New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide

ABSTRACT: Although melanoma is a relatively chemoresistant malignancy, systemicchemotherapy remains the primary treatment for metastatic melanoma. Theobservation of vasculogenic mimicry in aggressive melanoma has promptedinvestigation into using an antiangiogenic agent to enhance the antitumoractivity of chemotherapy in metastatic melanoma. Thalidomide (Thalomid) exhibitsantiangiogenic activity and other biological modulatory effects that may provideadditive or synergistic antitumor effects when given concurrently withchemotherapy. A phase I/II study of thalidomide and temozolomide in thetreatment of metastatic melanoma is in progress. Preliminary results of thiscombination therapy have shown significant antitumor activity, including somestriking responses in brain metastases. [ONCOLOGY14(Suppl 13):25-28, 2000] Introduction The survival of patients with metastatic melanoma varies widely,ranging from only a few months to more than 10 years. Survival is primarilydependent on the sites of the first metastases, the number of metastatic sites,and responsiveness to treatment.[1] Melanoma can metastasize to virtually anyorgan or tissue. However, the initial sites of metastases are most commonly theskin, soft tissue, lymph nodes, and lung. The liver, bone, and brain are alsocommon, though less frequent, sites of initial relapse. Patients withnonvisceral disease (ie, skin, lymph nodes, and lung metastases) have a bettermedian survival, ranging from 12 to 15 months, and are more likely to respond tosystemic therapy.[1,2] Patients with visceral disease (ie, liver, bone, andbrain metastases) have a median survival of only 3 to 4 months, and few respondto treatment. In general, cure is not a realistic goal of treatment at thisstage of the disease. Therefore, treatment strategies must endeavor to preservequality of life while attempting to prolong life. Systemic Therapy The primary treatment for patients with metastatic melanoma issystemic therapy, in which response is associated with prolonged survival.Systemic therapy includes single- and multiagent chemotherapy, immunotherapy,and biochemotherapy. Melanoma is a relatively chemoresistant disease. The fewdrugs that have antitumor activity in melanoma have not surpassed the 10% to 20%response rates of dacarbazine (DTIC-Dome). Many combination chemotherapyregimens have been reported to have higher response rates and to be moreeffective for visceral metastases. However, most of the combination regimens areassociated with increased toxicity, with little evidence of improved survivalwhen compared to dacarbazine alone in phase III trials.[3] Even the addition ofhigh-dose tamoxifen (Nolvadex) to a combination regimen of cisplatin(Platinol)/carmustine (BCNU)/dacarbazine (the Dartmouth regimen) did not improvethe response rate or survival in a phase III study.[4] The administration of biological agents, such as interferon alfaand interleukin-2, has been shown to produce 10% to 15% responses in advancedmelanoma with occasional durable complete response. Good-prognosis groups aresimilar to those for chemotherapy, and include patients with good performancestatus, and metastatic disease in soft tissue, skin, and lymph nodes.Biochemotherapy or chemoimmunotherapythat is, the combination of chemotherapyand biological agentsis another treatment strategy intended to improve theantitumor effect of systemic therapy. The results of several phase II studieshave demonstrated high response rates and durable responses. Recently, a randomized phase III study comparing a chemotherapyregimen (composed of cisplatin, dacarbazine, and tamoxifen) with the samechemotherapy plus high-dose interleukin-2 and interferon alfa was reported bythe surgery branch at the National Cancer Institute.[5] The response rate was27% (4 out of 52 complete responses) for chemotherapy-treated patients and 44%(3 out of 50 complete responses) for biochemotherapy-treated patients. However,the tendency toward an increased response rate in patients who receivedbiochemotherapy did not translate into an increase in overall survival, andthere was, in fact, a trend for a survival advantage in patients receivingchemotherapy alone (median survival: 10.7 vs 15.8 months). Because of the severetoxicity associated with the biological agents, biochemotherapy iscontraindicated in elderly patients, or patients with central nervous system(CNS) metastases, known cardiac disease, or symptomatic pulmonary disease. Clearly, dacarbazine remains the most active drug and is thestandard chemotherapy for metastatic melanoma. However, response is seenprimarily in the skin, soft tissue, lymph nodes, and lung. It is estimated thatup to 70% of patients who die of metastatic melanoma have either known orsubclinical brain metastases. Like many other chemotherapy agents, dacarbazinedoes not penetrate the blood-brain barrier; thus it is inactive against CNSmetastases. Furthermore, disease relapse in the CNS is often a major problem inpatients responding to chemotherapy. Improving CurrentManagement Efforts to improve management of metastatic melanoma shouldfocus on the development of new antitumor agents and novel combination regimens.Desirable characteristics of new treatment strategies include improved responsein visceral metastases, penetration of the blood-brain barrier with activity inbrain metastases, improved survival, and preservation of quality of life in theform of reduced toxicity, improved tolerability, and ease of administration. Temozolomide Temozolomide, which was recently approved for the treatment ofrefractory anaplastic astrocytoma, is an oral alternative to dacarbazine. Theagent exhibits approximately 100% oral bioavailability, penetrates theblood-brain barrier, and has activity against brain tumors. The clinicalactivity of temozolomide against melanoma was confirmed in a large randomizedstudy, when patients were treated with a 5-day schedule of either dacarbazine ortemozolomide.[6] More interestingly, patients who responded to temozolomide hada four times lower incidence of melanoma relapse in the brain than did patientswho responded to dacarbazine.[7] As has been reported by Brock et al,[8] whentemozolomide is administered at an extended continuous schedule over a 7-weekperiod, it permits a 2.1-fold greater drug exposure over 4 weeks, in comparisonwith the 5-day schedule repeated every 28 days. In this phase I study, responses were observed in two of fourpatients with metastatic melanoma: a partial response in a patient withpulmonary metastases and a mixed response in a patient with CNS metastases. Theimproved clinical activity is postulated to be related to the cumulativedepletion of O6-alkylguanine-DNA-alkyl-transferase,a DNA repair protein involved in dacarbazine drug resistance of melanoma. It isanticipated that temozolomide will replace dacarbazine as first-line treatmentfor disseminated melanoma because of its ease of oral administration, improvedclinical activity, and ability to achieve adequate CNS penetration. Thalidomide Thalidomide has been shown to exert antiangiogenic effects,including inhibition of angiogenesis induced by basic fibroblast growth factorin the rabbit corneal micropocket assay.[9,10] Thalidomide has a number of otherbiological activities that may contribute to its role as an effective agent intreating melanoma; these include alteration of adhesion molecule expression,suppression of tumor necrosis factor-alpha, increased production ofinterleukin-10, and enhancement of cell-mediated immunity via directcostimulation of T cells resulting in increased interferon gamma andinterleukin-12 production.[11-15] CombinedAntiangiogenic and Cytotoxic Chemotherapy Prospects for new combination regimens have been heightened bythe recent discovery of vasculogenic mimicry in aggressive human uveal andcutaneous melanomas.[16] In particular, it has been shown that both primary andmetastatic melanomas can form tumor-cell-lined vascular channels, and thatthis activity is correlated with tumor aggressiveness and clinical outcomes.These findings suggest that the therapy directed against both endothelial- andtumor-cell compartments of a tumor is more effective than therapy against tumorcells only. Thus, combining standard chemotherapy with an antiangiogenic agenthas the potential to improve its antitumor effect for this chemoresistantmalignancy. We initially used thalidomide on a compassionate-use basis inselect patients with disease progression who had received standard chemotherapyor immunotherapy. One case was that of a 60-year-old woman who developedmultiple in-transit metastases in the leg and metastases in the inguinal lymphnodes 37 years after a primary melanoma was removed from her ankle. She wastreated initially with inguinal lymphadenectomy and isolated limb perfusion withcarboplatin (Paraplatin). Postoperatively, she received adjuvant high-dose interferontherapy, but her disease recurred in the leg shortly after completion of 1 yearof adjuvant therapy; treatment included isolated limb perfusion with melphalan(Alkeran) and tumor necrosis factor. Subsequently, her disease progressed in thepelvis and retroperitoneum and interleukin-2 systemic therapy was used. However,disease progression continued not only in the leg, pelvis, and retroperitoneum,but new metastases had also developed in the liver and mesentery with massivemalignant ascites. On initial presentation, the patient was cachectic with adistended abdomen and had a Karnofsky performance status of 40%. She was startedon thalidomide at 100 mg/d and dacarbazine on an every-3-week schedule. After 3months, not only did the ascites completely resolve, but significant shrinkageof metastases in the liver and mesentery was observed, the retroperitonealadenopathy had completely resolved, and the pelvic adenopathy had markedlyimproved. The patient elected to discontinue dacarbazine, but remained onthalidomide at a maximum dose of 200 mg/d. After an additional 3 months,resolution of the liver metastases continued and virtually no adenopathy wasdetected. The patient has now been on single-agent thalidomide at 200 mg/d forover 1 year since stopping dacarbazine and recently has exhibited recurrenceonly in the leg. These encouraging results prompted us to combine thalidomidewith the Dartmouth regimen in two additional patients who had diseaseprogression after treatment with this combination chemotherapy regimen;treatment resulted in stable disease in one patient and a minor response in theother. PhaseI/II Study of Thalidomide and Temozolomide Prompted by the observation of disease responses in thesepatients treated with thalidomide and chemotherapy, we have initiated a phaseI/II study of thalidomide and temozolomide in advanced melanoma. The rationalesfor this study include the following: (1) It is anticipated that temozolomide will replace dacarbazineas first-line treatment for disseminated melanoma because of its ability to begiven orally, its potential for improved activity using a prolonged dailyschedule, and its ability to achieve adequate CNS penetration. (2) Compelling data indicate that thalidomide is an immunemodulator, and that it can modulate many cellular activities in melanoma. Thus,thalidomide has the potential to enhance the therapeutic efficacy oftemozolomide when both are administered on an extended continuous schedule. (3) The mechanism of the antitumor action of thalidomide may berelated to antiangiogenesis. Since antiangiogenic drugs target the endothelialcells and not the tumor cells per se, they could potentially be synergisticagainst chemotherapy-resistant tumors when they are combined with cytotoxicagents. (4) Thalidomide has a broad spectrum of activity, is availablein a well-tolerated oral form, has predictable side effects that can be managedeasily, and does not enhance the toxicity of other anticancer agents (as shownin combination with the Dartmouth regimen and temozolomide). Study Design The phase I portion of the study is intended to determine themaximum tolerated dose of temozolomide using an extended, continuous schedule incombination with thalidomide. Thalidomide is being administered at 200 mg/d forthe first 2 weeks, followed by an increase of 100 mg/d at 2-week intervals untilthe maximum dose of 400 mg/d is reached. Temozolomide is being administered atfour dose levels consisting of 50 mg/m2/d for 6weeks followed by a 4-week rest period, and 75 mg/m2/dfor 6 weeks followed by rest periods of 4, 3, or 2 weeks. In the phase IIportion, responses to the combination using an extended continuous schedule atthe maximum tolerated dose are being assessed in 30 patients with advancedmetastatic melanoma without CNS metastases and in 15 patients with CNSmetastases. Striking Responses Two remarkable CNS responses have been observed to date in thephase I portion of the study. In one case, a 43-year-old woman with metastaticmelanoma in the brain, lung, and subcutaneous soft tissue developed newleptomeningeal disease after whole-brain radiation for bilateral multiplelesions. After she received two cycles of this combination therapy, she wasnoted to have near complete response in all sites of metastases, resolution ofmultiple hemorrhagic intracranial lesions, and diffuse leptomeningeal disease,as well as resolution of subcutaneous nodules, and reduction in lung nodules.The patient has now received the combination therapy for a year and her diseaseis in complete remission. She continues to work full time and refuses to stoptherapy. In another case, a 39-year-old woman developed metastaticmelanoma in the brain, lung, mediastinum, spleen, and pelvis, after completing ayear of high-dose adjuvant interferon alfa therapy. After receiving one cycle ofthis combination treatment, she exhibited a dramatic response in the pituitarystalk and multiple intracranial lesions, near resolution of the largemediastinal mass, and significant reductions in splenic and pelvic disease. Thepatient continues on treatment. Conclusion The ability to achieve such striking responses with the combineduse of temozolomidea cytotoxic agentand thalidomidea cytostatic agentraisesthe hope that this approach will indeed improve the treatment for metastaticmelanoma. A better idea of whether this promise is to be borne out awaitsfindings from the phase II portion of the study. References: 1. Balch CM, Soong S-J, Murad TM, et al: A multifactorialanalysis of melanoma. IV. Prognostic factors in 200 melanoma patients withdistant metastases. J Clin Oncol 1:126, 1983. 2. Klimek VM, Wolchok JD, Chapman PB, et al: Systemicchemotherapy. Clin Plast Surg 27:451, 2000. 3. Chapman PB, Einhorn LH, Meyer ML, et al: Phase IIImulticenter randomized trial of the Dartmouth regimen versus dacarbazine inpatients with metastatic melanoma. J Clin Oncol 17:2745-2751, 1999. 4. Rusthoven J, Quirt IC, Iscoe NA, et al: Randomized, doubleblind, placebo-controlled trials comparing the response rates of carmustine,dacarbazine, and cisplatin with and without tamoxifen in patients withmetastatic melanoma. J Clin Oncol 14:2083-2090, 1996. 5. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al:Prospective randomized trial of the treatment of patients with metastaticmelanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone orin combination with interleukin-2 and interferon alpha-2b. J Clin Oncol17:968-975, 1999. 6. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phaseIII study of temozolomide versus dacarbazine in the treatment of patients withadvanced metastatic melanoma. J Clin Oncol 18:158-166, 2000. 7. Summers Y, Middleton MR, Calvert H, et al: Effect oftemozolomide on central nervous system relapse in patients with advancedmelanoma (abstract 2048). Proc Am Soc Clin Oncol 18:531a, 1999. 8. Brock CS, Newlands ES, Wedge SR, et al: Phase I trial oftemozolomide using an extended continuous oral schedule. Cancer Res58:4363-4367, 1998. 9. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is aninhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994. 10. Kruse FE, Jousee AM, Rohrschneider K, et al: Thalidomideinhibits corneal angiogenesis induced by vascular endothelial growth factor.Graefes Arch Clin Exp Ophthalmol 236:461-466, 1998. 11. Geitz H, Handt S, Zwingenberger K: Thalidomide selectivelymodulates the density of cell surface molecules involved in the adhesioncascade. Immunopharmacol 31:213-221, 1996. 12. Sampaio EP, Sarno EN, Galilly R, et al: Thalidomideselectively inhibits tumor necrosis factor alpha production by stimulated humanmonocytes. J Exp Med 173:699-703, 1991. 13. Corral LG, Muller GW, Moreira AL, et al: Selection of novelanalogs of thalidomide with enhanced tumor necrosis factor a inhibitoryactivity. Mol Med 2:506-515, 1996. 14. Haslett PAJ, Corral LG, Albert M, et al: Thalidomideco-stimulates primary human T lymphocytes, preferentially inducingproliferation, cytokine production, and cytotoxic responses in the CD8+ subset.J Exp Med 187:1885-1892, 1998. 15. McHugh SM, Rifkin IR, Deighton J, et al: Theimmunosuppressive drug thalidomide induces T helper cell type 2 (Th2) andconcomitantly inhibits Th1 cytokine production in mitogen- andantigen-stimulated human peripheral blood mononuclear cell cultures. Clin ExpImmunol 99:160-167, 1995. 16. Maniotis AJ, Folberg R, Hess A, et al: Vascular channelformation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. AmJ Pathol 155:739-752, 1999.