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Originally published as JCO Early Release 10.1200/JCO.2005.02.5791 on October 31 2005 © 2005 American Society of Clinical Oncology.
Low-Dose Outpatient Chemobiotherapy With Temozolomide, Granulocyte-Macrophage Colony Stimulating Factor, Interferon-
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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PATIENTS AND METHODS: Thirty-one patients with histologically confirmed unresectable measurable metastatic melanoma were enrolled onto an open-label, multicenter phase II study. The treatment regimen consisted of oral temozolomide followed by subcutaneous biotherapy with granulocyte macrophage colony-stimulating factor, interferon-alfa, and recombinant interleukin-2 (rIL-2).
RESULTS: Twenty-eight patients (90%) had M1c disease, and 58% had three or more sites of metastasis. Four patients (13%), all with M1c disease, had a complete response, and four patients had a partial response. The median progression-free survival was 4.9 months and the median overall survival was 13.1 months. Two patients (6%) developed CNS metastasis as the first site of disease progression, and 7 (23%) of 30 experienced CNS progression after receiving chemobiotherapy. A total of 112 cycles of therapy were administered. Toxicity occurred in 78% of the cycles and was grade 1 or 2 in the majority of cases and easily managed. Grade 4 toxicity occurred in 3% of the cycles.
CONCLUSION: This low-dose chemobiotherapy combination produces clinical responses in patients with metastatic melanoma, even in those with M1c disease, is well tolerated, and allows home dosing. It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease. Furthermore, it may protect against the development of brain metastases.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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de Gast et al conducted trials of chemobiotherapy with temozolomide, granulocyte macrophage colony-stimulating factor (GM-CSF), low-dose rIL-2, and interferon-alfa (IFN-
) in patients with metastatic melanoma or renal cell carcinoma.1-3 The rationale for this combination of cytokines for the biologic therapy component of the regimen is that they improve antigen presentation (GM-CSF), cause expansion and activation of T cells (rIL-2 + GM-CSF), increase effector-cell function (IFN), and cause immunosensitization of the tumor cells by increased expression of human leukocyte antigen, tumor-associated antigens, and adhesion molecules (IFN). de Gast et al3 reported that the regimen is well tolerated, has toxicities manageable on an out-patient basis, and may have superior clinical benefit to that found currently approved therapies. We pursued evaluation of this regimen to gain additional information about its safety and efficacy.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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70, adequate hematologic, liver, and renal function, and life expectancy greater than 12 weeks. Patients were permitted to have received therapy for prior disease but must have completed therapy at least 1 month before study entry. Patients with brain metastases were eligible provided that the brain metastases were controlled. Investigations were performed after approval by the local Human Investigations Committees of the participating institutions and patients gave written informed consent for participation in the study.
Treatment Regimen
For the first treatment cycle, patients received oral temozolomide: 200 mg/m2 (150 mg/m2 daily for patients with a previous history of chemotherapy) daily for 5 days (Table 1). Since temozolomide is highly lipophilic, there was concern that use of the full calculated body-surface area (BSA) might lead to overdosing in obese subjects. Therefore, the dose of temozolomide was limited to a maximum BSA calculation of 2.0. The temozolomide treatment was followed by 12 daily subcutaneous injections of biotherapy starting on day 6. The biotherapy consisted of a combination of GM-CSF (125 µg/m2 to a maximum 250 µg), IFN (5 MU), and rIL-2 (4 MU/m2). This was followed by an 11-day period of rest. This 28-day treatment cycle was repeated as clinically indicated with the same treatment sequence and dosage of each individual medication, or adjusted per-dosing modifications based on adverse events and the investigator's judgment. Patients intolerant (experiencing grade 3 or grade 4 toxicities or at the investigator's discretion) of the biotherapy received a decreased dose of rIL-2 of 2 MU/m2. The dosage of temozolomide was adjusted on the basis of the nadir absolute neutrophil count and/or nadir platelet count. The dosages of GM-CSF and IFN were not adjusted. In the absence of disease progression or unacceptable toxicity, patients were permitted to continue to receive treatment with the protocol medications for up to eight treatment cycles from initial dose. At the investigator's discretion, patients continuing with at least stable disease or in response could be treated beyond eight cycles after discussion with the principal investigator.
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CNS Metastases
During the course of this study, O'Day et al6 reported results of their analysis of 163 patients treated with DTIC-based concurrent biochemotherapy regimen (DTIC, vinblastine, cisplatin, decrescendo IL-2, and IFN), pointing out that CNS progression occurs frequently in the setting of relative control of systemic disease and is the cause for a significant number of biochemotherapy treatment failures and death (unpublished data). Therefore, although the analysis was not planned in advance, we collected information on the incidence of CNS metastases in the patients during and following low-dose outpatient chemobiotherapy. In addition, we determined the timing of the appearance of CNS metastases relative to progression of disease elsewhere.
Statistical Methods
This study was a phase II, open-label trial of chemobiotherapy for patients with unresectable metastatic melanoma. The study was intended to include 30 patients, but one additional patient was treated. All analyses were based on the intent-to-treat principle (ie, all study participants were included in the analyses, regardless of whether they violated protocol or completed the study). Only descriptive analyses of safety parameters were planned and conducted. Response and progression were evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.4 Patients were considered responders to this treatment regimen, if, by the end of the treatment period, they had achieved an objective response (either a partial response (PR) or complete response (CR) of at least 28 days duration). Time to progression (TTP) and survival were measured from day 1 of chemobiotherapy. The duration of progression-free and overall survival, TTP, and survival curves were generated using the Kaplan-Meier method.5 The 95% CIs were calculated using Greenwood's formula for the SE. The incidence of CNS metastases in patients receiving this low-dose, outpatient chemobiotherapy protocol was compared with the incidence of CNS metastases in patients receiving a high-dose inpatient biochemotherapy (O'Day et al, unpublished data) using Fisher's exact test. Univariate Cox proportional hazards models were run to evaluate the relationship among prior therapy, the duration of progression-free survival, and overall survival.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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Response
Four patients (13%) achieved a CR and four patients (13%) had a PR (Table 3). Thus, the objective response rate was 26% (95% CI, 12% to 45%). An additional seven patients (23%) had stable disease for > 4 months, bringing the overall rate of benefit to 48% (95% CI, 30% to 67%).
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Twenty-nine patients (94%) experienced disease progression (Table 5). The median duration of progression-free survival was 4.9 months (95% CI, 2.8 to 6.9 months; Fig 1). The overall progression-free rate was 29% at 1 year and 10% at 2 years. Twenty-six patients (84%) died (Table 5). The median duration of survival was 13.1 months (95% CI, 7.8 to 18.3 months; Fig 1) for all patients and 25.9 months for patients experiencing an objective response. The overall survival rate was 52% at 1 year and 25% at 2 years.
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CNS Metastases
All patients were assessable for development of new or progressive brain metastases as the first site of metastasis with or without systemic progression. Two patients (6%) developed brain metastases as the first site of disease progression, whereas development of brain metastases as the first site of disease progression occurred in 54 (33%) of the 163 patients on the high-dose inpatient regimen (P = .002, Fig 2). Furthermore, the two patients treated with the low-dose chemobiotherapy regimen described herein who had brain metastases previously treated with stereotactic radiotherapy before study entry are still alive and never developed progressive brain lesions.
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Toxicity
The treatment was generally well tolerated. Initially, patients were hospitalized for 1 day when they started receiving therapy with rIL-2. However, because rIL-2 was well tolerated, the requirement for hospitalization was dropped. Otherwise, the treatment was conducted entirely on an outpatient basis.
Adverse events were noted in 78% of all treatment cycles (Table 6). These events were generally mild (grade 1 or 2) and easily managed. Grade 4 toxicity was noted in 3% of the cycles, including hematologic toxicity (thrombocytopenia) in two cycles (thought to be caused by temozolomide) and psychosis in one cycle (thought to be possibly related to the biologic therapies) that required hospitalization and discontinuation of treatment, even though the disease was responding to therapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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In an analysis of prognostic factors in 1,158 patients with stage IV metastatic melanoma, it was found that the most significant differences were noted when visceral versus nonvisceral sites were compared.7 This analysis formed the basis for the M classification in the current staging system of the American Joint Commission on Cancer (AJCC).8 Many earlier reports also identified visceral metastases as an important indicator of poor prognosis.9,10 The analysis that formed the basis for the current AJCC staging system did not incorporate information regarding the number of metastatic sites, so this was not included in the staging.7 However, a number of other studies have determined that the number of metastatic sites is, indeed, an important prognostic indicator.9-11
The incidence of the development of CNS metastasis in this study was significantly different from that reported by O'Day et al (unpublished data) in terms of CNS as the first site of disease progression, either alone or in combination with systemic progression, and approached significance in terms of incidence of CNS metastases during or following therapy. In a retrospective analysis of patients with metastatic melanoma responding to DTIC- or temozolomide-based chemotherapy (n = 41), Paul et al12 also found a statistically significant decrease in the development of CNS relapse in the patients receiving the regimen containing temozolomide. The Hellenic Cooperative Oncology Group conducted a study of temozolomide in combination with docetaxel in patients with advanced melanoma (n = 62) and reported that of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months.13 In a pilot trial of concurrent biochemotherapy in which temozolomide was substituted for DTIC used in an earlier combination regimen, Atkins et al14 found that initial CNS progression was significantly less frequent in the temozolomide-based regimen than in the DTIC-based biochemotherapy regimen (two of 22 v 12 of 19; P = .001), but this analysis was limited to patients responding to biochemotherapy. When all patients who entered the temozolomide-based regimen were considered, the incidence of CNS progression was 67%.
The inclusion of temozolomide in the regimen described herein, rather than DTIC as used in other regimens, may account for this difference in outcome, because temozolomide crosses the blood-brain barrier,15,16 whereas DTIC does not. Temozolomide is approved for the treatment of anaplastic astrocytoma and glioblastoma and has been reported to have activity in the treatment of brain metastases from malignant melanoma.17
Given the dismal outcome with previous therapeutic approaches, especially the US Food and Drug Administration–approved monotherapies DTIC18-20 and rIL-2,21-23 there has been enthusiasm for using chemotherapy and chemobiotherapy combinations. In many uncontrolled trials, of complex combinations of chemotherapy with and without cytokines, results were consistent with improved response rates and, possibly, survival. Results of randomized trials, however, showed that combination chemotherapy is no better than therapy with single-agent DTIC.19 One randomized, single-institutional trial showed an improved objective response rate, time to progression, and a trend towards increased survival among patients randomly assigned to sequential biochemotherapy compared with chemotherapy alone.24 However, randomized trials reported at the 2003 Annual Meeting of the American Society of Clinical Oncology (ASCO; Chicago, IL, May 31-June 3, 2003) indicated that chemobiotherapy is no better than combination chemotherapy.25-27 This led L.M. Schuchter, in her 2003 ASCO lecture, to conclude that it's time to "wipe the slate clean and start over."28
The high-dose biochemotherapy regimens require hospitalization and are disruptive of lifestyle in patients in whom life expectancy may be limited. Some studies have shown promising results in the outpatient setting, such as the temozolomide-thalidomide combination.29-31 However, a trial of temozolomide and thalidomide in patients with melanoma metastatic to the brain was recently closed to accrual because of thrombotic events, presumably associated with thalidomide. Studies of outpatient regimens using lower doses of biologics in combination with chemotherapy have also appeared promising.32,33 The study results described in this manuscript indicate that this low-dose chemobiotherapy regimen has activity, even in patients with M1c disease, and can be administered on an outpatient basis with manageable toxicity.
Three phase III trials of new agents for therapy of stage IV melanoma have been concluded in 2004 with disappointing negative results. These include a randomized trial of high-dose Revlimid (lenalidomide; Celgene Corp, Summit, NJ) versus low-dose Revlimid in patients who had experienced treatment failure with first-line chemotherapy for metastatic melanoma.34 A similar trial in Europe comparing high-dose Revlimid versus placebo in the same patient population also failed to show clinical benefit of Revlimid therapy.34 A trial in melanoma patients with hepatic metastases of Maxamine (histamine dihydrochloride; Maxim Pharmaceuticals, San Diego, CA) with low-dose rIL-2 versus low-dose rIL-2 alone failed to show benefit of the combination therapy.35 Finally, a trial of Genasense (oblimersen sodium, Genta Inc, Berkeley Heights, NJ), an inhibitor of BCL2, administered with DTIC compared with DTIC alone failed to show benefit of the combination.36
O'Day et al6 have reported a maintenance biotherapy regimen that offers the potential to extend the clinical benefit in patients responding to the high-dose inpatient biochemotherapy regimen. This regimen includes subcutaneous rIL-2 and GM-CSF with monthly decrescendo intravenous rIL-2. It is noteworthy that three patients who received chemobiotherapy on this protocol subsequently received the maintenance regimen off protocol. The role of maintenance therapy should be considered in future studies.
There is no question that more-effective and less-toxic therapies for metastatic melanoma are desperately needed. The US Food and Drug Administration–approved therapy with single-agent chemotherapy, DTIC, has limited activity in patients with visceral metastasis. The alternative US Food and Drug Administration–approved therapy with high-dose rIL-2 requires inpatient administration, is associated with significant toxicity, and is most effective in patients with M1a disease. We strongly advocate recommendation to patients with metastatic melanoma that they participate in clinical trials that offer the potential for greater efficacy and less toxicity. However, for patients who decline the US Food and Drug Administration–approved therapies, and who are not candidates for or do not choose to participate in clinical trials, the regimen described herein has potential for clinical benefit (including the possibility of causing disease regression, benefiting progression-free and overall survival, and preventing or delaying the development of brain metastases) with limited toxicity in a regimen that permits home dosing. A randomized trial would be required to determine whether this combination provides greater efficacy and less toxicity than the currently approved therapies.
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Authors' Disclosures of Potential Conflicts of Interest |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
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Acknowledgment |
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NOTES |
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L.E.S. is a member of the Cogenix Speaker's Bureau, supported by Berlex Oncology, Seattle, WA. L.E.S. and R.A. are members of the Board of Directors of the Melanoma Research Institute, Tiburon, CA.
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003, and at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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2. Groenewegen G, Bloem A, de Gast GC: Phase I/II study of sequential chemoimmunotherapy (SCIT) for metastatic melanoma: Outpatient treatment with dacarbazine, granulocyte-macrophage colony-stimulating factor, low-dose interleukin-2, and interferon-alpha. Cancer Immunol Immunother 51:630-636, 2002[Medline]
3. de Gast GC, Batchelor D, Kersten MJ, et al: Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFN alpha in patients with metastatic melanoma. Br J Cancer 88:175-180, 2003[CrossRef][Medline]
4. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
5. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]
6. O'Day SJ, Boasberg PD, Piro L, et al: Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res 8:2775-2781, 2002
7. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622-3634, 2001
8. Cancer Staging Manual AJCC (ed 6). New York, NY, Springer, 2002
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14. Atkins MB, Gollob JA, Sosman JA, et al: A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma. Clin Cancer Res 8:3075-3081, 2002
15. Ostermann S, Csajka C, Buclin T, et al: Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 10:3728-3736, 2004
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17. Agarwala SS, Kirkwood JM, Gore M, et al: Temozolomide for the treatment of brain metastases associated with metastatic melanoma: A phase II study. J Clin Oncol 22:2101-2107, 2004
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19. Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745-2751, 1999
20. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-166, 2000
21. Atkins MB, Lotze MT, Dutcher JP, et al: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105-2116, 1999
22. Sparano JA, Fisher RI, Sunderland M, et al: Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11:1969-1977, 1993
23. Phan GQ, Attia P, Steinberg SM, et al: Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477-3482, 2001
24. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 20:2045-2052, 2002
25. 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 21:2847a, 2003
26. 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 21:2848a, 2003
27. Del Vecchio MM, Bajetta E, Vitali M, et al: 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 21:2849a, 2003
28. Schuchter LM: Overview of randomized biochemotherapy studies. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003
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31. Hwu WJ, Krown SE, Panageas KS, et al: Temozolomide plus thalidomide in patients with advanced melanoma: Results of a dose-finding trial. J Clin Oncol 20:2610-2615, 2002
32. Thompson JA, Gold PJ, Markowitz DR, et al: Updated analysis of an outpatient chemoimmunotherapy regimen for treating metastatic melanoma. Cancer J Sci Am 3:S29-S34, 1997 (suppl 1)
33. Thompson JA, Gold PJ, Fefer A: Outpatient chemoimmunotherapy for the treatment of metastatic melanoma. Semin Oncol 24:S44-S48, 1997[Medline]
34. Celgene Announces Plans to Stop Phase III Trials In Melanoma Due to Lack of Efficacy. http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=520356&highlight=revlimid, 2004
35. Maxim Pharmaceutical Phase 3 Trial for Advanced Malignant Melanoma Fails to Meet Primary Endpoint. http://investors.maxim.com/releaseDetail.cfm?releaseID=143390, 2004
36. Genta Announces Updated Results from its Phase 3 Trial of Genasense for Advanced Melanoma. http://www.genta.com/Genta/InvestorRelation/2004/press_20040607.html, 2004
Submitted May 3, 2005; accepted August 15, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2b, and Recombinant Interleukin-2 for the Treatment of Metastatic Melanoma
