Annals of Oncology

Annals of Oncology Advance Access originally published online on March 24, 2006
Annals of Oncology 2006 17(6):952-956; doi:10.1093/annonc/mdl056

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© 2006 European Society for Medical Oncology

Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG)

M. E. Trudeau^1,*, M. Crump², D. Charpentier³, L. Yelle³, L. Bordeleau¹, S. Matthews⁴ and E. Eisenhauer⁴

¹ Toronto Sunnybrook Regional Cancer Centre, Toronto, ON; ² Princess Margaret Hospital, Toronto, ON; ³ CHUM-Hopital Notre-Dame, Montreal, QC; ⁴ National Cancer Institute of Canada – Clinical Trials Group, Kingston, ON, Canada

^* Correspondence to: Dr M. Trudeau, Department of Medical Oncology, Toronto Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 Canada. Tel: +1-416-480-5145; Fax: +1-416-480-6002; E-mail: Maureen.Trudeau{at}sw.ca

	Abstract

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Background: Temozolomide is an oral alkylating agent that crosses the blood–brain barrier, and has preclinical activity in breast cancer. This phase II trial sought to determine the activity and toxicity of temozolomide in metastatic breast cancer (MBC). Temozolomide was administered in a dose dense schedule of 150 mg/m² on days 1–7 and 15–21 in a 28-day cycle.

Materials and methods: Patients had unidimensional disease for response assessment by RECIST criteria, up to two prior chemotherapy regimens for MBC, and may have had brain metastases if radiation was not expected to be required within 4 weeks.

Results: Nineteen women were entered on the study. All were evaluable for toxicity and 18 were evaluable for response. The median age was 54 years; 14 had prior chemotherapy for MBC and 12 had prior hormones. Sites of disease included bone, brain, liver and lung. Treatment was well tolerated with 14/19 receiving >90% planned dose intensity. Common grade 1–3 drug-related effects included nausea, fatigue, vomiting, anorexia and skin rash. Grade 3–4 hematologic toxicities included granulocytopenia and thrombocytopenia. Of the 18 evaluable patients, there were no objective responses; three had stable disease and 15 progressive disease.

Conclusions: No responses to temozolomide were documented in these heavily pretreated women with extensive MBC including brain metastases.

Key words: brain metastases, metastatic breast cancer, temozolomide

	introduction

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Temozolomide is a second-generation imidazotetrazine pro-drug with excellent oral bioavailability [1]. It is an oral alkylating agent which crosses the blood–brain barrier with demonstrated activity in glioma and melanoma [2] and preclinical activity in breast cancer [3]. In a controlled trial of glioblastoma the 6-month rate for progression-free survival for temozolomide was 21% compared with 8% for procarbazine [4]. More importantly, a phase III trial of concomitant radiotherapy and adjuvant temozolomide in newly diagnosed gioblastoma multiforme has recently been published [5]. This showed that temozolomide 75 mg/m² p.o. daily for 6 weeks then 150–200 mg/m² daily on days 1–5 every 28 days for six cycles improved survival when given with focal radiation therapy to a total dose of 6000 cGy (30 x 200 cGy) compared with radiation alone. Median overall survival with radiation alone was 12.1 months and with temozolomide plus radiation therapy was 14.6 months (P < 0.0001). Two-year survival was 10% for radiation versus 26% for temozolomide plus radiation. In a randomized trial in metastatic melanoma first-line treatment, the median overall survival with temozolomide based on Kaplan–Meier estimates was 7.7 months, 1.3 months longer than that observed with dacarbazine [6]. Furthermore, the overall survival rate at 6 months, although not significant, was greater for temozolomide compared with dacarbazine (61% versus 51%; P = 0.06). Thus temozolomide had modest activity in melanoma similar to that of dacarbazine.

In the treatment of metastatic breast cancer, the introduction of taxane compounds as well as capecitabine, vinorelbine and gemcitabine, and the addition of trastuzumab (Herceptin) to chemotherapy for HER2 neu over-expressing tumors, has resulted in improved progression-free and overall survival and has produced longer periods of stable metastatic disease outside the central nervous system (CNS). However, the great majority of drugs (including Herceptin) used to treat breast cancer do not cross the blood–brain barrier, and increasing numbers of patients are experiencing progression in the CNS. The incidence of CNS metastases has been reported to be up to 34% in patients using taxanes [7] or Herceptin [8]. Temozolomide seemed an attractive agent to study in the treatment of metastatic breast cancer because of its oral formulation, ability to cross the blood–brain barrier and demonstrated success in other tumor sites. Furthermore, as a cytotoxic alkylating agent it is chemically unrelated to other drugs used to treat breast cancer. For these reasons, the NCIC – Clinical Trials Group investigated the activity of temozolomide in women with metastatic breast cancer previously treated with chemotherapy. A dose dense schedule (standard doses [9] every 2 weeks rather than every 4 weeks) of treatment with 150 mg/m² on days 1–5 every 2 weeks was chosen to enhance the possibility of response.

Other phase II studies have investigated the activity of temozolomide in patients with brain metastases, including those secondary to breast cancer [10–12]. Temozolomide in combination with cisplatin (CDPP), which like temozolomide reduces the DNA repair enzyme MGMT (O⁶-alkylguanine-DNA alkyltransferase), has been shown to result in partial responses (PR), both in brain and extracranial sites in breast cancer patients [10]. Six of 15 women enrolled in a phase II trial conducted by the Hellenic Cooperative Oncology Group achieved PR, using 150–200 mg/m² on days 1–5 every 28 days with CDDP 75 mg/m² on day 1, including four patients who had received prior whole brain radiotherapy but had progressed. A previous phase II study conducted by the same group [11] evaluating temozolomide alone failed to demonstrate any responses in breast cancer patients. A third study showed no responses in 10 breast cancer patients, but stable disease in the brain for 8 weeks in four patients [12]. This phase II trial represents the first study of single-agent temozolomide solely in breast cancer patients.

	materials and methods

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This was a non-randomized, non-blinded multicenter open label phase II trial of the NCIC – Clinical Trials Group.

Patients were eligible if they had locally advanced or metastatic breast cancer with at least one unidimensionally measurable lesion (20 mm, or 10 mm if spiral CT scan), ECOG performance status of 2 and were 16 years of age or older. Prior adjuvant chemotherapy was permitted as well as up to two prior chemotherapy regimens for metastatic disease. Prior hormonal or radiation therapy was also permitted. Patients were allowed to have documented brain metastases: either newly diagnosed and not expected to require palliative radiotherapy within 4 weeks of study entry, or previously treated at least 4 weeks prior to study entry provided the patient was clinically stable.

Excluded from this study were pregnant or lactating women, women of childbearing potential who did not agree to practice effective birth control, or women with previous or concurrent malignancies excluding curatively treated in situ carcinoma of the cervix or bladder or non-melanoma skin cancer. Patients with other malignancies who were believed cured and who had completed all therapies at least 5 years prior to entry to the study were eligible. No concurrent treatment with other experimental drugs or anti-cancer therapy was allowed. Patients must have been able to tolerate oral medication and to swallow. Signed consent was obtained for each participant and the study was approved by the Research Ethics Board of each institution.

Pretreatment investigations included medical history, physical examination, evaluation of residual toxicity from previous therapy and baseline symptoms, and hematology and biochemistry within 7 days of registration. Radiological assessment included chest X-ray, abdominal CT scan, bone scan or other scans as necessary to document disease within 21 days of registration. Treatment consisted of temozolomide 150 mg/m² orally on days 1–7 and days 15–21 every 4 weeks. The drug was administered using a small number of capsules and was rounded up to the nearest 5 mg. It was recommended that temozolomide be administered at least 2 h after or 1 h before eating. Capsules were to be swallowed in rapid succession with approximately 8 oz of water and not to be chewed. Prophylactic anti-emetics with standard therapy were advised, beginning with non-HT3 antagonists with a subsequent change to HT3 antagonists if necessary, based on symptoms.

Evaluations during treatment consisted of physical examinations on day 1 of each cycle. Weekly blood counts were performed for cycles 1 and 2 and then days 1 and 15 thereafter. Biochemistry including creatinine, electrolytes, bilirubin, alkaline phosphatase, aspartate (AST), alanine aminotransferase (ALT) and serum protein was performed on day 1 of each cycle. Radiological examinations to assess measurable disease were repeated at the end of every other cycle (every 8 weeks). Toxicity was evaluated after each cycle and was graded using the NCI Common Toxicity Criteria Version 2.0. Patients who received at least one dose of temozolomide were evaluable for toxicity.

Treatment was to be discontinued in the case of serious or unmanageable toxicity, or at the patient's request. Duration of therapy depended on the best response obtained. For complete response (CR), treatment was to be continued for a maximum of two cycles after CR was confirmed. For partial response, treatment was continued until progressive disease or for four cycles after the documentation of stable partial response. Treatment was continued for a maximum of six cycles for stable disease. Patients discontinued therapy once objective progression was documented clinically and/or radiographically.

Temozolomide doses were delayed or reduced for hematologic or other toxicities that were at least possibly related to protocol therapy. Dose reductions were based on nadir counts in the previous 2-week treatment interval and the absolute granulocyte and platelet counts. For absolute granulocyte counts of <0.5 x 10⁹/l, platelet count <50 x 10⁹/l, febrile neutropenia or grade 3 thrombocytopenic hemorrhage, doses were reduced by 25%. For treatment on day 1 and day 15, absolute granulocyte count and platelet counts were required to be 1.5 x 10⁹/l and 100 x 10⁹/l, respectively, in order to treat on time with no change in dose. If these criteria were not met, treatment was delayed for at most 3 weeks until recovery, after which the patient was off study. For non-hematological toxicity, grade 3 toxicity mandated a delay until full recovery of grade 1 or less with a decrease in dose of 25%, and any grade 4 toxicity other than unpremedicated nausea or vomiting mandated discontinuation of protocol therapy. No changes were made for grade 0–2 toxicity. Granulocyte colony-stimulating factor (filgastrim, G-CSF) and other hematopoietic growth factors were not prohibited, but their use could not be substituted for any protocol-required dose reduction.

	response criteria

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Response and progression were evaluated using RECIST (response evaluation criteria in solid tumors) [16]. All patients who received at least one cycle of therapy and had their disease re-evaluated were evaluable for response. Response duration was measured from the time of measurement criteria for complete response or partial response, whichever was recorded first or first met, until the first date that recurrent or progressive disease was objectively documented. Stable disease duration was measured from the time of start of therapy until the criteria for progression were met.

	statistical considerations

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The primary objective of the study was to assess the efficacy as measured by objective tumor response of temozolomide given orally on days 1–7 and days 15–21 every 4 weeks in up to 30 evaluable patients with measurable advanced or metastatic breast cancer. The secondary objectives were to determine duration of response, time to progression and the toxic effects of temozolomide when administered in this fashion.

A two-stage design was used for patient accrual. This was to permit termination of patient accrual after evaluation of the first 15 patients in the event that extreme results, either very disappointing or very successful, were obtained. It was assumed that this regimen would be of interest if the tumor response rate was 20% or higher and that temozolomide would be of no interest in the treatment of metastatic breast cancer if the tumor response rate was 5% or less.

	results

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Nineteen patients were accrued at seven centers across Canada. The characteristics of patients registered are outlined in Table 1. The average age was 54 years (range 43–75) and five had ECOG status 2. Thirteen had prior neo/adjuvant chemotherapy, 14 had prior chemotherapy for metastatic disease and 12 had prior hormones for metastatic disease. Six patients had received three previous chemotherapy regimens, two for metastatic disease as well as adjuvant treatment. Sites of disease included bone in 13, the brain in five, the liver in nine and the lung in 12 patients. Furthermore, 12 patients had three or more sites of disease. A total of 37 cycles were administered; the median number of cycles administered was two (range 1–4). Temozolomide treatment was fairly well tolerated with 14/19 patients receiving 90% planned dose intensity.

View this table: [in this window] [in a new window]   Table 1. Patient characteristics (n = 19 patients)

 
All patients were evaluable for toxicity (Table 2). The most common drug-related toxicities were nausea, anorexia, fatigue, vomiting and skin rash. The toxicities were generally between grade 1 or 2 in severity although a few patients had grade 3 events. The hematological toxicities were all grade 2 or less (Table 3), except for three patients: one with grade 3 thrombocytopenia and granulocytopenia, one with grade 3 thrombocytopenia and another with grade 4 granulocytopenia and grade 3 thrombocytopenia. The biochemical toxicities were also generally grade 1 or less (Table 4) except for three patients with elevated (grade 2–3) liver enzymes, all of whom had extensive liver metastases.

View this table: [in this window] [in a new window]   Table 2. All treatment related non-hematolofsgic toxicities—worst by patient (n = 19 patients)

 

View this table: [in this window] [in a new window]   Table 3. Hematologic toxicity (worst by patient) (n = 19 patients)

 

View this table: [in this window] [in a new window]   Table 4. Biochemical toxicity (worst by patient)

 
Two patients discontinued therapy due to toxicity from treatment. One refused to continue treatment with temozolomide after 1 week on study due to grade 4 lethargy and grade 2 anorexia and nausea. Another stopped treatment after three cycles due to persistent grade 2 anemia, leukopenia and thrombocytopenia. Fifteen patients discontinued treatment for progression (14 objective progression and one symptomatic). An additional patient died on study due to progressive disease. Another discontinued treatment at the investigator's discretion.

Accrual continued until the first stopping point. No partial or complete responses were observed in the 18 patients evaluable, for an overall response rate of 0%. Stable disease (range 2.7–5.6 months) was documented in only three patients. In the five patients with documented brain metastases, no significant improvement was seen in any brain lesion. Time to progression was 1.8 months.

	discussion

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Temozolomide's unique mechanism of action, oral administration and activity in patients with brain tumors provide ample rationale for its evaluation in metastatic breast cancer. Despite the advances reported with new agents in this disease, none have been able to address the problem of CNS metastases. Systemic therapy for brain metastases from breast cancer has been attempted with high-dose methotrexate, CMF (cyclophosphamide, methotrexate and fluorouracil) and FAC (5-fluorouracil, doxorubicin and cyclophosphamide), but these approaches have produced variable response rates [13, 14]. More recently, the combination of cisplatin and etoposide has shown promising activity in phase II or cohort studies [15]. Unfortunately, in the current study, temozolomide produced no responses in the 18 evaluable patients entered, including five with brain metastases. The lack of response might be explained on the basis of several factors. First, the patient population studied had extensive disease and was rather heavily pretreated with 12 patients having received two or more previous chemotherapy regimens (including adjuvant). The expected response in this group of patients might be small and the activity of temozolomide could therefore have been missed. Secondly, the drug could be inactive in breast cancer. Finally, it is possible temozolomide is active but that the schedule we used was not optimal, although other schedules could be more toxic in a heavily pretreated population.

Although this patient population was not one in which a high response rate or prolonged time to progression was expected, a response rate of less than 20% was not considered to be important for further evaluation of the drug. Given the response rate of 0%, it is highly unlikely that significant activity was missed in this study.

Temozolomide inactivates the DNA repair enzyme O⁶-alkylguanine-DNA alkyltransferase (MGMT) [2]. However, breast tumors have been found to contain very high MGMT levels, so that DNA crosslinks caused by temozolomide are repaired [17]. Hence, MGMT activity may lead to resistance to treatment with alkylating agents such as temozolomide [18]. Attempts have been made to deplete MGMT with the use of methylating agents prior to the administration of temozolomide without success [18, 19]. However, a more recent study evaluating the inactivation of MGMT using non-toxic pseudosubstrates for the protein has shown success in cells and xenografts [20]. Although a dose-dense 2 weekly regimen was evaluated, protracted temozolomide schedules such as continuous 21-day administration may be more successful at depleting MGMT activity, even at relatively low daily doses [17].

This study demonstrated the lack of systemic activity for temozolomide in a heavily pretreated, heterogeneous group of breast cancer patients. It also illustrates the difficulty of conducting trials in this patient population where response is unlikely and progression of disease is rapid. It may be worth re-examining a less heavily pretreated population of metastatic breast cancer patients, specifically for the treatment of brain metastases from breast cancer with other schedules of administration of temozolomide, especially in combination with an MGMT inhibitor [20].

	Acknowledgements

 
The authors would like to thank the following investigators who enrolled patients on this trial: Dr K. Laing, Dr H. Bliss Murphy Cancer Centre, St. John's, NFLD; Dr R. Goel, Ottawa Regional Cancer Centre, Ottawa ON; Dr K. I. Pritchard, Toronto Sunnybrook Regional Cancer Centre, Toronto ON, Dr S. Burdette-Radoux, McGill University Department of Oncology, Montreal, QC; Dr K. Belanger, CHUM-Hopital Notre Dame, Montreal QC.

This study was supported by grants from the Canadian Cancer Society via the National Cancer Institute of Canada and from Schering Canada Inc.

Received for publication May 2, 2005. Revision received February 13, 2006. Accepted for publication February 14, 2006.

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This Article Abstract FREE Full Text (PDF) All Versions of this Article: 17/6/952    most recent mdl056v1 E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (11) Request Permissions Disclaimer Google Scholar Articles by Trudeau, M. E. Articles by Eisenhauer, E. Search for Related Content PubMed PubMed Citation Articles by Trudeau, M. E. Articles by Eisenhauer, E. Social Bookmarking          What's this?

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