RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known if chemotherapy is more effective with or without radiation therapy in treating brain metastases.

PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy with or without radiation therapy to the brain in treating patients who have stage IV melanoma with asymptomatic brain metastases.

Condition	Treatment or Intervention	Phase
Stage IV Melanoma Recurrent Melanoma brain metastases	Drug: temozolomide  Procedure: chemotherapy  Procedure: radiation therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the efficacy of temozolomide with or without radiotherapy in terms of overall survival in patients with stage IV melanoma with asymptomatic brain metastases.
• Compare the time to appearance of neurological symptoms in patients treated with these regimens.
• Compare the progression-free survival of patients treated with these regimens.
• Compare the quality of life and quality-adjusted survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to LDH levels (less than 225 U/L vs 225 U/L or more), concurrent metastases (visceral vs soft tissue), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral temozolomide once daily on days 1-5. Treatment continues every 4 weeks for a maximum of 1 year in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive temozolomide as in arm I and whole brain radiotherapy on days 8-12 and 15-19 during the first course of chemotherapy. Quality of life is assessed before beginning each course and then every 4 weeks after completion of study drug.

Patients are followed every 4 weeks.

PROJECTED ACCRUAL: A total of 250 patients will be accrued for this study within 2 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed unresectable metastatic melanoma
• Must have asymptomatic brain metastasis that is not amenable to surgery or stereotactic radiosurgery (gamma knife, Linac)
• Must have concurrent visceral/soft tissue metastases
• At least 1 site of measurable disease (not necessarily the brain metastasis)
• Documented evidence of disease progression defined by 1 of the following conditions:
• More than 25% increase in the size of at least 1 measurable lesion
• Appearance of a new lesion
• A significant increase in the size of nonmeasurable disease
• No neurological symptoms, including signs of elevated intracranial pressure

PATIENT CHARACTERISTICS: Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10 g/dL

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• SGOT or SGPT less than 3 times ULN
• Alkaline phosphatase less than 3 times ULN

Renal:

• Urea less than 1.5 times ULN
• Creatinine less than 1.5 times ULN

Other:

• No frequent vomiting or medical condition (e.g., partial bowel obstruction) that would interfere with oral medication intake
• No other prior or concurrent malignancy except surgically cured carcinoma in situ of the cervix or basal cell or squamous cell skin cancer
• No uncontrolled infection
• HIV negative
• No AIDS-related illness
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No psychological, familial, sociological, or geographical condition that would preclude study

PRIOR CONCURRENT THERAPY: Biologic therapy:

• Prior cytokine via isolated limb perfusion for local-regional melanoma allowed
• No other prior cytokine for metastatic melanoma
• No concurrent colony-stimulating factors, including epoetin alfa or filgrastim (G-CSF)
• No other concurrent immunologic or biologic therapy

Chemotherapy:

• Prior chemotherapy via isolated limb perfusion for local-regional melanoma allowed
• No other prior chemotherapy for metastatic melanoma
• No other concurrent chemotherapy

Endocrine therapy:

• Concurrent corticosteroids allowed during radiotherapy (arm II only)
• No concurrent hormonal therapy

Radiotherapy:

• See Disease Characteristics
• No other concurrent radiotherapy

Surgery:

• See Disease Characteristics
• Recovered from the effects of any prior major surgery

Other:

• No other concurrent investigational drugs

Austria
      Krankenhaus der Elisabethinen, Linz,  4020,  Austria
Belgium
      Clinique Notre Dame de Grace, Gosselies,  6041,  Belgium
      Hopital Universitaire Erasme, Brussels,  1070,  Belgium
      Institut Jules Bordet, Brussels,  1000,  Belgium
      Universitair Ziekenhuis Antwerpen, Edegem,  B-2650,  Belgium
Czech Republic
      Onkologicka Klinka A Onkologicka Lab, Prague,  128 08,  Czech Republic
France
      Centre Eugene Marquis, Rennes,  35042,  France
      Centre Hospital Regional Universitaire de Limoges, Limoges,  87042,  France
      CHU Ambroise Pare, Boulogne-Billancourt,  F-92104,  France
      CHU de Bordeaux - Hopital Pellegrin, Bordeaux,  33076,  France
      Hopital L'Archet - 2, Nice,  F-06202,  France
      Institut Gustave Roussy, Villejuif,  F-94805,  France
Germany
      Eberhard Karls Universitaet, Tuebingen,  D-72076,  Germany
      Federal Armed Forces Hospital of Ulm - Department of Dermatology, Blaustein,  D-89134,  Germany
      Georg August Universitaet, Goettingen,  D-37075,  Germany
      Haematologisch-Onkologische Praxis Altona, Hamburg,  D-22765,  Germany
      III Medizinische Klinik Mannheim, Mannheim,  D-68305,  Germany
      Universitaet Wuerzburg/Hautkrankheiten, Wuerzburg,  D-97080,  Germany
      Universitaets - Augenklinik - Erlangen, Erlangen,  D-91054,  Germany
      Universitaetsklinikum Benjamin Franklin, Berlin,  D-12200,  Germany
Italy
      Istituto Nazionale per la Ricerca sul Cancro, Genoa (Genova),  16132,  Italy
Netherlands
      Erasmus University Medical Center, Rotterdam,  3075 EA,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands
Norway
      Norwegian Radium Hospital, Oslo,  N-0310,  Norway
Portugal
      Instituto Portugues de Oncologia de Francisco Gentil - Centro de Lisboa, Lisbon,  1093,  Portugal
Switzerland
      UniversitaetsSpital, Zurich,  CH-8091,  Switzerland
United Kingdom, England
      Addenbrooke's NHS Trust, Cambridge,  England,  CB2 2QQ,  United Kingdom
      Christie Hospital N.H.S. Trust, Manchester,  England,  M20 9BX,  United Kingdom
      Clatterbridge Centre for Oncology NHS Trust, MERSEYSIDE,  England,  CH63 4JY,  United Kingdom
      Royal Marsden NHS Trust, London,  England,  SW3 6JJ,  United Kingdom
      Southend NHS Trust Hospital, Westcliff-On-Sea,  England,  SS0 0RY,  United Kingdom
      St. James's Hospital, Leeds,  England,  LS9 7TF,  United Kingdom
      Weston Park Hospital, Manchester,  England,  M20 9BX,  United Kingdom

Study chairs or principal investigators

Juergen Becker, MD, PhD,  Study Chair,  Universitaet Wuerzburg/Hautkrankheiten   

Study ID Numbers:  CDR0000068723; EORTC-18981
Record last reviewed:  September 2003
Last Updated:  October 13, 2004
Record first received:  July 11, 2001
ClinicalTrials.gov Identifier:  NCT00020839
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08