NCMC Logo Appointments   |  News  |  Video Q & A  |  Links  |  Library  |  Disclaimer  |  About  |  Contact Us
















Northern California Melanoma Center San Francisco - 2007

Therapy of disseminated melanoma depends on the specific details of the disease in the individual patient and the patient’s philosophy. This document is intended to provide an overview of therapeutic options which can be considered. The only agents approved by the FDA for therapy of patients with metastatic melanoma are dacarbazine (DTIC) and Interleukin-2 (IL-2).


Surgery remains the most effective treatment for malignant melanoma and offers the best potential for cure in patients who have undergone hematogenous dissemination of disease. It is an appropriate consideration in patients with a solitary metastasis such as a solitary pulmonary nodule. It is important that there are no unrecognized metastases elsewhere, so a complete metastatic workup, including CT scans of the chest and abdomen, MRI of the brain, and PET scan should be done before contemplating such surgery. Long term survival in patients who have undergone surgical excision of a solitary hematogenous metastasis is about 20%.

Supportive Care

One appropriate consideration in certain circumstances is to provide supportive care only. This might be considered when the patient is asymptomatic and the presence of metastatic disease has been discovered through routine follow up. If the patient is feeling well, it must be recognized that any therapeutic maneuvers currently available will produce symptoms and make the patient feel sicker. The patient may choose to delay beginning therapeutic attempts in this circumstance. It should be recognized, however, that in general the agents currently available are more effective when given early in the course of disease then when given later. In a patient with widespread, rapidly progressing disease, older patients who do not tolerate therapeutic attempts well, or in patients who have failed therapeutic attempts, supportive care may also be appropriate consideration.

Single Agent Chemotherapy

There are a number of agents which have been reported to have activity in therapy of malignant melanoma. These include dacarbazine (DTIC), carmustine (BCNU), lomustine (CCNU) cisplatin, temozolomide, and vincristine. All are relatively well tolerated and have response rates of 15 to 20%. In patients whose metastatic disease is relatively limited in amount and/or not rapidly progressive or in patients who do not want the toxicities associated with more aggressive therapy, a therapeutic trial of single agent chemotherapy might be considered. At the Northern California Melanoma Center, we prefer to use temozolomide since this chemotherapy is administered in pill form and does not require hospitalization.1 It has the advantage of being less disruptive of the patient’s lifestyle. The drug also is one of the few agents active in melanoma which does cross the blood brain barrier.

Combination Chemotherapy

In an attempt to improve the therapeutic outcome in patients with metastatic melanoma, a number of combination chemotherapy regimens have been tried. The most widely used of these is known as the “Dartmouth Regimen” and consists of quadruple drug therapy with DTIC, cisplatin, BCNU, and tamoxifen. This combination was reported to give a higher response rate than that reported for single agents or combinations previously tried.2,3 Experience summarized from studies of 197 patients treated in 5 centers indicates an overall response rate of 47%. Patients with liver metastases have potential for responding to this combination. The drugs are usually given in the hospital for three days every three to four weeks. Side effects include nausea, vomiting, bone marrow depression, renal damage, and neuropathy. The value of tamoxifen in the regimen has been questioned and, in a randomized trial, reported to have no beneficial effect.5 For patients who cannot tolerate cisplatin because of their renal status or for other reasons, an alternate regimen, called the “Finnish Regimen”, consisting of DTIC, vincristine, bleomycin, CCNU and * interferon has been described with promising results.6 In a large randomized trial which included 240 patients, it was reported that the combination chemotherapy regimen described above as the “Dartmouth Regimen” was no better than therapy with single agent DTIC in terms of tumor response or survival.7


Interleukin-2 (IL-2) has been extensively studied over the past several years at many centers and is approved by the FDA for therapy of patients with metastatic melanoma.8-11 It has been used alone or in combination with chemotherapy, lymphokine activity killer cells (LAK) or tumor infiltrating lymphocytes (TIL) or biologics such as interferon. It is also being given in high doses, low doses, and by various infusion schedules such as bolus and continuous infusion. With all these approaches, response rates have not exceeded 15-20%, except for some of the biochemotherapy regimens recently reported. Side effects of IL-2 are generally dose related and can be severe and consist of chills, fever, malaise, hypotension, fluid retention, and renal and hepatic dysfunction. Use of IL-2 offers the potential for a durable response in a small percentage of patients.12 Responses are strongly associated with the site of metastasis, with patients who had only subcutaneous and/or cutaneous metastasis showing a significantly higher response rate than patients with metastases to other sites.13

Alpha interferon has direct activity in inhibiting the growth of melanoma cells and also has immunological effects.14,15 The response rate in melanoma is 15-20%.16 Side effects include flu-like syndrome with chills, fever, and malaise. Since the therapy is administered on a continuous, ongoing basis, the patients experience symptoms continually rather than intermittently. For this reason, many patients prefer to choose temozolomide which has fewer side effects and has a similar response rate.

Tumor vaccines are being widely used as adjuvant therapy of melanoma. Vaccines have potential for preventing recurrence and prolonging survival when patient has been rendered clinically tumor-free by standard means, such as surgery, but is known to be at high risk for recurrence. Preliminary results in this circumstance have been promising, but definitive studies have not yet been completed. Because of these promising results in patients clinically tumor-free, and the low toxicity of vaccines, patients with metastatic disease are also seeking vaccine treatment. It must be recognized that the circumstances in the therapy of metastatic disease are different from adjuvant therapy. With adjuvant therapy, the tumor burden is minimal, and there is potential for the immune response to overcome this minimal tumor burden. In patients with demonstrated metastases which cannot be treated with surgery or other standard means, the tumor burden is much greater and it is too much to expect successful therapy in a large percentage of patients with the vaccines currently available. It is simply asking too much of the immune response to be able to overcome a substantial tumor burden. The response rate to tumor vaccines in patients with metastatic disease is in the range of 10 to 20%. Single centers have reported regressions of metastatic disease with some of these vaccines, but these observations remain to be confirmed. Recently, it has been reported that the combination of a vaccine with a monoclonal antibody (anti-CTLA-4) was effective in causing regression of metastases in patients with melanoma, but these regressions were associated with toxicity mainly consisting of autoimmune phenomena.17


Because chemotherapeutic and biologic agents have activity in therapy of melanoma, combinations have been tried in an effort to provide clinical benefit to patients in terms of improved responses and longer survival. The one being most extensively used was described by Legha et al.18 It involves the use of the CVD chemotherapy regimen (cisplatin, vinblastine and dacarbazine) combined with biologics (interferon alfa and interleukin-2). In a study which involved 53 patients, they reported 21% of the patients had a complete response and 43% had partial responses for an overall objective response rate of 64%. The median time to disease progression for all patients was 5 months and the median survival was 11.8 months. Nine percent of the patients achieved a durable complete remission (over 50 months). In another study, a modified Dartmouth regimen (dacarbazine, cisplatin, and BCNU) was combined with IL-2 and interferon alfa.19 In a study of 42 patients with metastatic melanoma, a 57% response rate was reported. In a follow-on study of 83 patients, including patients with brain metastases, a 55% response rate was reported.20 The median time to disease progression was 7 months and the median survival was 12.2 months. There was greater than 10% disease-free survival beyond 4 years indicating that there may be a long-term benefit for some patients. An outpatient regimen has been developed in which patients are treated with combination chemotherapy (dacarbazine, BCNU, cisplatin, and tamoxifen) plus self-administered subcutaneous IL-2 and interferon alfa.21 In a Phase II trial in 32 patients, there were 13% complete responses and 30% partial responses for an overall response rate of 43%. Evaluations of the various biochemotherapy regimens are ongoing and studies are being done to determine whether or not they are, in fact, better than therapy with single agents. Recent studies have shown that outcomes in patients treated with biochemotherapy are no better than outcomes in patients treated with combination chemotherapy.22-24 The Northern California Melanoma Center recently reported promising results with a new, low-dose outpatient biochemotherapy regimen that is well-tolerated and effective.25

Brain Metastases

Previously, surgery was the best treatment for brain metastases of melanoma if the number of metastases was limited to one or two and if they were in a location where they could be excised without leaving a great neurological deficit. Recently, a new treatment modality for brain metastases of melanoma is stereotactic radiosurgery.26,27 This can be accomplished in the outpatient setting with a single treatment. Radiation is administered in such a way that it is focused directly on the tumor, thus sparing normal tissues. This allows a huge dose to be administered directly to the tumor. It is a very effective way of controlling individual lesions. There is a limit to the size of lesions which can be treated; multiple lesions can be treated. Because of the availability of this new, effective therapy, early diagnosis of brain metastases is important. Accordingly, we recommend single sequence MRI scans (single sequence, with gadolinium) every 6 months in patients at high risk for brain metastasis, such as those with Stage III disease with 4 or more positive nodes or with Stage IV disease, surgically excised. If the patient undergoes surgery or radiosurgery for brain metastases of melanoma, follow-up with whole brain irradiation should be considered. If melanoma has shown a propensity for spread in the brain by showing up as a metastatic cerebral lesion, it is likely that additional microscopic metastases are present. Whole brain irradiation has the potential for eradicating these microscopic foci and has been shown to provide clinical benefit to patients when administered following surgery or radiosurgery for brain metastases.28-31

Other treatments for brain metastases of melanoma include administration of corticosteroids to reduce the swelling caused by the metastases. This treatment does not affect the tumor itself, but can provide relief of symptoms caused by the swelling. If surgery or radiosurgery cannot be done, whole brain irradiation is the treatment of choice and can cause shrinkage of the tumors. Administration of concomitant chemotherapy may make the radiation more effective. Chemotherapy alone is generally not helpful in treatment of brain metastases of melanoma, since most chemotherapeutic agents do not cross the blood-brain barrier. Of the chemotherapeutic agents commercially available in the US, temozolomide32.33 and BCNU do cross the blood-brain barrier and could be tried.

Bulky Disease

Sometimes melanoma can grow rapidly and create pain and discomfort as well as other problems such as impairment of blood flow, lymphatic drainage, or organ function. In the circumstance of a large tumor mass, the combination of radiation and chemotherapy, given at the same time, may be more effective than either given alone.34 If there is bulky disease confined to an extremity, heated limb perfusion offers potential for an effective means of therapy.35,36

Ocular Melanoma

Melanoma of the eye may spread to the liver, and in this case, it is very resistant to treatment. One approach which has been reported to be effective is a procedure called “chemoembolization” in which the chemotherapy is given directly into the hepatic artery in combination with a substance designed to block the blood vessels and slow the removal of the chemotherapy from the liver.37

Investigational Agents

Patients often have the idea that investigational agents may be more effective and less toxic than the more conventional approaches described above. While that may be the case, patients should be aware of the clinical trial process. When a new therapeutic drug is to be evaluated, this is done in a “Phase I” trial. The primary goal of the Phase I trial is to evaluate the safety of the treatment whereas efficacy is the goal of Phase II and Phase III trials. The dose of the drugs used in the Phase I trials is often very low at first, since it is not known what a safe dose will be. Patients who are considering participating in a Phase I trial should weigh the risks and potential benefits of the trial as compared to the standard treatments described above and investigational agents which are in Phase II or Phase III trials. A treatment called “gene therapy” has been popular with patients recently, probably because the name sounds like it has great potential. In fact, most trials of gene therapy at the present time are Phase I trials. Patients contemplating such trials should discuss the potential benefit carefully with their doctors.

Recently two drugs (Celpene and Revlimid) that held promise for therapy of metastatic melanoma failed in Phase III trials. Histamine dihydrochloride (Celpene) was studied in combination with low-dose IL-2. A Phase III trial was conducted and failed to show a difference in outcome between patients who received the Celpene with IL-2 versus those who received IL-2 alone.38 When a subpopulation analysis was done, however, Celpene appeared to provide benefit in patients with liver metastasis. The Company applied to the FDA for approval in this subpopulation but was told that a new study focusing only on patients with liver metastasis was necessary. This study has just been completed and it was a negative study; there was no difference in outcome in patients with liver metastasis of melanoma who received Celpene with IL-2 versus those who received IL-2 alone.39

Revlimid is a congener of thalidomide, designed to be more effective and less toxic. In a Phase I trial, it was found to be well tolerated in patients with metastatic melanoma and to produce immune activation.40 On the basis of this information, Celgene Pharmaceuticals launched two randomized Phase III trials of Revlimid in patients with metastatic melanoma who had failed first line therapy. They recently reported that both trials were negative; in the US, there was no difference in outcome between patients who received a high-dose versus a low-dose of Revlimid and in Europe there was no difference in outcome between patients who received Revlimid and those who received placebo.41

Recently a number of new agents have entered clinical trials. One of the most promising is a monoclonal antibody called anti-CTLA-4.This antibody had the effects of “taking the brakes off” the immune system thereby causing enhancement of the patient’s immune responses to the tumor. Unfortunately, it also causes enhancement of autoimmune responses, especially in the gastrointestinal tract and the liver. Some of these autoimmune responses can be quite serious and may even result in death. Clinical responses (shrinkage of the tumors) correlate with the occurrence of autoimmune responses. Fortunately, the autoimmune responses can be treated with steroids without abrogating the anti-tumor efficacy. There are two anti-CTLA-4 monoclonal antibodies undergoing advanced testing currently and they may be approved by the FDA soon, which would make them available outside of clinical trials. One of these is Ticilimumab, produced by Pfizer, and the other is Ipilimumab, also known as MDX-010, produced by Bristol-Myers Squibb and Medarex.

Another new agent which is in advanced clinical trials in combination with chemotherapy for melanoma therapy is Sorafenib (Nexavar), a product that inhibits growth of tumor vasculature and is already approved for therapy of kidney cancer. There are a number of new agents that inhibit growth of tumor vasculature (antiangiogenesis) that are in earlier stages of development, including Avastin (Genentech) and Sutent (Pfizer). A useful source for what clinical trials are currently being conducted and their locations is the Website


1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A et al.: Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma. J Clin Oncol. 18: 158, 2000.

2. Del Prete SA, Maurer LH, O'Donnell J, et al: Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep 68:1403-5, 1984

3. McClay EF, Mastrangelo MJ, Bellet RE, et al: Combination chemotherapy and hormonal therapy in the treatment of malignant melanoma. Cancer Treat Rep 71:465-9, 1987

4. McClay EF, McClay ME: Tamoxifen: is it useful in the treatment of patients with metastatic melanoma? [see comments]. J Clin Oncol 12:617-26, 1994

5. Rusthoven JJ, Quirt IC, Iscoe NA, et al: Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14:2083-90, 1996

6. Pyrhonen S, Hahka-Kemppinen M, Muhonen T: A promising interferon plus four-drug chemotherapy regimen for metastatic melanoma. J Clin Oncol 10:1919-26, 1992

7. Saxman SB, Meyers ML, Chapman PB, et al: A Phase III multicenter randomized trial of DTIC, cisplatin, BCNU and tamoxifen versus DTIC alone in patients with metastatic melanoma., Proceedings of the American Society of Clinical Oncology, 1999, pp 2068 (Abstract)

8. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT et al.: Observations on the systemic administration of autologous lymphokine- activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 313: 1485-92, 1985.

9. Philip PA, Flaherty L: Treatment of malignant melanoma with interleukin-2. Semin Oncol 24:S32-8, 1997

10. West WH, Tauer KW, Yannelli JR, et al: Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898-905, 1987

11. Sznol M, Parkinson DR: Clinical applications of IL-2. Oncology (Huntingt) 8:61-7; discussion 67, 71, 74-5, 1994

12. Legha SS: Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alpha and chemotherapy. Semin Oncol 24:S39-43, 1997

13. Phan GQ, Attia P, Steinberg SM, White DE and Rosenberg SA: Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol. 19: 3477-82, 2001.

14. Creagan ET, Ahmann DL, Green SJ, et al: Phase II study of low-dose recombinant leukocyte A interferon in disseminated malignant melanoma. J Clin Oncol 2:1002-5, 1984

15. Creagan ET, Ahmann DL, Green SJ, et al: Phase II study of recombinant leukocyte A interferon (rIFN-alpha A) in disseminated malignant melanoma. Cancer 54:2844-9, 1984

16. Legha SS: The role of interferon alfa in the treatment of metastatic melanoma. Semin Oncol 24:S24-31, 1997

17. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ et al.: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 100: 8372-7, 2003.

18. Legha SS, Ring S, Eton O, et al: Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16:1752-9, 1998

19. Richards JM, Mehta N, Ramming K, et al: Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol 10:1338-43, 1992

20. Richards JM, Gale D, Mehta N, et al: Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 17:651-7, 1999

21. Thompson JA, Gold PJ, Fefer A: Outpatient chemoimmunotherapy for the treatment of metastatic melanoma. Semin Oncol 24:S44-8, 1997

22. Atkins MB: 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: Proc Am Soc Clin Oncol, 2003, pp 2847a.

23. Keilholz U: Dacarbazine, cisplatin and IFN-a2b with or without IL-2 in advanced melanoma: Final analysis of EORTC randomized phase III trial 18951.: Proc Am Soc Clin Oncol, 2003, pp 2848a.

24. Del Vecchio MM, Bajetta E, Vitali M, Gattinoni L, Santinami M, Daponte A, Sertoli MR, Queirolo P, Bernengo MG and Cascinelli N: Multicenter phase III randomized trial of cisplatin, vindesine and dacarbazine (CVD) versus CVD plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-alpha-2b (IFN) in metastatic melanoma patients (pts). Proc Am Soc Clin Oncol, 2003, pp 2849a.

25. Weber RW, Rose M, Good J, Meyer J, Allen R, Wade M, Gonzalez R, O'Day S and Spitler LE: Phase II trial of chemobiotherapy with temozolomide (TMZ), GM-CSF, INF-alpha-2b, and IL-2 in patients with metastatic melanoma: Proceedings of ASCO. Chicago, 2003, vol. 22, pp 2881(a).

26. Adler JR, Cox RS, Kaplan I, et al: Stereotactic radiosurgical treatment of brain metastases. J Neurosurg 76:444-9, 1992

27. Loeffler JS, Larson DA, Shrieve DC, et al: Radiosurgery for the treatment of intracranial lesions. Important Adv Oncol :141-56, 1995

28. Patchell RA, Tibbs PA, Regine WF, et al: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial [see comments]. Jama 280:1485-9, 1998

29. Nussbaum ES, Djalilian HR, Cho KH, et al: Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 78:1781-8, 1996

30. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age [see comments]. Int J Radiat Oncol Biol Phys 29:711-7, 1994

31. Pirzkall A, Debus J, Lohr F, et al: Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 16:3563-9, 1998

32. Bleehen NM, Newlands ES, Lee SM, et al: Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13:910-3, 1995

33. Brock CS, Newlands ES, Wedge SR, et al: Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58:4363-7, 1998

34. Tannock IF: Treatment of cancer with radiation and drugs. J Clin Oncol 14:3156-74, 1996

35. Stehlin JS, Giovanella BC, de Ipolyi PD, et al: Results of hyperthermic perfusion for melanoma of the extremities. Surg Gynecol Obstet 140:339-48, 1975

36. Brobeil A, Berman C, Cruse CW, et al: Efficacy of hyperthermic isolated limb perfusion for extremity-confined recurrent melanoma. Ann Surg Oncol 5:376-83, 1998

37 . Bedikian AY, Legha SS, Mavligit G, et al: Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors. Cancer 76:1665-70, 1995

38. Agarwala SS, Glaspy J, O'Day SJ, Mitchell M, Gutheil J, Whitman E, Gonzalez R, Hersh E, Feun L, Belt R et al.: Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol. 20: 125-33, 2002.

39. Maxim Pharmaceutical Phase 3 Trial for Advanced Malignant Melanoma Fails to Meet Primary Endpoint, 2004.

40. Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, Kristeleit H, Polychronis A, Pandha H, Muller GW, Stirling DI et al.: Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer. 90: 955-61, 2004.

41. Celgene Announces Plans to Stop Phase III Trials In Melanoma Due to Lack of Efficacy, 2004.


Home  |  NCMC Center  |  What is Melanoma?  |  How to Cope  |  Clinical Trials  |  Current Therapies