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Journal of Clinical Oncology, Vol 20, Issue 2 (January), 2002: 420-425
© 2002 American Society for Clinical Oncology

Temozolomide in Combination With Docetaxel in Patients With Advanced Melanoma: A Phase II Study of the Hellenic Cooperative Oncology Group

By D. Bafaloukos, H. Gogas, V. Georgoulias, E. Briassoulis, G. Fountzilas, E. Samantas, Ch. Kalofonos, D. Skarlos, A. Karabelis, P. Kosmidis

From the Metaxa’s Cancer Hospital, Piraeus; University of Athens, Laiko Hospital, Agioi Anargiri Cancer Hospital, Athens Medical Center, and Ygeia Hospital, Athens; University of Crete, Iraklion; University of Ioannina, Ioannina; Ahepa Hospital, Aristotle University of Thessaloniki, Thessaloniki; and University of Patras, Rio, Greece.

Address reprint requests to Dimitrios Bafaloukos, MD, Metaxa’s Cancer Hospital, 51, Botassi Str, Piraeus 18537, Greece; email: hesmo{at}compulink.gr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma.

PATIENTS AND METHODS: Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m2) on day 1 and oral temozolomide (150 mg/m2) on days 1 to 5, every 4 weeks, for a maximum of six cycles.

RESULTS: Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. 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. Myelosuppression was the primary toxicity.

CONCLUSION: The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
IN 2001, THERE WERE AN estimated 51,400 new cases of melanoma in the United States and approximately 7,800 related deaths.1 Although the prognosis for patients with early-stage disease is favorable and adjuvant interferon alfa (IFN-{alpha}) therapy has been shown to improve disease-free and overall survival (OS) in patients with stage IIb and stage III disease,2,3 the prognosis remains poor for patients with systemic metastases. The median survival for patients with stage IV melanoma is only 6 to 9 months, with an estimated 5-year survival rate of less than 5% to 10%.4,5 Unfortunately, these survival figures have not changed in over 22 years of clinical study.

A number of chemotherapy agents have demonstrated activity in metastatic melanoma, including dacarbazine (DTIC), the nitrosoureas, platinum analogs, vinca alkaloids, and the taxanes. Objective response rates are generally less than 20%,6 and complete responses generally occur in fewer than 5% of treated patients.7,8 Docetaxel, a semisynthetic taxoid, has also demonstrated activity in phase I and II trials in patients with advanced melanoma, with overall response rates of 13% to 17%.9-11 Unfortunately, responses to chemotherapy are generally of short duration (5 to 6 months).8 Presently, DTIC remains the mainstay of most chemotherapy regimens. Unfortunately, DTIC penetrates poorly into the CNS, and consequently, few if any responses have been achieved in patients with brain metastases. This is particularly problematic, as studies have shown that approximately 75% of patients with stage IV melanoma may eventually develop brain involvement.12 Therefore, novel chemotherapy agents or combinations are needed in the treatment of advanced melanoma.12 Interleukin-2 (IL-2)–based immunotherapy has produced more durable responses compared with chemotherapy,13 and immunotherapy in combination with DTIC and cisplatin-based chemotherapy has produced high objective response rates.14 However, none of these regimens has demonstrated activity in the CNS.

Temozolomide is a novel oral alkylating agent that has demonstrated antitumor activity against a broad range of tumor types, including malignant glioma, melanoma, and carcinoma of the ovary and colon.15-20 It has recently been approved for the treatment of refractory anaplastic astrocytoma. Temozolomide, like DTIC, is converted to the active metabolite [3-methyltriazen-1-yl]imidazole-4-carboxamide (MTIC). However, the metabolism of DTIC occurs only in the liver, and MTIC itself is unable to penetrate the blood-brain barrier. In contrast, temozolomide can cross the blood-brain barrier and is spontaneously converted to MTIC in the CNS.17,21-23 Consequently, temozolomide can achieve effective concentrations in the brain.23-26 This suggested that temozolomide may be effective in the treatment of brain metastases and could prevent metastasis to the CNS.

In phase I and II trials, patients with advanced metastatic melanoma achieved overall response rates of 17% to 21% with single-agent temozolomide.17,18 The most common dose-limiting toxicity was noncumulative myelosuppression. In a large, randomized, phase III trial in 305 patients with advanced metastatic melanoma, temozolomide demonstrated efficacy equivalent to that of single-agent DTIC.19 Further, temozolomide treatment was associated with improvements in OS, progression-free survival, and quality of life compared with DTIC.

The present study was designed to assess the efficacy and safety of combination therapy with temozolomide plus docetaxel in patients with advanced metastatic melanoma and to assess the impact of this regimen on brain metastases.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Patients with histologically confirmed stage IV melanoma were registered at the Hellenic Cooperative Oncology Group office, with all inclusion and exclusion criteria reviewed by the principal investigator. Eligible patients were required to have measurable or assessable disease, be less than 75 years of age, and have adequate hepatic, cardiac, and renal function. In addition, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a life expectancy of at least 3 months. Patients who had previously received adjuvant chemotherapy >= 12 months before the initiation of treatment were included in the study. In addition, radiotherapy to nonindicator lesions or immunotherapy with IFN-{alpha} and/or IL-2 more than 4 weeks earlier was permitted. Patients with cerebral metastases were eligible if they met the above criteria. All patients gave informed written consent, according to institutional guidelines.

Treatment
Docetaxel was administered on day 1 of each cycle at a dose of 80 mg/m2 as a 1-hour intravenous infusion in 250 mL of normal saline. To reduce the risk of fluid retention and hypersensitivity reactions associated with docetaxel infusion, patients were premedicated with oral corticosteroids (16 mg of methylprednisolone) 6 and 12 hours before infusion. Temozolomide was administered orally at a dose of 150 mg/m2 on days 1 to 5, every 4 weeks, for a maximum of six cycles. Daily doses were rounded to the nearest 5 mg. For patients with myelosuppression, dose modification was allowed. Drug administration was postponed by 1 week if there was not full hematologic recovery (WBC count > 3,000 cells/mL, platelet count > 100,000/mL) from the prior cycle of treatment. If the WBC count was less than 1,000 cells/mL or the platelet count was less than 25,000/mL after a 1-week delay, a 50% dose reduction was indicated.

Assessment of Efficacy
Patients were assessable for response if they received one or more cycles of treatment. If there was no disease progression after one cycle, at least two cycles were administered with continuation for a maximum of six cycles if a response occurred. Patients were assessable for toxicity if they had received at least one cycle of treatment. The primary end points were objective response rate, time to progression (TTP), and OS. The secondary end points were safety and tolerability. Standard response criteria were used. Toxicity was classified according to the World Health Organization’s criteria.


   RESULTS
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 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Patient demographics and baseline disease characteristics are shown in Table 1. From January 1998 until January 2000, a total of 65 patients with stage IV melanoma were entered onto the study. The median age was 57 years, and approximately 75% of the patients had an ECOG performance status of 0 or 1. The majority of patients had lung, lymph node, or soft tissue metastases, and eight patients had brain metastases at study entry. Forty-eight patients (74%) had two or more metastatic sites, and 24 patients (37%) had received prior adjuvant therapy, including immunotherapy, chemotherapy, and combination chemoimmunotherapy.


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  		Table 1.  Patient Demographics and Baseline Disease Characteristics (N = 65)
 
Efficacy of Treatment
Three patients were ineligible, the first because of inadequate performance status, the second because of refusal of treatment, and the third because of incorrect evaluation of abdominal magnetic resonance imaging scans during enrollment onto the study (the patient had no liver metastases and stage II instead of stage IV disease). Among the 62 eligible patients, there were 17 objective responses (27%), including five complete (8%) and 12 partial responses (19%) (Table 2). The median response duration was 9.5 months (range, 1 to 16 months). In addition, 14 patients (23%) had stable disease. Median TTP for all patients was 4 months (range, 0.2 to 21 months), compared with a median TTP of 11.2 months (range, 3 to 25.4 months) among responders. The Kaplan-Meier estimates of TTP for all patients and for responders are shown in Fig 1. The TTP of responders was significantly longer compared with that of nonresponders (P < .0001). The median survival time for the entire patient population was 11 months (range, 0.3 to 21 months), compared with 16 months for responders (Fig 2). The 1-year survival rate for all patients was 46%; at a median follow-up of 14 months, 33 patients remained alive.


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  		Table 2.  Summary of Response (eligible patients)
 


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  		Fig 1. Kaplan-Meier estimate of TTP for responders (n = 17) versus all eligible patients (n = 62).

 


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  		Fig 2. Kaplan-Meier estimate of OS for responders (n = 17) versus all eligible patients (n = 62).

 
Tumor responses by site are shown in Table 3. The majority of objective responses were documented in lung, lymph node, soft tissue, and brain metastases. Among eight patients who presented with brain metastases, three (38%) achieved a partial response, with durations of 5, 6, and 12 months, and one patient remained stable for 4 months but subsequently died from cerebral hemorrhage. The median TTP for these eight patients was 3 months, and their median OS was 4 months. The three patients with brain metastases who responded to temozolomide and docetaxel also demonstrated improved neurologic status, with an improvement in ECOG performance status from 2 to 1 and a reduction of corticosteroid use by 25% to 50%. Among the 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. One patient who initially had a partial response in the lung presented 2 months later with brain metastases. The remaining three patients who developed brain metastases never achieved a response to treatment.


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  		Table 3.  Response According to Site of Metastasis (eligible patients)
 
Safety of Treatment
A total of 251 cycles of chemotherapy were administered, with a median number of cycles of three per patient. Only the 62 eligible patients were assessable for safety. The most frequently reported adverse events were leukopenia, neutropenia, anemia, thrombocytopenia, alopecia, and nausea/vomiting (Table 4). As expected, the major dose-limiting toxicity was transient myelosuppression, which typically persisted for 1 to 6 days. Sixteen patients developed grade 3/4 leukopenia, and eight patients developed grade 3/4 neutropenia. Of six patients with grade 4 neutropenia, two were hospitalized for infection. Five patients had grade 3 anemia, and four patients had grade 3/4 thrombocytopenia. One patient discontinued treatment after the first cycle because of persistent grade 4 thrombocytopenia. A 50% dose reduction of both drugs was required in two patients because of thrombocytopenia. The primary nonhematologic adverse events included alopecia, nausea/vomiting, fever, diarrhea, and arthralgia/myalgia. Grade 3 alopecia occurred in 18 patients, and three patients experienced grade 3/4 nausea/vomiting. Allergic reactions to docetaxel occurred in four patients. There were no treatment discontinuations or deaths caused by toxicity. There were no treatment-related deaths.


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  		Table 4.  Summary of Adverse Events (eligible patients)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Chemotherapy for advanced metastatic melanoma remains largely palliative, and survival times after diagnosis are typically short. Visceral and brain metastases are particularly refractory to treatment. Dacarbazine, a standard chemotherapy agent for the treatment of melanoma, penetrates poorly into the CNS and, therefore, offers little benefit to patients with brain metastases. Although IL-2–based immunotherapy regimens and immunotherapy in combination with DTIC and cisplatin-based regimens have produced high response rates and some durable complete remissions even in patients with visceral metastases, these regimens have not demonstrated efficacy in the CNS.13,14 Radiotherapy may offer some palliation of symptoms for patients with brain metastases, but there is no evidence that survival is prolonged.27 Temozolomide is a novel oral alkylating agent that penetrates the CNS23,26 and has demonstrated antitumor activity in the CNS.15,16,18 In a large, randomized, phase III study, temozolomide was shown to be as effective as DTIC in the treatment of advanced metastatic melanoma and had a similar safety profile19; however, this trial did not include patients with brain metastases. Recently, however, it has been reported that temozolomide may reduce the incidence of CNS relapse compared with DTIC.28

We have demonstrated in this phase II study that the combination of temozolomide plus docetaxel has substantial antitumor activity in the CNS, inducing regression of brain metastases in patients with advanced melanoma. This regimen was also found to be safe, well tolerated, and effective overall for the treatment of metastatic melanoma. The overall objective response rate of 27% achieved in this study compares favorably with rates reported for single-agent DTIC (average rate of 21% in 1,133 patients),29 single-agent temozolomide (13% to 21%),17-19 single-agent paclitaxel and docetaxel (13% to 17%),9-11,30 and DTIC plus IFN-{alpha} (18% in 273 patients).31 Other DTIC-containing combination regimens, including DTIC plus nitrosoureas and DTIC plus cisplatin, have demonstrated similar response rates.6,32,33 Indeed, the response rate achieved with temozolomide plus docetaxel in this study seems to be better than that for either agent alone, and the responses were fairly durable (median duration, 9.5 months; maximum duration, 16 months) compared with other chemotherapy agents. Moreover, the median TTP was substantially longer in responders compared with all treated patients (10.5 v 4 months). These results suggest that temozolomide plus docetaxel is a highly active regimen in metastatic melanoma.

The demonstration of three partial responses (38% response rate) in brain metastases in this study is particularly noteworthy. Bleehen et al18 were the first to report complete regression of a small brain metastasis (8 x 8 mm) in one patient treated with temozolomide in the Cancer Research Campaign phase II study. Taken together, these results suggest that temozolomide may be more effective against brain metastases than other available agents. Responses in brain metastases have rarely been achieved with other chemotherapy agents. In addition, few patients in this study developed CNS involvement, further suggesting that temozolomide may reduce the occurrence of metastasis to the brain. Summers et al28 reported that among 40 patients with advanced melanoma, the incidence of CNS metastases was lower in those patients treated with temozolomide (two [11%] of 19 patients) compared with DTIC (eight [38%] of 21 patients). In addition, among 40 patients with melanoma who responded or had disease stabilization after treatment with temozolomide plus immunotherapy (IL-2, IFN-{alpha}, and granulocyte-macrophage colony-stimulating factor), none developed CNS metastases.34 In the current study, only four (8%) of 52 patients treated with temozolomide and docetaxel developed CNS metastases, with a median follow-up of 14 months.

The responses in brain metastases induced by temozolomide plus docetaxel in this study most likely resulted from the activity of temozolomide rather than that of docetaxel. Several studies investigating the levels of docetaxel and paclitaxel in tissues of rats and mice have concluded that systemically administered docetaxel and paclitaxel have limited, if any, access to the CNS in rodents.35-37 In addition, Glantz et al36 concluded that paclitaxel delivered systemically has limited access to the CSF of patients with CNS malignancies. Although single-agent docetaxel has been used as first-line monotherapy for CNS malignancies, its activity in this setting may be dependent on disruption of the blood-brain barrier, and the high rates of relapse in this setting suggest that docetaxel has limited activity in CNS malignancies.38 A phase II study conducted at our own institution has further shown that the combination of docetaxel and DTIC was ineffective against brain metastases in patients with advanced melanoma.39 Although the objective response rate was 24% for all treated patients, none of five patients with brain metastases responded to docetaxel plus DTIC. Therefore, temozolomide seems to be the active agent against brain metastases when combined with docetaxel.

This regimen was well tolerated, and adverse events were mild to moderate in the majority of patients. Myelosuppression, the predominant toxicity associated with temozolomide therapy, was reversible and noncumulative. Only one patient discontinued treatment due to persistent grade 4 thrombocytopenia. Emesis was experienced by one third of the patients, but only two patients required hospitalization. No toxicity-related treatment discontinuations or deaths occurred. Therefore, temozolomide can be safely combined with docetaxel at the doses used in this study.

In conclusion, the combination of temozolomide with docetaxel is safe and effective in the treatment of advanced metastatic melanoma. The responses achieved in brain metastases and the small number of patients who developed CNS metastases after the completion of treatment are extremely encouraging. Clearly, temozolomide represents an important addition to the currently available treatment options for patients with advanced melanoma, especially for patients with brain metastases.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51: 15–36, 2001[Abstract/Free Full Text]

2. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial ES. J Clin Oncol 14: 7–17, 1996[Abstract]

3. Kirkwood JM, Ibrahim J, Lawson DH, et al: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: Results of the multicenter Eastern Cooperative Oncology Group phase II trial E2696. J Clin Oncol 19: 1430–1436, 2001[Abstract/Free Full Text]

4. Barth A, Wanek LA, Morton DL: Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg 181: 193–201, 1995[Medline]

5. Buzaid AC, Ross MI, Balch CM, et al: Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol 15: 1039–1051, 1997[Abstract/Free Full Text]

6. Atkins MB: The treatment of metastatic melanoma with chemotherapy and biologics. Curr Opin Oncol 9: 205–213, 1997[Medline]

7. Ryan L, Kramar A, Borden E: Prognostic factors in metastatic melanoma. Cancer 71: 2995–3005, 1993[CrossRef][Medline]

8. Legha SS: The role of interferon alfa in the treatment of metastatic melanoma. Semin Oncol 24: S24–S31, 1997 (suppl 4)[Medline]

9. Aamdal S, Wolff I, Kaplan S, et al: Docetaxel (Taxotere) in advanced malignant melanoma: A phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer 30A: 1061–1064, 1994[CrossRef]

10. Bedikian AY, Weiss GR, Legha SS, et al: Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy. J Clin Oncol 13: 2895–2899, 1995[Abstract]

11. Stevens MF, Hickman JA, Stone R, et al: Antitumor imidazotetrazines: 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, a novel broad-spectrum antitumor agent. J Med Chem 27: 196–201, 1984[CrossRef][Medline]

12. Dreiling L, Hoffman S, Robinson WA: Melanoma: Epidemiology, pathogenesis, and new modes of treatment. Adv Intern Med 41: 553–604, 1996[Medline]

13. 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[Abstract/Free Full Text]

14. Legha SS, Ring S, Bedikian A, et al: Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol 7: 827–835, 1996[Abstract/Free Full Text]

15. Yung WKA, Prados MD, Yaya-Tur R, et al: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17: 2762–2771, 1999[Abstract/Free Full Text]

16. Yung WK, Albright RE, Olson J, et al: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83: 588–593, 2000[CrossRef][Medline]

17. Newlands ES, Blackledge GR, Slack JA, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65: 287–291, 1992[Medline]

18. Bleehen NM, Newlands ES, Lee SM, et al: Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13: 910–913, 1995[Abstract]

19. 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[Abstract/Free Full Text]

20. Carter CA, Waud WR, Plowman J: Responses of human melanoma, ovarian, and colon tumor xenografts in nude mice to oral temozolomide. Proc Am Assoc Cancer Res 35: 297, 1994 (abstr)

21. Stevens MF, Hickman JA, Langdon SP, et al: Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47: 5846–5852, 1987[Abstract/Free Full Text]

22. Newlands ES, Stevens MF, Wedge SR, et al: Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23: 35–61, 1997[CrossRef][Medline]

23. Baker SD, Wirth M, Statkevich P, et al: Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 5: 309–317, 1999[Abstract/Free Full Text]

24. Patel M, McCully C, Godwin K, et al: Plasma and cerebrospinal fluid pharmacokinetics of temozolomide. Proc Am Soc Clin Oncol 14: 461, 1995 (abstr)

25. Marzolini C, Decosterd LA, Shen F, et al: Pharmacokinetics of temozolomide in association with fotemustine in malignant melanoma and malignant glioma patients: Comparison of oral, intravenous, and hepatic intra-arterial administration. Cancer Chemother Pharmacol 42: 433-440, 1998 (published erratum appears in Cancer Chemother Pharmacol 43:439–440, 1999)[CrossRef][Medline]

26. Meikle SR, Matthews JC, Brock CS, et al: Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: A feasibility study. Cancer Chemother Pharmacol 42: 183–193, 1998[CrossRef][Medline]

27. Somaza S, Kondziolka D, Lunsford LD, et al: Stereotactic radiosurgery for cerebral metastatic melanoma. J Neurosurg 79: 661–666, 1993[Medline]

28. Summers Y, Middleton MR, Calvert H, et al: Effects of temozolomide (TMZ) on central nervous system (CNS) relapse in patients with advanced melanoma. Proc Am Soc Clin Oncol 18: 531a, 1999 (abstr 2048)

29. Balch CM, Reintgen DS, Kirkwood JM, et al: Cutaneous melanoma, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology. Philadelphia PA, Lippincott-Raven, 1997, pp 1947–1994

30. Wiernik PH, Einzig AI: Taxol in malignant melanoma. J Natl Cancer Inst Monogr 15: 185–187, 1993

31. Hauschild A, Garbe C, Stolz W, et al: Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: A randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 84: 1036–1042, 2001[CrossRef][Medline]

32. Mulder NH, van der Graaf WT, Willemse PH, et al: Dacarbazine (DTIC)-based chemotherapy or chemoimmunotherapy of patients with disseminated malignant melanoma. Br J Cancer 70: 681–683, 1994[Medline]

33. Lee SM, Betticher DC, Thatcher N: Melanoma: Chemotherapy. Br Med Bull 51: 609–630, 1995[Abstract/Free Full Text]

34. Kersten M, Boogerd W, Batchelor D, et al: Combined immunotherapy with GM-CSF, IL-2 and IFN{alpha} allows dose escalation of temozolomide with prevention of lymphocytopenia and brain metastases in metastatic malignant melanoma. Proc Am Soc Clin Oncol 19: 569a, 2000 (abstr 2244)

35. Sparreboom A, van Tellingen O, Nooijen WJ, et al: Preclinical pharmacokinetics of paclitaxel and docetaxel. Anticancer Drugs 9: 1–17, 1998[CrossRef][Medline]

36. Glantz MJ, Choy H, Kearns CM, et al: Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. J Natl Cancer Inst 87: 1077–1081, 1995[Abstract/Free Full Text]

37. Sparreboom A, van Tellingen O, Nooijen WJ, et al: Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs 7: 78–86, 1996[Medline]

38. Trudeau ME, Eisenhauer E, Dent S, et al: Central nervous system (CNS) relapse following chemotherapy with docetaxel for metastatic breast cancer: Update of a study by the National Cancer Institute of Canada—Clinical Trials Group (NCIC-CTG). Proc Am Soc Clin Oncol 15: 101, 1996 (abstr)

39. Bafaloukos D, Samantas E, Fountzilas G, et al: Docetaxel and dacarbazine in patients with advanced melanoma: A phase II study of the Hellenic Cooperative Oncology Group. Presented at ECCO 11: The European Cancer Conference, Lisbon, Portugal, October 21–25, 2001 (poster)

Submitted December 7, 2000; accepted September 5, 2001.


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L. Tentori, C. Leonetti, M. Scarsella, G. d'Amati, M. Vergati, I. Portarena, W. Xu, V. Kalish, G. Zupi, J. Zhang, et al.
Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma
Clin. Cancer Res., November 1, 2003; 9(14): 5370 - 5379.
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W.-J. Hwu, S. E. Krown, J. H. Menell, K. S. Panageas, J. Merrell, L. A. Lamb, L. J. Williams, C. J. Quinn, T. Foster, P. B. Chapman, et al.
Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma
J. Clin. Oncol., September 1, 2003; 21(17): 3351 - 3356.
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