This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Avril, M.F. Articles by Menu, Y. Search for Related Content PubMed PubMed Citation Articles by Avril, M.F. Articles by Menu, Y. Social Bookmarking                            What's this?

Fotemustine Compared With Dacarbazine in Patients With Disseminated Malignant Melanoma: A Phase III Study

From the Institut Gustave Roussy, Villejuif; CHU Sainte-Marguerite; CHRU de la Timone, Marseille; Centre Oscar Lambret, Lille; CHU Ambroise Paré, Boulogne Billancourt; Hôpital Beaujon, Clichy; Hôpital Foch, Suresnes, France; Universitäts-Hautklinik, Kiel; Dermatologisches Zentrum, Buxtehude; Allg. Krankenhaus St. Georg; Universitäts Krankenhaus Eppendorf, Hamburg; Friedrichs-Wihelms-Universitäts, Bonn; Fachklinik Hornheide, Münster, Germany; National Institute of Oncology, Budapest, Hungary; Norwegian Radium Hospital, Oslo, Norway; Instituto Valenciano de Oncología, Valencia; Clinica CONIM, Madrid; Hospital Central de Asturias, Oviedo, Spain; Allg. Krankenhaus, Wien, Austria; and Prednosta Internej Kliniky, Brastislava, Slovakia

Address reprint requests to Marie Françoise Avril, MD, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejiuf Cedex, France; e-mail: avril{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma.

PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m² weekly for 3 weeks or DTIC 250 mg/m²/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m² or DTIC 250 mg/m² for 5 days).

RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n = 229; 15.2% v 6.8%; P = .043) and in full analysis set (n = 221) (15.5% v 7.2%; P = .053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P = .059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P = .067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms.

CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Malignant melanoma (MM) is an aggressive tumor, since it is responsible for 65% of skin cancer deaths [1]. The incidence of melanoma has increased approximately 3-fold over the last 40 years. Distant metastases of MM are associated with a poor prognosis; the median survival time of patients with advanced disease, depending on the patient’s performance status as well as location and number of metastases, is only about 4 to 6 months [2]. At this stage of the disease, surgery is rarely curative, and radiotherapy is only palliative.

Many mono- as well as poly-chemotherapeutic regimens have been tested in advanced melanoma, but the single-agent dacarbazine (DTIC) remains the standard chemotherapy [3] with response rates ranging from 11% to 25%. Complete responses were rare and short in duration (3 to 6 months). The median survival time ranged from 4.5 to 6 months [4-6]. No multiagent chemotherapy has yet proved superior to single-agent DTIC chemotherapy in phase III clinical trials [3,7,8]. Recently, no significant difference was evidenced between the efficacy of the novel oral alkylating agent temozolomide and that of DTIC in patients with advanced metastatic MM [9].

The chloroethyl-nitrosourea fotemustine was shown to be effective as single agent against MM with an overall response rate of 24% in a large phase II trial including 153 assessable patients [10]. The study showed substantial activity with respect to brain metastases [11]. The efficacy of fotemustine was confirmed in international phase II studies with objective response rates (ORR) ranging from 12% to 47% and median duration of responses ranging from 18 to 26 weeks [12-14]. Fotemustine was well tolerated, with myelosuppression as the main side-effect.

The primary objective of the current study was to compare the overall response rate (ORR) of metastatic MM in patients with or without brain metastases treated with either fotemustine or DTIC as first-line therapy. Secondary objectives included comparisons of time to progression (TTP), duration of response, time to occurrence of brain metastases in patients without brain metastases at baseline, health-related quality of life (QoL), safety profile, and overall survival.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patients
Adult patients (18 to 75 years old) with histologically confirmed disseminated non-ocular MM, with or without brain metastases, who met the following eligibility criteria were included in the study: At least one bidimensional measurable target, performance status (PS) 1, life expectancy greater than 3 months, adequate bone marrow function (WBC 4000/mm³; neutrophils 2000/mm³; platelet 100,000/mm³; hemoglobin 110 g/L), and satisfactory hepatic and renal functions (bilirubin within normal range, transaminases and alkaline phosphatase 2.5 x upper normal limit (UNL), or 2.6 to 5.0 x UNL in case of liver metastases for the latter parameter; creatinine < 1.5 x UNL). Patients were required to have had no prior chemotherapy or immunotherapy, except adjuvant immunotherapy completed at least 1 month before random assignment, no prior radiotherapy within the last 4 weeks before random assignment, no prior brain radiotherapy or apparently complete excision of brain metastasis, and in case of the presence of brain metastases those had to be unresectable. Local ethical review committees approved the study. All patients gave written informed consent before random assignment.

Treatment
Patients were randomly assigned to receive intravenously either fotemustine or DTIC. The random assignment was stratified by country, on the presence or absence of brain metastases, and assessment method for CNS sites (magnetic resonance imaging v computed-tomography [CT] scan). Fotemustine (Muphoran, Servier Laboratories, France) was administered weekly for 3 consecutive weeks (days 1, 8, and 15) at 100 mg/m² as a 60-minute infusion, followed by a 5-week rest period (defined as induction treatment). In the control arm, DTIC was administered as a 60-minute infusion once a day for 5 consecutive days at 250 mg/m² every 4 weeks (days 1 to 5 and 29 to 33), for two cycles as induction treatment. A maintenance therapy was initiated in nonprogressive patients consisting of fotemustine 100 mg/m² every 3 weeks or DTIC 250 mg/m²/d for 5 consecutive days every 4 weeks (days 57 to 61, 85 to 89...) until progression or unacceptable toxicity. Dose adjustments or delays were planned in case of severe toxicities. A delay greater than 2 weeks and any grade 4 or irreversible/recurrent grade 3 nonhematologic toxicities (except for alopecia or vomiting) led to a permanent treatment discontinuation. Concomitant treatments including antiemetic treatments were allowed.

Response and Toxicity Assessments
Complete tumor imaging (brain CT or magnetic resonance image, chest-x-ray or chest CT, ultrasonography or CT scan of the abdomen and pelvis, bone scan) was performed at baseline, at the end of the induction treatment, then 4 weeks later in case of stabilization or response. During maintenance treatment, tumor measurements were performed every 8 to 9 weeks. Responses were recorded using WHO criteria [15]. The ORR was defined as percentage of patients with a confirmed complete response (CR) or partial response (PR). An independent centralized radiologic committee (two radiologists not involved in the study) performed a blinded review of all radiologic files of patients who had CR, PR, or stable disease on the investigator’s evaluation. Imaging of patients declared progressive disease (PD) as a best response were not reviewed. Analysis was made on a consensus mode between the two radiologists. They were aware of all imaging examinations at different time points for every patient, but they did not know the results of investigator’s measurements and decision nor the clinical events like complications or patient’s decision to stop the treatment. The two radiologists confirmed if the patient was eligible according to the protocol, and measured the targets at different time points. If any target was evaluated by physical examination or ultrasonography (like superficial lymph nodes) and not seen on reviewed images, the investigator’s findings were validated. Finally, a decision on the response was made by the radiologists according to their evaluation and the results of validated investigator’s data.

For responder patients, response duration was calculated from the start of chemotherapy to the date of first observation of PD. TTP and time to occurrence of brain metastases (in patients without brain metastases at inclusion) were calculated from the date of random assignment to documentation of overall PD and date of first brain metastases, respectively.

The severity of recognized adverse events (AE) were graded using National Cancer Institute Common Toxicity Criteria [16]. Other toxic effects were graded as mild, moderate, severe, or life-threatening.

Health-Related Quality of Life
Health-related QoL was assessed using the self-administered European Organization for Research and Treatment of Cancer QoL Questionnaire (QLQ-C30, version 2.0) [17,18]. The QoL questionnaire was given before random assigment in both arms, at the end of the induction cycle, at each maintenance cycle, then at the end of the study in the fotemustine arm and at each cycle and end of study in the DTIC arm.

Statistical Analysis
The primary objective was to compare the response rates between fotemustine and DTIC arms using a Pearson ² or exact Fisher test. Percentage difference between groups and 95% CI were calculated as well as the odds ratio (and its 95% CI). Secondary objectives were to assess the median duration of responses, TTP, time to occurrence of brain metastases, and overall survival using Kaplan-Meier’s estimate in each arm. The survival curves were compared using a log-rank test. For main QoL criterion, the changes in global health status score from baseline to the end of the induction period were compared between groups using Mann-Whitney-Wilcoxon test. Prognostic factors at inclusion were compared between both arms using a ² test or an exact Fisher test in the randomly assigned population.

A minimum of 102 patients per arm had to be included to allow a detection of 17% difference in ORR between treatments with 80% power at the 5% level of significance (two-tailed), assuming a response rate of 13% in the control arm.

Response analyses were performed on the full analysis set (FAS, ICH-E9, 1997) and on the intent-to-treat (ITT) populations (defined as all randomly assigned patients). The QoL analyses were performed on the QoL population defined as all patients of the FAS who had assessable questionnaires at baseline and between baseline and end of induction treatment. Safety analyses were performed in all patients receiving at least one treatment infusion.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patients
From February 1998 to October 2000, 229 patients were randomly allocated to receive either fotemustine (n = 112) or DTIC (n = 117) in 19 centers from seven European countries. Five patients were not treated because of non-medical reason (all in the DTIC arm) and the remaining 224 patients were evaluated for safety analyses (112 in each arm). Three additional patients, who prematurely withdrew from the study without any postbaseline evaluation nor suspicion of PD, were also excluded from the FAS (two in the fotemustine arm and one in the DTIC arm). The remaining 221 patients (110 in fotemustine arm and 111 in DTIC arm) made up the FAS. Patients demographics were comparable in both treatment groups (Table 1).

Responses and Time to Progression
At the end of induction treatment, the ORR was 13.6% in fotemustine arm versus 6.3% in DTIC arm (P = .069) in the FAS, and 13.4% versus 6.0% (P = .057) in the ITT population. The responses were observed on skin and superficial lymph nodes sites (15.9% in fotemustine arm v 8.3% in DTIC arm), lung sites (15.4% vs 13.6%, respectively), brain (5.9% v 0%, respectively), and other visceral sites (12.1% v 6.3%, respectively) in the FAS.

The best ORR (ie, during maintenance treatments) was also higher in the fotemustine arm (15.5%) than in the DTIC arm (7.2%) in the FAS (P = .053; odds ratio = 2.35; 95% CI, 0.97 to 5.71; Table 2). CR occurred in three patients with fotemustine and one patient with DTIC. The probability of being responder (CR or PR) was higher in the fotemustine arm than in the DTIC arm after more than 3 months (26.5% v 16.4% at 3 months; 17% v 9% at 6 months; 9% v 0% at 12 months, respectively). In the ITT population, the best ORR was significantly higher in the fotemustine arm (15.2%) than in the DTIC arm (6.8%; P = .043; Table 2).

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of time to disease progression (months) in the full analysis set.

View larger version (13K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of time of occurrence of brain metastases in the full analysis set.

View larger version (13K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plot of overall survival in the randomized set.

Hematologic Toxicity
Myelosuppression was the most common AE in both arms (Table 3). In the fotemustine arm, neutropenia was observed in 79 patients (71%) with occurrence of grade 3 to 4 toxicity in 51% of patients. Two patients experienced febrile neutropenia. Thrombocytopenia was noted in 105 patients (94%) with occurrence of grade 3 to 4 toxicity in 43% of patients. Grade 3 to 4 anemia was infrequent. Myelosuppression occurred mainly during induction treatment, and very few patients exhibited grade 3 toxicity during maintenance treatments (one patient had neutropenia, two had thrombocytopenia). In the DTIC arm, myelosuppression was less frequent than in the fotemustine arm (Table 3). Neutropenia was observed in 16 patients (14%) with grade 3 to 4 toxicity occurring in 5% of patients. Thrombocytopenia was noted in 64 patients (57%) with grade 3 to 4 toxicity occurring in 6% of patients. Grade 3 to 4 anemia remained uncommon.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

When considering response by metastatic sites, the percentages of objective responses were markedly higher in the fotemustine group than in the DTIC group for lymph nodes (15.9% v 8.3%), brain sites (5.9% v 0) and other visceral sites (12.1% v 6.3%) at the end of induction period. The best ORR obtained with fotemustine appeared lower than that reported in the pivotal phase II trial [10,11]. Similarly, the best ORR reported for DTIC was lower than that reported in two comparative randomized phase III trials: 12% in comparison with temozolomide [9], and 10% in comparison with the Dartmouth regimen [19]. These differences could be explained by a more extended disease at inclusion in the present study with a visceral-dominant involvement, which is known to be an unfavorable prognostic factor. Patients had a high tumor burden; 86% of them presented visceral metastases, including 19% of patients with evidence of brain metastases. Furthermore, a centralized radiologic review is commonly known to decrease the response rates.

A relatively low percentage of cerebral responses was observed after treatment with fotemustine (5.9%) compared to those published earlier with fotemustine as single agent [10-14,20]. Results of five independent phase II studies with fotemustine as single agent therapy showed ORR in brain metastases of 21% (95% CI, 12% to 30%) in patients with MM [10-14]. Mornex et al [20] reported a brain ORR of 7% after induction treatment and a best cerebral ORR of 11% with fotemustine in a population of patients with unfavorable prognostic factors. No brain response was observed with DTIC in the present study, although its analog temozolomide recently yielded some responses in CNS metastases, either as single agent or in combination with thalidomide or radiotherapy [21-23]. Sixteen patients in the fotemustine arm and 21 in the DTIC arm developed cerebral metastases during the study period. The median time of occurrence of these brain metastases was about three times longer in the fotemustine group (22.7 months) than in the DTIC group (7.2 months; P = .059). Therefore, fotemustine did not decrease the number of relapses in brain sites, but a trend to a longer delay before CNS relapses was observed. Median overall survival time was prolonged in the fotemustine group as compared to the DTIC group (7.3 v 5.6 months in ITT population), but the difference was not significant (P = .067).

Both drugs were well tolerated by patients and toxic effects were reversible, noncumulative, and manageable, and no toxic death was observed. As foreseen, grade 3 to 4 hematologic toxicity (except anemia) was more frequent in the fotemustine group with neutropenia and thrombocytopenia occurring in 51% and 43% of patients, respectively. The rate of severe hematotoxicity, which was mostly observed after the induction treatment, was comparable to the previously published data using the same treatment schedule [10,20]. No severe hemorrhagic syndrome was reported. In the case of nonhematological toxicities, nausea and vomiting were reported at a similar frequency in both groups with few cases of severe toxicity. Approximately 90% of the patients received preventive antiemetic treatment. Pain and fever were more frequently reported in the DTIC group than in the fotemustine group. One case of severe hepatotoxicity was noted in the DTIC arm. Comparison between groups should take into consideration that exposure to treatment was higher in the fotemustine group than in the DTIC group.

No statistically significant difference between groups was evidenced for QoL during the induction treatment. The general tendency was degradation over time in both groups. The disease progression and PS alteration were the main factors for QoL impairment.

Finally, two facts may have been at an unfair disadvantage for DTIC. Firstly, ORR results in the ITT population have to be considered, since five patients on the DTIC arm did not receive any treatment. Secondly, at the time of analysis, an unexpected confounding factor related to drug administration schedules was identified for the induction period. Whereas fotemustine total dose was delivered at once (ie, in the first 3 weeks) to patients allocated to this group, patients of the DTIC arm had a 24-day interval between the two cycles. It appeared that, at the time of the second cycle, PD was so evident in some patients that the treatment was stopped, although they had received only half of the intended dose during the induction treatment. Thus, the fotemustine administration schedule was more favorable in this group of melanoma patients with high tumor burden.

In conclusion, the present study shows that fotemustine treatment is associated with a significant improvement in best ORR compared to DTIC treatment in patients with MM. A trend in favor of fotemustine was also evidenced in terms of overall survival and time to occurrence of brain metastases. Both treatments were well tolerated with reversible and manageable hematologic toxicities, and no difference between treatment groups was noted for QoL. This phase III study confirms the activity of fotemustine as single agent in first line treatment of MM.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
This work was supported by the Institut de Recherches Internationales Servier, Courbevoie, France.

This work was presented at the Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
1. Balch CM, Reintgen DS, Kirkwood JM: Cutaneous melanoma, in De Vita VT Jr, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott-Raven, 1997, pp 1947-1994

2. Tilgen W: Malignant melanoma: Current therapeutic concepts. Onkologie 18:534-547, 1995

3. Serrone L, Zeuli M, Sega FM, et al: Dacarbazine-based chemotherapy for metastatic melanoma: Thirty year experience overview. J Exp Clin Cancer Res 19:21-34, 2000[Medline]

4. Luce JK, Thurman WG, Isaacs BL, et al: Clinical trials with the antitumor agent 5-(3,3-dimethy-1-triazeno)imidazole-4-carboxamide. Cancer Chemother Rep 54:119-124, 1970[Medline]

5. Hill GJ, Moss SE, Golomb FM, et al: DTIC and combination therapy for melanoma. Cancer 47:2556-2562, 1981[CrossRef][Medline]

6. Falkson G, Van der Merwe AM, Falkson HC: Clinical experience with 5-(3,3-bis(2-chloroethyl)-1-triazeno)-imidazole-4-carboxamide (NSC 82196) in the treatment of metastatic malignant melanoma. Cancer Chemother Rep 56:671-677, 1972[Medline]

7. Middleton MR, Lorigan P, Owen J, et al: A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 82:1158-1162, 2000[CrossRef][Medline]

8. Falkson CI, Ibrahim J, Kirkwood JM, et al: Phase III trial of dacarbazine versus dacarbazine with interferon -2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 16:1743-1751, 1998[Abstract]

9. 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]

10. Jacquillat CI, Khayat D, Banzet P, et al: Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer 66:1873-1878, 1990[CrossRef][Medline]

11. Jacquillat CI, Khayat D, Banzet P, et al: Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma. Cancer Chemother Pharmacol 25:263-266, 1990[CrossRef][Medline]

12. Calabresi E, Aapro M, Becquart D, et al: Multicenter phase II trial of the single agent fotemustine in patients with advanced malignant melanoma. Ann Oncol 2:377-378, 1991[Free Full Text]

13. Kleeberg UR, Engel E, Israels P, et al: Phase II trial of fotemustine in patients with metastatic melanoma (EORTC-MCG 18881). Onkologie 14:81-83, 1991

14. Schallreuter KU, Wenzel E, Brassow FW, et al: Positive phase II study in the treatment of advanced malignant melanoma with fotemustine. Cancer Chemother Pharmacol 29:167-171, 1991[CrossRef][Medline]

15. World Health Organization: Handbook for reporting results of cancer treatment. WHO publication no. 48. Geneva, Switzerland, World Health Organization, 1979

16. National Cancer Institute: Investigator’s Handbook: A manual for participants in clinical trials of investigational agents sponsored by DCTD, NCI. Bethesda, MD, National Cancer Institute, 1993

17. Fayers PM, Hopwood P, Harvey A, et al: Quality of life assessment in clinical trials guidelines and a checklist for protocol writers: The UK Medical Research Council Experience. Eur J Cancer 33:20-28, 1997

18. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993[Abstract/Free Full Text]

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[Abstract/Free Full Text]

20. Mornex F, Thomas L, Mohr P, et al: A prospective randomised multicenter phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma Res 13:97-103, 2003[CrossRef][Medline]

21. Paul MJ, Summers Y, Calvert AH, et al: Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Melanoma Res 12:175-178, 2002[CrossRef][Medline]

22. Margolin K, Atkins MB, Thompson JA, et al: Temozolomide and whole brain irradiation in melanoma metastatic to the brain: A phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol 128:214-218, 2002[CrossRef][Medline]

23. 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[Abstract/Free Full Text]

Submitted April 23, 2003; accepted December 23, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. O'Day, R. Gonzalez, D. Lawson, R. Weber, L. Hutchins, C. Anderson, J. Haddad, S. Kong, A. Williams, and E. Jacobson Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma J. Clin. Oncol., November 10, 2009; 27(32): 5452 - 5458. [Abstract] [Full Text] [PDF]

				D. Cornish, C. Holterhues, L. V. van de Poll-Franse, J. W. Coebergh, and T. Nijsten A systematic review of health-related quality of life in cutaneous melanoma Ann. Onc., August 1, 2009; 20(suppl_6): vi51 - vi58. [Abstract] [Full Text] [PDF]

				A. Hauschild, S. S. Agarwala, U. Trefzer, D. Hogg, C. Robert, P. Hersey, A. Eggermont, S. Grabbe, R. Gonzalez, J. Gille, et al. Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma J. Clin. Oncol., June 10, 2009; 27(17): 2823 - 2830. [Abstract] [Full Text] [PDF]

				A. I. Daud, J. Dawson, R. C. DeConti, E. Bicaku, D. Marchion, S. Bastien, F. A. Hausheer III, R. Lush, A. Neuger, D. M. Sullivan, et al. Potentiation of a Topoisomerase I Inhibitor, Karenitecin, by the Histone Deacetylase Inhibitor Valproic Acid in Melanoma: Translational and Phase I/II Clinical Trial Clin. Cancer Res., April 1, 2009; 15(7): 2479 - 2487. [Abstract] [Full Text] [PDF]

				S. Gill, J. Shapiro, D. Westerman, and H. M. Prince Long-Term Survival and Secondary Acute Leukemia After Fotemustine Therapy for Metastatic Melanoma J. Clin. Oncol., October 1, 2007; 25(28): 4493 - 4494. [Full Text] [PDF]

				M. Middleton, A. Hauschild, D. Thomson, R. Anderson, S. Burdette-Radoux, K. Gehlsen, K. Hellstrand, and P. Naredi Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin-2, interferon-{alpha}2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma Ann. Onc., October 1, 2007; 18(10): 1691 - 1697. [Abstract] [Full Text] [PDF]

				A. F. Eichler and J. S. Loeffler Multidisciplinary Management of Brain Metastases Oncologist, July 1, 2007; 12(7): 884 - 898. [Abstract] [Full Text] [PDF]

				A. Y. Bedikian, M. Millward, H. Pehamberger, R. Conry, M. Gore, U. Trefzer, A. C. Pavlick, R. DeConti, E. M. Hersh, P. Hersey, et al. Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group J. Clin. Oncol., October 10, 2006; 24(29): 4738 - 4745. [Abstract] [Full Text] [PDF]

				S. Peters, V. Voelter, L. Zografos, S. Pampallona, R. Popescu, M. Gillet, W. Bosshard, G. Fiorentini, M. Lotem, R. Weitzen, et al. Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients Ann. Onc., April 1, 2006; 17(4): 578 - 583. [Abstract] [Full Text] [PDF]

				R. W. Weber, S. O'Day, M. Rose, R. Deck, P. Ames, J. Good, J. Meyer, R. Allen, S. Trautvetter, M. Timmerman, et al. Low-Dose Outpatient Chemobiotherapy With Temozolomide, Granulocyte-Macrophage Colony Stimulating Factor, Interferon-{alpha}2b, and Recombinant Interleukin-2 for the Treatment of Metastatic Melanoma J. Clin. Oncol., December 10, 2005; 23(35): 8992 - 9000. [Abstract] [Full Text] [PDF]

				R. J. Abi-Habib, J. O. Urieto, S. Liu, S. H. Leppla, N. S. Duesbery, and A. E. Frankel BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin Mol. Cancer Ther., September 1, 2005; 4(9): 1303 - 1310. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Avril, M.F. Articles by Menu, Y. Search for Related Content PubMed PubMed Citation Articles by Avril, M.F. Articles by Menu, Y. Social Bookmarking                            What's this?