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Temozolomide (Temodur®) Treatment and Immunodeficiency in Melanoma Patients
Abstract & Commentary
Synopsis: Temozolomide has been used for the treatment of melanoma with effects comparable to DTIC, and regimens are currently under development that involve more extensive administration. In this report from Memorial Sloan Kettering, patients treated on a daily schedule for 6 weeks or more before a treatment break were observed to develop significant lymphopenia and a higher-than-expected incidence of opportunistic infections.
Source: Su YB, et al. J Clin Oncol. 2004;22:610-616.
Temozolomide (TMZ) is an oral chemotherapeutic agent that is metabolized to the alkylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboximimide, which is the active metabolite of dacarbazine (DTIC). Like DTIC, TMZ has shown some activity against melanoma,1 but, unlike DTIC, it is 100% bioavailable after oral dosing. The schedule most commonly used for TMZ in the treatment of melanoma is 150-200 mg/m2 orally, daily for 5 days every 4 weeks. Su and colleagues at Memorial Sloan Kettering Cancer Center used a more intensive dosing schedule of TMZ in an effort to improve response rates. TMZ was administered to 97 patients at 75 mg/m2/d orally for 6 weeks followed by a 2-week rest period (17 patients were continued without the 2-week break). Thalidomide was also given to 73 of the patients, and 7 patients received low-dose interferon alfa. The median duration of TMZ treatment was 113 days; 29% received > 24 weeks of therapy.
Upon retrospective analysis, lymphopenia was observed in 60% of patients (absolute lymphocyte count of < 800/uL) with a median of 101 days of treatment to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4+ compartment preferentially. One patient developed documented Pneumocystis carinii pneumonia, with another 2 patients meeting clinical criteria that were not biopsy-proven. In addition, one case of Aspergillus pneumonia, 4 cases of Herpes simplex, 4 cases of Herpes zoster, 11 cases of mucocutaneous candidiasis, and 1 case of Kaposi’s sarcoma were observed. All of the patients who developed infections were lymphopenic except for 2 patients who developed Herpes zoster and 2 patients who developed mucocutaneous candidiasis.
Comment by William B. Ershler, MD
The treatment of melanoma remains frustrating. DTIC is the only FDA-approved chemotherapeutic agent for this indication, and combinations, including biotherapies, have not proven to offer any advantage in long-term survival. TMZ, when used in the 5-day/month schedule is comparable and offers the practical advantage of oral administration. The more intensive regimen used at Memorial is a reasonable approach to improving efficacy. Su and colleagues are to be credited for recognizing the treatment-associated immunodeficiency as indicated by the CD4+ lymphopenia and reporting the disproportionate occurrence of opportunistic infection.
As pointed out by Su et al, and in an accompanying editorial,2 there are several important clinical implications of this report. First, if it turns out that the more intensive TMZ schedule offers improved outcomes in terms of tumor regressions and prolonged survival, then it would be prudent to consider Pneumocystis carinii pneumonia prophylaxis in treated patients and subject all treated patients to careful scrutiny for opportunistic infections. Secondly, evolving treatment strategies that involve immunomodulating approaches will need to take into consideration the deflating effect of TMZ on CD4 cell number and presumably function. For example, strategies that involve co-administration of interleukin-2 may be ineffective because of the countering effect of TMZ on the target cells of the immunoenhancing cytokine.
Finally, clinical investigators aware of the TMZ effect on CD4 T cells may explore the role of this drug as an immunosuppressant (eg, in the post-transplant setting) or in the treatment of tumors of CD4 lineage, such as in subsets of cutaneous T-cell lymphomas.
Dr. Ershler is from INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.