Management of Metastatic Cutaneous Melanoma

Dr. Buzaid's article, "Management of Metastatic Cutaneous Melanoma," is a review of available treatment options with a historical perspective. The conclusion includes a recommendation for the use of aggressive combination therapy in patients who are young and otherwise healthy enough to tolerate the toxicities of these aggressive forms of therapy, and consideration of single-agent therapy for those who cannot tolerate aggressive combination regimens. While this review article includes the published reports as of the time of its submission, there are additional agents and regimens that warrant mention due to their likelihood of improving the treatment landscape for future patients with this devastating disease. Furthermore, some of the promising regimens mentioned in this review should be more closely scrutinized. The following commentary will cover the topics included in Dr. Buzaid's report as well as updates on the current status and future of selected investigational agents. Single-Agent Chemotherapy
The currently available drugs, which include dacarbazine(Drug information on dacarbazine) (DTICDome), temozolomide(Drug information on temozolomide) (Temodar), and cisplatin(Drug information on cisplatin), are still used as single agents with occasional responders in this disease. While response rates ranging from 10% to 20% are often quoted for dacarbazine and its oral analog, temozolomide, recent trials with close monitoring of patient outcomes suggest a more modest benefit, with overall objective responses seen in less than 10% of patients and complete responses occurring rarely. Despite this disappointing level of activity, dacarbazine continues to be held as the treatment standard for this disease and to be used as the "control" arm of therapy in randomized, controlled trials of new agents for licensing applications. Although temozolomide did not meet the clinical benefit criteria of the US Food and Drug Administration (FDA) for approval in this disease, the drug's superior ease of administration has led to its routine use by many practitioners for patients treated with single-agent therapy. Its high level of central nervous system (CNS) penetration led to the early adoption of its use alone or in combination with radiotherapy in melanoma patients with brain metastases. Ironically, since patients with CNS metastases are routinely excluded from clinical trials, this practice has occurred in the setting of insufficient published data. Despite the initial promise of data from retrospective subset analysis of randomized trials,[1,2] a very large single-arm trial of temozolomide alone demonstrated a response rate of only 7% in 117 previously untreated melanoma patients with CNS metastases,[ 3] and a phase II trial of temozolomide with whole-brain radiotherapy in previously untreated patients had only 3 responders among 31 patients.[4] Although a subsequent trial of the addition of thalidomide(Drug information on thalidomide) (Thalomid) to temozolomide in combination with whole-brain radiotherapy has not yet been analyzed, a preliminary evaluation of the data suggest that this regimen will also be disappointing (personal communication, Atkins and McDermott, 2004), despite its earlier promise in single-institution studies.[ 5] These results temper enthusiasm for the addition of temozolomidebased regimens to aggressive regional therapy such as surgical excision or stereotactic radiosurgery for patients with metastatic melanoma amenable to such approaches. Biologically Modulated Single Agents
The experience with modulation of "standard" agents by adding biologic agents has been similarly disappointing. Thus, the addition of thalidomide to temozolomide, while reportedly more active than temozolomide alone based on small singleinstitution phase II trials[5] and phase II randomized trials,[6] has not yet been confirmed to be superior in a randomized controlled trial. Thalidomide, a drug with remarkable immunomodulatory activities and a purported antiangiogenic mechanism of action in some malignancies, is not only toxic but also very expensive and cumbersome to obtain for cancer patients. Thus, its true value in combinations for melanoma will need to stand up to rigorous testing and may be eclipsed by newer agents such as CC-5013 (Revimid), a related immunomodulatory agent that is currently under investigation. Oblimersen sodium (G3139, Genasense), an oligodeoxynucleotide antisense molecule that inhibits the synthesis of the antiapoptotic molecule Bcl-2 in cancer cells, failed to meet FDA approval criteria for providing clinical benefit when combined with dacarbazine for metastatic melanoma. However, if this interesting agent proves active in other diseases, it may become available for further investigation in new combinations for melanoma. The most exciting new agent to be combined with chemotherapy for advanced melanoma is an oral inhibitor of the Raf kinase enzyme that is mutated at a unique site to a constitutively activated form in a majority of melanomas (BAY 43-9006, Sorafenib(Drug information on sorafenib)). The drug does not appear to possess single-agent activity but has shown a very encouraging level of antitumor activity in combination with carboplatin(Drug information on carboplatin) (Paraplatin) plus paclitaxel(Drug information on paclitaxel). Although the chemotherapeutic agents in this regimen were chosen in part for application to lung cancer, these agents are probably at least as active as dacarbazine in melanoma. Interestingly, the responses in melanoma patients did not appear to correlate with the activating mutations of the enzyme. It is now believed that the inhibition of other targets by this agent, particularly the kinase activities of both the vascular endothelial growth factor receptor type 2 and platelet-derived growth factor, may account for its activity via inhibition of angiogenesis in melanoma as well as in other tumors such as clear cell carcinoma of the kidney.[7] Nonspecific and Specific Immunotherapies
The review by Buzaid provides a comprehensive summary of the role for currently available and approved biologic agents. While interferon (IFN)-alfa, generally used as a single agent in the adjuvant setting, has modest activity in delaying or preventing relapse and virtually no proven role in combination with chemotherapy, it should not be abandoned altogether. It remains of interest as a molecule that can enhance the expression of human leukocyte antigen (HLA) molecules and tumor antigens, the activity of antigen-specific T cells, and the level of antibody-dependent cell-mediated cytotoxicity. Low-dose, metronomically scheduled IFN-alfa appears to have antiangiogenic potential, which is unlikely to work as a single agent but may have potential in combinations (with the caveat that unique toxicities and drug interactions may emerge even at doses considered to be safe and well tolerated).[8] Although interleukin (IL)-2 (Pro- leukin) in high doses has unequivocal activity and may be the only single agent with the potential for durable complete responses in a small fraction of patients, its use is limited to practitioners and investigators with experience in patient selection and toxicity management. Its potential as an adjunct to antigen-specific approaches remains under investigation, and the safety and efficacy of combinations with other cytokines will also require carefully designed trials based on relevant preclinical models. Nevertheless, high-dose IL-2 should not be overlooked in the selection of aggressive therapy for advanced melanoma in patients with adequate organ function and a good performance status, and it appears to have similar activity whether used in first-line treatment or as salvage therapy for metastatic melanoma.[9] Conclusions
Dr. Buzaid has summarized the literature on biochemotherapy regimens from the point of view of one who has participated in many of the relevant early clinical trials as well as from the vantage point of a practicing oncologist who must select therapy for melanoma patients with a variety of clinical characteristics. While clearly citing the early promise of phase II studies, this review addresses the disappointing and now reproducibly negative results of virtually all of the randomized biochemotherapy trials. Nevertheless, the author's concluding remarks leave the reader with the impression that biochemotherapy combinations remain the regimens of choice for the "best" melanoma patients (young patients who are otherwise healthy and do not have CNS metastases). This perception is based in part on the recognition that optimal results (better than those achieved in the large, cooperative group trials) may be possible in the hands of experienced, aggressive oncologists. The reader should consider the alternative view-that even under the best of circumstances, biochemotherapy regimens are difficult to deliver, difficult to tolerate, and not as effective as originally believed to be. Highdose IL-2 may be as safe, at least as effective, and quite possibly better tolerated than biochemotherapy due to the rapid reversibility of its side effects and the more-intense but less frequent schedule of administration. Finally, but probably most importantly, the first line of therapy for most melanoma patients should be referral for participation in a clinical trial.