Management of Metastatic Cutaneous Melanoma

ABSTRACT: The results of treatment for metastatic melanoma remain disappointing.Single-agent chemotherapy produces response rates ranging from8% to 15%, and combination chemotherapy, from 10% to 30%. However,these responses are usually not durable. Immunotherapy, particularlyhigh-dose interleukin (IL)-2 (Proleukin), has also shown a lowresponse rate of approximately 15%, although it is often long-lasting.In fact, a small but finite cure rate of about 5% has been reported withhigh-dose IL-2. Phase II studies of the combination of cisplatin-basedchemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy,have shown overall response rates ranging from 40% to60%, with durable complete remissions in approximately 8% to 10% ofpatients. Although the results of the phase II single-institution studieswere encouraging, phase III multicenter studies have reported conflictingresults, which overall have been predominantly negative. Variousfactors probably explain these discrepancies including differentbiochemotherapy regimens, patient selection, and, most importantly,“physician selection.” Novel strategies are clearly needed, and the mostencouraging ones for the near future include high-dose IL-2 in combinationwith adoptive transfer of selected tumor-reactive T cells afternonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy,and the combination of chemotherapeutic agents andbiochemotherapy with oblimersen sodium (Genasense).The treatment of advanced melanomaremains a great challenge,with patient survival dictatedprimarily by the site and pace ofthe disease.[1] Patients with melanomaand distant metastatic disease havea 5-year survival rate of less than 5%.Median survival for these patientsranges from 6 to 9 months, but it canvary depending on several prognosticparameters. For instance, patients withmetastases to the skin, subcutaneoustissue, distant lymph nodes, or lungshave median survivals ranging from12 to 15 months, whereas patients withmetastases in the liver, brain, or boneshave median survivals of only 3 to4 months.[1]Treatment options include chemotherapy,immunotherapy, and thecombination of chemotherapy andinterleukin (IL)-2 (Proleukin) and interferon(IFN)-alfa, referred to as biochemotherapy.This article willprovide a brief overview of the majortreatment options, with a special focuson the results of cisplatin-basedbiochemotherapy regimens in patientswith advanced melanoma.Chemotherapy AloneThe most active chemotherapeuticdrugs in the treatment of advancedmelanoma include dacarbazine(DTIC-Dome), temozolomide (Temodar),cisplatin, the 2-chloroethylnitrosoureas(carmustine [BiCNU],lomustine [CeeNU], and fotemustine),the vinca alkaloids (vincristine andvinblastine), and the taxanes (paclitaxeland docetaxel [Taxotere]).[2]Observed overall response rates tothese single agents have usuallyranged from 7% to 20%, with completeremissions observed in fewerthan 5% of patients.[2] Furthermore,responses are usually not durable. Althoughno single agent is clearly moreactive than dacarbazine alone, a recentrandomized phase III study comparingdacarbazine (n = 117) withfotemustine (n = 112) showed a trendfor a higher response rate (15.5% vs7.2%, P = .053) and overall survival(7.4 vs 5.8 months, P = .073) favoringthe fotemustine arm.[3]Temozolomide
Temozolomide is an imidotetrazinederivative that, at physiologic pH,spontaneously converts to MTIC, theactive metabolite of dacarbazine.[2]It has the advantages of being absorbedorally and possessing bettercentral nervous system penetration.In a phase II study in patients withmetastatic melanoma, temozolomidewas well tolerated and produced objectiveresponses in 21% of patients,including complete responses in5%.[4] Of interest, one of four patientswith cerebral metastases exhibiteda partial response.A subsequent phase III trial comparedtemozolomide (200 mg/m²/dorally for 5 days every 4 weeks) todacarbazine (250 mg/m²/d intravenouslyfor 5 days every 3 weeks) in305 patients without brain metastases.[5] Temozolomide produced apparentimprovement in medianprogression-free survival (1.9 vs 1.5months) and health-related quality oflife relative to dacarbazine, but hadno significant impact on response rate(13.5% vs 12.1%) or overall survival(7.7 vs 6.4 months).[5] Of note, in asubset of patients who had regularlyscheduled computed tomography scansof the head, fewer central nervous systemrelapses were observed in the patientsreceiving temozolomide.Using novel dosing schedules andcombinations, investigations of temozolomideare continuing. Regimensinvolving multiple doses per day orprolonged daily exposure have beenstudied in an effort to circumventDNA repair processes and more optimallycoordinate with radiation therapyschedules. A temozolomide doseof 75 mg/m² daily for 6 weeks hasbeen determined to be the maximumtolerated dose for the prolonged dailyschedule.The pilot experience of Hwu et alsuggested a synergistic interactionbetween temozolomide and thalidomide(Thalomid). The authors subsequentlyconducted a phase II study oftemozolomide, 75 mg/m²/d for 6weeks, with thalidomide, 200 mg atbedtime (escalating to 400 mg if welltolerated), in 38 patients without brainmetastases. They observed 1 completeand 11 partial responses, for an overallresponse rate of 32%.[6]The results of a randomized phase IIstudy with a total of 180 patientsassigned to temozolomide alone, temozolomideplus IFN-alfa, and temozolomideplus thalidomide showedoverall response rates of 9%, 18%,and 15%, respectively, providing furthersupport for a synergistic interactionbetween temozolomide andthalidomide.[7] Furthermore, temozolomideand thalidomide were bettertolerated than temozolomide and IFNalfa.Hwu et al[8] more recently reportedpreliminary data in patientswith central nervous system metastasesand identified two complete responsesand one partial responseamong 11 treated patients. These dataare clearly encouraging, and this combinationis undergoing further evaluationby other investigators.Dacarbazine/Oblimersen
Another interesting and promisingstrategy is the combination ofdacarbazine with bcl-2 antisense(oblimersen sodium, Genasense).[9]Preliminary results of a recently completedphase III randomized trialcomparing dacarbazine alone vs dacarbazineplus oblimersen were recentlyreleased.[10] A total of 771 patientswere included in this large study, whichshowed an increased response rate(11.7% vs 6.8%, P = .019) and time toprogression (74 vs 49 days, P = .0003)for the combination arm but only atrend toward improved overall survival(9.1 vs 7.9 months, P = .18).Other Combinations
The next step will be to incorporateoblimersen with other agents,particularly in biochemotherapy strategies.Most chemotherapeutic agentsare inactive in previously treated patients.Paclitaxel, however, has shownactivity even in patients who failedprior chemotherapy. For instance,Zonder et al[11] reported a 13% responserate with weekly paclitaxel(150 mg/m² over 1 hour for 6 weeksfollowed by 2 weeks' rest) among 15treated patients and Bedikian et al[12]reported a response rate of 15.6% in32 assessable patients treated with aregimen of paclitaxel at 90 mg/m² IVover 80 minutes every 4 days for threecycles, repeated every 3 weeks.Combination chemotherapy, includingwell-known regimens such as CVD(cisplatin/vinblastine/dacarbazine) andthe Dartmouth regimen (cisplatin/carmustine/dacarbazine/tamoxifen), hasproduced responses in about 10% to30% of patients (in phase III studies),but durable complete responses havebeen rare.[2] In three phase III studiescomparing combination chemotherapywith single-agent dacarbazine, resultsshowed only a slight increase in response(not statistically significant) favoringthe chemotherapy combinationbut no improvement in overall survival.[2] In this author's opinion, combinationchemotherapy should beconsidered when the objective responseis important, as for instance, in patientswith metastases in the head and neckregion or brachial plexus involvement.Immunotherapy AloneThe disappointing results observedwith chemotherapy alone shifted theattention of many investigators to thebiologic agents, of which IFN-alfa andIL-2 have been the most extensivelystudied. High-dose IL-2 results inoverall responses in approximately15% of patients, with durable remissionsin about 5%.[13,14] Despite thelow response rate, high-dose IL-2 hascurative potential.Because the response rate to highdoseIL-2 is low and toxicity high,great effort has been made to identifypredictors of response. The NationalCancer Institute (NCI) experience sug-gests that patients with only subcutaneousand/or skin metastases have asignificantly higher chance of responding(overall response: 53%)compared with patients with visceralmetastases (overall response: 10% to15%).[15] Furthermore, a recent studyfrom the NCI suggested that pretreatmentmolecular profiling may allowus to better separate responders fromnonresponders.[16] Lower-dose IL-2regimens, IFN-alfa, or other immunotherapyapproaches have generallyproduced lower response rates and fewdurable remissions.[17]Based on preclinical data that suggesteda synergistic interaction betweenIFN-alfa and IL-2, these biologics havebeen combined in various clinical studiesof patients with advanced melanoma.Overall response rates have rangedfrom 10% to 41%, with the averagebeing 20%.[2] In a small randomizedtrial, however, the combination of IL-2plus IFN-alfa failed to produce a statisticallysignificant higher response ratethan IL-2 alone.[18]Novel Strategies
A promising and novel strategy wasrecently reported by Rosenberg'sgroup and consisted of adoptive transferof highly selected tumor-reactiveT cells directed against overexpressedself-derived differentiation antigensafter a nonmyeloablative regimen withcyclophosphamide (Cytoxan, Neosar)and fludarabine (Fludara).[19] Of 13patients who previously failed standardtherapy, including high-doseIL-2, 6 achieved a partial response.Five of the responders demonstratedsigns of autoimmune reaction such asvitiligo and anterior uveitis. This approach,although complex and expensive,is very promising and will likelybe evaluated in other cancers.High-dose IL-2 (NCI regimen) wasalso evaluated in patients who failedprior biochemotherapy. In the Universityof Pittsburgh experience, of 18 patientstreated, 3 achieved a completeremission.[20] In our experience at theHospital Sirio-Libanes, of 10 patientstreated, 1 patient achieved a completeremission of 6-month duration, and 3achieved a partial response. All responseswere of rapid onset. A representativepatient, who did not respondto concurrent biochemotherapy andachieved a solid partial response tohigh-dose IL-2 is shown in Figure 1.

Another strategy still under evaluationis the combination of subcutaneousIL-2 with histamine dihydrochloride.A subgroup analysis of a randomizedphase III trial comparing subcutaneousIL-2 therapy with and without histaminesuggested an improvement inoverall survival in patients with livermetastases.[21] This finding, however,remains to be confirmed by anotherrandomized trial specifically addressingthis patient cohort.BiochemotherapyThe limited results observed withchemotherapy and immunotherapyalone have prompted many investigatorsto empirically combine chemotherapydrugs with IL-2 and IFN-alfa,referred to as "biochemotherapy" or"chemoimmunotherapy."[1] Of all thecurrently employed treatment modalitiesfor metastatic melanoma, cisplatin-based regimens combined withbiologic agents such as IFN-alfa andIL-2 appear to have attained the highestresponse rates.[1] The combinationof IL-2 or IFN-alfa with non-cisplatinbasedregimens was disappointing andrapidly abandoned.Phase II Studies of Cisplatin-Based Biochemotherapy
Phase II studies of cisplatin-basedbiochemotherapy regimens haveshown overall response rates rangingfrom 40% to 60%, with complete remissionrates on the order of 10% to20%.[22-34] Durable remissions exceeding5 years were seen in approximately5% to 10% of patients. Ofinterest, relapses occurring beyond2 years were distinctly uncommon,suggesting that these patients exhibitingdurable responses may be"cured."[22,24-26] Furthermore, response to biochemotherapy is usuallyrapid and observed after the first cycle.A representative case is shown inFigure 2.

The results of select phase II studieswith IL-2 administered intravenouslyare shown in Table 1.[22-28,32-34]One of the most popular regimensdeveloped at M. D. Anderson CancerCenter is the CVD regimen administeredconcurrently with IL-2 and IFNalfafor a maximum of six cycles.Tumor responses were observed in34 of 53 patients (64%), with 20%complete responses and 9% durablecomplete responses.[25] In anotherstudy, this regimen was modified inan effort to reduce toxicity. Modificationsincluded antibiotic and granulocytecolony-stimulating factor (G-CSF[Neupogen]) prophylaxis, prohibitionof long-term central venous access,and restriction to a maximum of fourcycles of therapy. Tumor responseswere seen in 19 of 40 evaluable patients(response rate: 48%) including8 complete responses.[28] Biochemotherapywas also evaluated as secondlinetherapy in melanoma patients andfound to have negligible activity inthis patient population, producing anoverall response rate of only 6% comparedwith 37% in previously untreatedpatients.[28]O'Day et al recently reported theuse of IL-2 and granulocyte macrophagecolony-stimulating factor (GMCSF[Leukine]) as maintenancetherapy in patients who achieved apartial response or stable disease onbiochemotherapy. Preliminary resultsof this pilot experience were encouragingin terms of progression-free andoverall survival, compared with historicalcontrols.[35] A larger phase IImulticenter trial has been initiated inan effort to confirm these results.

• Efforts to Reduce Toxicity-Manyof these biochemotherapy regimens requireinpatient treatment because theyhave substantial toxicity. A numberof investigators have endeavored todevelop regimens with less toxicitythat could be administered in the outpatientsetting (Table 2).[29-32,36]They simplistically replaced IL-2 administeredintravenously with thesubcutaneous route and frequentlyreduced the IL-2 dose to improvetolerance. Unfortunately, biochemotherapyregimens involving subcutaneousadministration and lower dosesof IL-2 appear to produce lower responserates than were generallyobserved with regimens involving intravenousIL-2.For example, Flaherty et al[32] reportedthe results of a randomizedphase II trial of two outpatient biochemotherapyregimens involvingdacarbazine, cisplatin, and IFN-alfawith IL-2 administered either intravenouslyor subcutaneously. There were16 responses including 5 completeresponses in the 44 patients who receivedthe IV IL-2 regimen (responserate: 36%), compared with only 6 responses(including 1 complete) in the36 patients assigned to receive thesubcutaneous IL-2 regimen (responserate: 17%).[32]In addition, a study in which patientswere randomly assigned to receiveeither the Dartmouth regimenor the Dartmouth regimen precededby IL-2 administered subcutaneously(day -2 to 0) and followed by IFNalfa(days 1 to 3) showed no differencein response rate (22% forbiochemotherapy vs 27% for the Dartmouthregimen alone), median durationof response (2.8 vs 2.5 months),or survival (5 vs 5.5 months).[36] Thelower overall response rates for thebiochemotherapy regimens involvingsubcutaneous IL-2 in these two studiesrelative to the intravenous IL-2biochemotherapy regimens mentionedpreviously suggest a potential schedule,dose, and route of administrationeffect for IL-2 in biochemotherapycombinations.

Results of Meta-analysis

Two recent meta-analyses suggestedimproved response rates andpossibly improved survival for combinationsinvolving cisplatin, IL-2, andIFN-alfa, compared with either chemotherapyor immunotherapy alone.In one analysis of 631 patients, biochemotherapyregimens produceda response rate of 45% compared to21% and 15% with IL-2 and IFN orIL-2 alone, respectively. Survival,however, was not significantly differentbetween groups (10.5 months),with 20% and 10% survival rates at 2and 5 years.[37]Another meta-analysis that analyzed154 studies involving over 7,000patients revealed the highest responserate of 47% for patients who receivedcisplatin, dacarbazine, IL-2, and IFNalfa.[38] The results of these two metaanalysesclearly support the phase IIdata that show a higher response ratefor biochemotherapy compared to chemotherapyor immunotherapy alone.

Phase III Studies

To date, the results of seven randomizedphase III studies comparingbiochemotherapy with chemotherapyor immunotherapy alone have beenreported (Table 3).[39-45] The resultshave been mixed but predominantlynegative.

• First EORTC Study-The firstEuropean Organization for Researchand Treatment of Cancer (EORTC)study compared the "decrescendo"IL-2 and IFN regimen of Keilholz,with or without cisplatin.[39] In thisstudy, 138 patients (126 assessable)were randomized to IL-2 plus IFNalfaalone vs cisplatin followed byIL-2 plus IFN-alfa. The biochemotherapyregimen produced a statisticallysuperior response rate (P = .04),but there was no difference in time toprogression or overall survival.
• French Study-Dorval et al[40]reported the results of a randomizedtrial that compared the Salpetriereregimen of cisplatin followed by IL-2plus IFN-alfa vs cisplatin followed byIL-2 without IFN-alfa, thus testing thevalue of IFN-alfa in this biochemotherapycombination. Although theresponse rate in the cisplatin, IL-2,and IFN-alfa arm was higher than thatseen with cisplatin plus IL-2 alone(25% vs 16%), this difference wasnot significant. Furthermore, there wasno difference in time to progressionor survival.
• NCI Study-Rosenberg et al[41]reported the results of a phase III studyconducted at the NCI. Patients wererandomized to receive cisplatin, dacarbazine,and tamoxifen, or cisplatin,dacarbazine, and tamoxifenfollowed by IL-2 plus IFN-alfa. In 52patients treated with chemotherapyalone, there were 14 objective responses(27%), including 4 completeresponses. In 50 patients treated withbiochemotherapy, there were 22 objectiveresponses (44%; P = .071),including 3 complete responses.The study also revealed a trendtoward a survival advantage amongpatients receiving chemotherapy alone(P = .052; median survival of 15.8months compared with 10.7 months).This unusual survival finding is dueto either the administration of highdoseIL-2 or other forms of salvagetherapy to patients failing to respondto chemotherapy and/or, most likely,an imbalance between the treatmentarms that is often seen with such smallnumbers of patients.

• Italian Study-Study-Ridolfi et al[43]recently reported the results of arandomized trial that compared chemotherapyalone with cisplatin, dacarbazine(plus optional carmustine),or the same chemotherapy regimenfollowed by low doses of subcutaneousIL-2 and IFN-alfa. There was nodifference in the overall response rate(25% vs 20%), time to progression,and overall survival. These data are inconformity with the phase II data suggestinga significantly lower responsewith biochemotherapy regimens thatuse subcutaneous IL-2 in low doses.
• M. D. Anderson Study-Study-My colleaguesand I reported the results ofthe M. D. Anderson Cancer Centerrandomized study comparing sequentialbiochemotherapy with chemotherapyalone.[42] A total of 190 patientswere enrolled in the study; of these,91 were evaluable in the biochemo-therapyarm and 92 in the CVD arm.The overall response rate was 48%for the biochemotherapy arm vs 25%for the CVD arm (P = .001), with sixcomplete responses in the biochemotherapyarm and two in the chemotherapyarm. The median time toprogression was 4.9 months for thebiochemotherapy arm vs 2.4 monthsfor the chemotherapy arm (P = .008),and the median survival was 11.9months vs 9.2 months for the twogroups, respectively (P = .06).
• Second EORTC Study-Keilholzet al[44] reported at the 2003 AmericanSociety of Clinical Oncology(ASCO) meeting the final results of theEORTC trial comparing IV cisplatin(30 mg/m² on days 1 to 3), IV dacarbazine(250 mg/m² on days 1 to 3),and subcutaneous IFN (10 mU/m² ondays 1 to 5) with the same regimen incombination with IL-2 using the decrescendoregimen (days 4 to 9). Enrollinga total of 360 patients, this isthe second largest randomized trial inthis setting. Overall, there was no differencein response rate, time to progression,or overall survival. A subsetanalysis of patients with a Karnofskyperformance status of 100 (n = 192)showed a trend for increased overallsurvival (P = .13).
• Intergroup Study-Also at the2003 ASCO meeting, Atkins et al[45]presented the preliminary results ofIntergroup study E-3695, which comparedconcurrent biochemotherapyusing a modified M. D. AndersonCancer Center regimen with CVDalone. This is the largest phase IIIstudy evaluating the role of biochemotherapycompared with chemotherapyalone in patients withadvanced melanoma.The results were disappointing,with no difference in overall responserate, time to progression, or survival.As one of the major differences in theeligibility criteria between the M. D.Anderson trial and the Intergroupstudy was the inclusion of patientswith prior adjuvant IFN-alfa therapyin the latter, a subset analysis of patientswith no prior IFN-alfa therapywas conducted. The results of this assessmentwere also negative, exceptfor an increase in progression-freesurvival in patients with no prior IFNtherapy (2 vs 6 months), but againwith no difference in response rate orsurvival.
• Reflections on the Phase IIIResults-Although the results of thephase II, single-institution studieswere encouraging, the phase III studieshave not demonstrated consistentresults. In fact, aside from the M. D.Anderson study, all other trials werecompletely negative. The major factorsthat likely explain the differentresults include different biochemotherapyregimens, patient selection,and, most importantly, "physicianselection." While multicenter trialsrepresent the "real world," the experiencewith IL-2-based regimens ofmost treating physicians was usuallyvery limited and likely compromisedthe results. This clearly contrasts withthe M. D. Anderson study, which wasconducted by five full-time medicaloncologists who had extensive experiencewith IL-2-based regimens andwere directly involved almost entirelyin the care of melanoma patients.Finally, the fact that the phase IIIstudies did not confirm the phase IIdata does not "erase" the fact thatapproximately 8% to 10% of the patientswith widely metastatic melanomawere cured with this treatmentmodality in phase II studies conductedby experienced oncologists. In myopinion, biochemotherapy remains animportant treatment modality in youngpatients with no central nervous systemmetastases. Patients should receivemore than two cycles only ifthey achieve at least a solid partialresponse. Otherwise, single-agent orcombination chemotherapy, which isclearly less toxic than biochemotherapy,should be considered.

Toxicity of BiochemotherapyRegimens

Cisplatin-based biochemotherapyregimens are associated with substantialtoxicity. The most common toxiceffects include fever, chills, edema,nausea, vomiting, skin rash, hypotension,peripheral neuropathy, and catheter-related infections.[46] Because ofthe severe toxicity, only patients withgood performance status, youngerthan 70 years of age, and no significantmedical illness such as chronicobstructive pulmonary disease, coronaryartery disease, ascites, or largepleural effusions should be treated.Furthermore, the use of corticosteroidsand all clinical entities that requireor may require steroids such asthose with central nervous system involvementor spinal cord compressionrepresent absolute contraindicationsto this type of therapy.A colleague and I recently reporteda detailed description of all thesemajor toxic effects as well as practicalguidelines concerning the mana-gement of biochemotherapy-relatedtoxicities that we believe may be usefulfor the practicing oncologist.[46]

Disclosures:

The author has no significant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

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