with a vast number of genetic alterations, conferring cellular proliferative advantages, coupled with resistance to apoptosis and apoptosis-inducing agents like chemotherapy and radiotherapy.1
Against this background of relative therapeutic impotence, the management of patients with metastatic melanoma presents a special set of challenges which are best met through the type of multidisciplinary approach pioneered at Sydney Melanoma Unit by Gerald Milton and William McCarthy. Central to this is the timely intervention with surgery and radiation therapy, even in patients with substantial metastatic burden, the early involvement of palliative care expertise and the coordination of care by a clinical nurse consultant.
Melanoma is notoriously variable in its pattern of spread. In selected patients the disease has a propensity to remain confined to loco-regional lymphatics for extended periods and some such patients have achieved long-term remissions even after hind-quarter amputation.2 In others, haematogenous dissemination occurs early and widely. In certain patients, years may pass between the primary presentation and the development of metastases. Certain patients may display serial presentations, each with relatively isolated metastases, remaining in clinical remission for many years between episodes of local (usually surgical) treatment of these exacerbations. Others will suddenly develop fulminant disease in many organs simultaneously with a very rapid demise. In some patients, the disease displays particular affinity for a particular organ or organs. Thus, certain individuals may develop extensive pulmonary involvement without ever developing liver metastases. Others will succumb to cerebral metastases without any extra-cranial disease. This wide spectrum of variability confounds the ability to make accurate prognosis. However, some broad guidelines may be drawn from statistical analyses of large numbers of patients who have died from metastatic melanoma.
The most common initial sites of metastasis are skin, subcutis, distant lymph nodes, lung, liver, bone, small intestine and brain.3 Approximately 4% of patients present with widespread metastases as the initial manifestation of metastatic disease.4 In a recent revision of the AJCC Staging System for Melanoma,5 Stage IV melanoma has been subdivided into three prognostic groups. The M1 category includes those patients with lymph node and/or subcutaneous metastases and has a median survival of >12 months and a two year survival of 15-20%. The M2 category has pulmonary metastases +/- subcutaneous or lymph node involvement and has a median survival of 9-12 months and a two year survival of 10%. The M3 category has other visceral involvement or any site with an elevated LDH. M3 patients have a median survival of four-six months and a two year survival of 5%.
Melanoma is associated with a wide range of paraneoplastic phenomena. The majority of these occur in the context of established metastatic disease. Many are presumed to be the result of cross-reactivity between novel expressed melanoma cell surface antigens and normal cellular epitopes.
Some of the paraneoplastic clinical conditions that have been reported more commonly include retinopathy, melanosis and melanuria, hypercalcaemia, cachexia-pyrexia, vitiligo, dermatomyositis, Sjogren’s (sicca) syndrome, inflammatory neuropathy and marantic endocarditis.3
The entire history of the patient’s melanoma and its treatment should be carefully documented. The original histology should be reviewed as the prognostic features may influence the decision to biopsy metastatic disease. The occurrence of locoregional recurrence and the disease-free interval are relevant to the prognosis of metastatic disease and possibly to the likelihood of response to systemic therapy. Previous normal X-rays and scans may be useful in determining the pace of disease progression.
Careful emphasis should be placed on the patient’s current major problems and the symptomatology most urgently calling for relief. Those with poor performance status are most unlikely to benefit from systemic anti-tumour therapy.
Cerebral metastases are so common in patients with advanced melanoma that it is mandatory to enquire about symptoms of raised intra-cranial pressure. Co-morbities should be reviewed in the light of their impact on therapeutic intervention and a survey of regular medications performed to seek those, such as corticosteroids, that may interfere with systemic therapies with, for example, immunostimulants and cytokines.
Physical examination should include careful palpation of all lymph node sites and palpation of the entire skin surface with the palms of both hands seeking the presence of cutaneous or subcutaneous metastases. Special attention should be paid to the neurological system, including the fundi and exclusion of the early signs of spinal cord compression.
Investigations should only be performed if they are to contribute to clinical management.
The full blood count and blood film are simple and informative. Anaemia is common in melanoma and most commonly shows the features of acute or chronic blood loss, the site of which is usually the gastrointestinal tract. A normochromic normocytic picture may also occur in the presence of extensive metastatic disease, without blood loss or marrow involvement. Occasionally, a leukoerythroblastic blood film may indicate bone marrow replacement.
Serum biochemistry should include an assessment of the hepatic and renal function. The serum LDH, although non-specific, is an independent prognostic indicator in metastatic disease.6 The serum calcium should be routinely measured, particularly in patients with known extensive bone metastases.
Positron emission tomography (PET) scanning may be particularly useful if extensive surgery is contemplated for metastatic disease, but has minimal role outside this. Computerised tomographic (CT) scanning of the abdomen and pelvis is a simple staging manoeuvre. Head CTs should be reserved for those in whom cerebral metastases are clinically suspected or major extracranial metastasectomy planned. Magnetic resonance imaging (MRI) scanning is the most sensitive test for the presence of cerebral metastases and is routine prior to planned cerebral metastasectomy. MRI is also the investigation of choice in screening for spinal cord compression and leptomeningeal metastases. Bone scans should be performed in patients with relevant symptoms. Hot spots in long bones should be subjected to plain X-ray examination to determine the extent of cortical bone erosion, a determinant of the need for prophylactic orthopaedic intervention.
Frequently, the patient is a young adult, with the financial, career and family responsibilities and aspirations of mid-life, mid-career and parenthood to teenage children. The devastation of diagnosis is compounded by the gloomy predictions of prior medical attendants and whatever factual material might have been frantically retrieved from the internet.
The initial consultation therefore requires particular attention and skill. A carer or relative should be present. In Sydney Melanoma Unit it is customary for the oncologist to be accompanied by an oncology nurse specialist who will take a key role in follow-up and coordination of care that often involves multiple professionals and the general practitioner. A principal objective of the initial consultation is to establish an environment of confidence and trust.
Some useful concepts in sustaining patients at this time of devastating news are: the idea that the oncology medical and nursing team are joining forces with the patient in fighting a battle; the news that certain vital organs are spared on the CT scans; optimistic anecdotes referring to the successful outcome of the treatment of a similar patient in the past; the rapid rate of progress in medical research and the speed with which new treatments are being developed; the fact that the team of melanoma clinicians are experienced, expert and informed and that patients will immediately receive the benefit of advances in knowledge.
The explicit delineation of a plan of management will do much to allay the fears and anxieties of patients and carers. The importance of symptom control and the objective of rapid absolute relief of pain requires particular attention and time. An emphasis on symptom control and on early engagement of community nursing support will facilitate smooth transition to palliative care at a later stage of the illness.
The heterogeneous nature of melanoma and its patterns of spread and progression, together with the fact that no existing form of systemic treatment has been shown to prolong survival in prospective randomised controlled clinical trials,1 means that for certain patients observation may be the most humane and rational choice. Patients best suited to observation are those with relatively low bulk disease who are without symptoms, whose disease has a slow rate of progression, who do not yet display constitutional features of anorexia, weight loss and decline in performance status and whose temperament is suited to such a plan. Typically, metastatic disease has been detected in these patients by the performance of routine staging investigations. Such patients may be eligible for clinical trials of new anti-melanoma drugs and immunotherapy. Patients may be reassured on observation programs by the knowledge that there is no evidence that delay of initiation of chemotherapy for melanoma jeopardises response, providing that deterioration in weight and performance status have not intervened. Supportive programs of counselling, diet and exercise may be useful adjuvants in maintaining morale in this group of patients.
Surgery and radiotherapy play a major role in the management of metastatic melanoma and are covered elsewhere in this issue of Cancer Forum.
Where possible, patients with metastatic melanoma should be entered on clinical trials. Given recent advances in the rational design of agents which may overcome inherent defences in the melanoma cells against apoptosis, together with major inroads into the molecular abnormalities common to melanoma cells, clinical trials will prove essential in refining the utility of a battery of new treatments.
Frequently, the eligibility criteria for participation in Phase II and Phase III trials for melanoma select out a small group of patients with good prognosis. The outcome of this is that, even in units with a high level of commitment to clinical research, there will be a number of patients who are ineligible for treatment with new agents. These patients are necessarily treated “off study”.
Metastatic melanoma is relatively resistant to treatment with cytotoxic drugs. No form of systemic therapy prolongs overall survival. Single agent treatment with dacarbazine (dimethyl triazeno imidazole carboxamide, DTIC) has been standard best systemic therapy since the late 1960s and its use in Australia was pioneered by Gerald Milton and William McCarthy at Sydney Melanoma Unit.7 Partial responses to dacarbazine and two other commonly used single-agent cytotoxic drugs, temozolamide and fotemustine, occur in less than 25% of treated patients, and complete responses in less than 5%.8-10However, in recent Phase III prospective randomised trials, in which dacarbazine has been standard therapy, response rates have been less than 10%.11,12 The use of combinations of cytotoxic drugs, even with the addition of potent cytokines like interleukin-2 and interferon-alpha,13 produces slightly higher transient response rates, but at considerable cost in toxicity and with no survival benefit.1
Predictors of response to dacarbazine include good performance status and disease confined to the skin, subcutis, lymph nodes and lungs.14,15 The median duration of response is five-six months.9 Only 1-2% of patients treated with dacarbazine sustain long-term complete responses, but those in complete remission more than two years after treatment tend not to relapse.16,17
A major advantage of dacarbazine is that it is simple, ambulatory and associated with minimal toxicity when administered with 5-HT(3)-antagonist anti-emetics. Alopecia does not occur with dacarbazine therapy and the drug is minimally myelosuppressive. Acute photosensitivity reactions may occur.
For certain patients, the prospects of response to chemotherapy are so low and/or the risks of toxicity so high that attempts at anti-tumour therapy are better abandoned and replaced with a policy of best supportive care. Patients who fall into this category include those with very poor performance status and extensive or rapidly progressing metastatic disease in multiple visceral sites. Patients who have failed initial chemotherapy may also fall into this group, as a recent review of the efficacy of salvage chemotherapy for metastatic melanoma in the Sydney Melanoma Unit revealed a response rate of less than 5%.
There have been highly encouraging recent advances in treating metastatic melanoma with immunoregulatory molecules. This subject is reviewed by Peter Hersey in this issue of Cancer Forum.
The molecular pathways so far identified as being central to melanoma are the subjects of intense investigation for their potential as targets for strategically directed therapy.
Growth factors, such as SCF, FGF and TGF-alpha are produced by the action of solar radiation on melanocytes and surrounding keratinocytes and fibroblasts. Resulting signals are transduced via the Ras and RAF signalling pathways and subsequently MEK-ERK-Mitf, or PI3K-Akt-mTOR. The transcription factor Mitf triggers the transcription of a suite of genes involved in cellular proliferation and migration. mTOR promotes the translational efficiency of growth regulatory gene products. Constitutive activating NRas and BRAF mutations are very common in melanoma and physiological “brakes” to this oncogenic activity, provided by the protein products of the CDKN2A gene, p16 and p14ARF, are also frequently disrupted in advanced tumours (reviewed in (1)). When defective, p16 is unable to inactivate CDK4 and 6, which phosphorylate Rb, leading to cell cycle progression. The molecule usually central to protection against DNA damage, p53, is rarely mutated early in melanoma, possibly one of a number of adaptations to permit survival of the cells responsible for generating sun-protective pigment18. However, mutations in p14ARF permit degradation of p53 by releasing its binding partner hdm2. As a further defence, melanoma cells frequently express high levels of the anti-apoptotic molecules bcl-2 and bcl-x.19 These are proving important targets for modern therapeutic attack on the tumour.
Targets undergoing experimental inhibition in melanoma therapy include antisense oligonucleotide to bcl-2 (oblimersen), CDK inhibitors (flavopiridol), receptor tyrosine kinase inhibitors (imatinib, bevacizumab), farnesyl transferase inhibitors, RAF inhibitors (sorafenib) and mTOR inhibitors.
Oblimersen is an antisense oligonucleotide to the anti-apoptotic molecule bcl-2 which is over-expressed in many melanomas. Phase III testing of DTIC plus oblimersen versus DTIC alone showed incremental benefits in progression-free survival but no overall survival benefit.20 The RAF inhibitor sorafenib has minimal activity as a single agent, but a combination of this agent with the cytotoxic drugs carboplatin and paclitaxel gave 14/35 partial responses (Flaherty, K.T. oral presentation, 40th Ann Meeting Amer Soc Clin Oncol, New Orleans, June 5-8, 2004) and response did not depend upon the presence of an activating RAF mutation.21 The prospect of using a number of targeted inhibitors in combination with chemotherapy provides some optimism and is the subject of planned Phase III trials.
In certain patients melanoma metastases fluctuate in size spontaneously. This is most frequently seen in subcutaneous deposits, lymph nodes and pulmonary metastases and may be due to immunological and inflammatory responses, necrosis induced by out-growth of blood supply and haemorrhage into highly vascular deposits. This behaviour, so characteristic of metastatic melanoma, is one particular reason for the rigorous control necessary in assessing response in clinical trials of new agents. Very rare complete spontaneous regressions of metastatic melanoma are also described.22
Motivated by their own despair, confronted with apparent helplessness and occasional negativity in health professionals, fuelled by the exaggerated and frequently bogus claims of the evangelical or unscrupulous in the popular press and on numerous websites and harassed by the well-meaning attentions of family and friends, patients with metastatic melanoma frequently seek alternative therapies.3
Patients and their carers may be assisted by a number of highly informative resources on alternative therapy, such as those available from the American Cancer Society and those contained in websites such as “Quackwatch” (www.quackwatch.com). Certain patients may also be fortified by the provision of safe supportive programs of sensible dietary and exercise advice, relaxation therapy, meditation and massage, aimed principally at improvement in quality of life and symptom control.
4. Balch CM, Soong SJ, Murad TM, Smith JW, Maddox WA, Durant JR. A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III). J Clin Oncol, 1: 126-134, 1983.
5. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm, MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. Final version of the American Joint Committee on cancer staging system for cutaneous melanoma. J Clin Oncol, 19: 3635-3648, 2001.
6. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A. Prognostic factors analysis of 17,600 melanoma patients: validation of the american joint committee on cancer melanoma staging system. J Clin Oncol, 19: 3622-3634, 2001.
10. Khayat D, Meric J-B, Rixe O. Systemic chemotherapy and biochemotherapy for non-resected and metastatic melanoma. In: J. F. Thompson, D. L. Morton, and B. B. R. Kroon (eds.), Textbook of Melanoma, pp. 586-601. London: Martin Dunitz, 2004.
11. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol, 18: 158-166, 2000.
12. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine Compared With Dacarbazine in Patients With Disseminated Malignant Melanoma: A Phase III Study. J Clin Oncol, 22: 1118-1125, 2004.
13. Atkins MB, Lee S, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM. A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. In: ASCO, Chicago, 2003, pp. Abstract No: 2847.
14. Einhorn LH, Burgess MA, Vallejos C, Bodey GP Sr, Gutterman J, Mavligit G, Hersh EM, Luce JK, Frei E d, Freireich EJ, Gottlieb JA. Prognostic correlations and response to treatment in advanced metastatic malignant melanoma. Cancer Res, 34: 1995-2004, 1974.
15. Nathanson L, Wolter J, Horton J, Colsky J, Shnider BI, Schilling A. Characteristics of prognosis and response to an imidazole carboxamide in malignant melanoma. Clin Pharmacol Ther, 12: 955-962, 1971.
17. Hill GJ d, Krementz ET, Hill HZ. Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. IV. Late results after complete response to chemotherapy (Central Oncology Group protocols 7130, 7131, and 7131A). Cancer, 53: 1299-1305, 1984.
20. Kirkwood JM, Bedikian AY, Millward MJ, Conry RM, Gore ME, Pehamberger HE, Sterry W, Pavlick AC, Deconti RC, Itri LM. Long-term survival results of a randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM). In: ASCO, Orlando, 2005, pp. Abstract 7506.
21. Flaherty KT. RAF kinase as therapeutic target in melanoma. In: M. C. Perry (ed.), American Society of Clinical Oncology Educational Book, pp. 532-534. Alexandria, VA: American Society of Clinical Oncology, 2004.