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First-Line Chemotherapy With Cisplatin Plus Fractionated Temozolomide in Recurrent Glioblastoma Multiforme: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia

From the Departments of Medical Oncology and Neurological Sciences, Azienda Ospedale-University Hospital, Padova; the Department of Radiochemotherapy, San Raffaele Hospital, Milan; and the Department of Medical Oncology, Bellaria Hospital, Bologna, Italy.

Address reprint requests to Alba A. Brandes, MD, Department of Medical Oncology-Direzione, Azienda Ospedale-Università Ospedale Busonera, Via Gattamelata 64, 35100 Padova, Italy; e-mail: aabrandes{at}unipd.it

	ABSTRACT

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PURPOSE: Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O⁶-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival.

PATIENTS AND METHODS: Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m² on day 1, TMZ 130 mg/m² bolus followed by nine doses of 70 mg/m² every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m² in 5 days.

RESULTS: A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%).

CONCLUSION: The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

	INTRODUCTION

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Glioblastoma multiforme (GBM), the most frequent brain tumor in adults, remains an incurable disease.

As shown in a published database on phase II trials that include 225 patients with recurrent GBM,¹ any benefit obtained from chemotherapy administered to patients with recurrent or progressive GBM is as yet unsatisfactory: the median progression-free survival (PFS) is 9 weeks, and PFS at 6 months (PFS-6) is 15%. New agents or novel synergic combinations are therefore needed.

Temozolomide (TMZ), an active agent in recurrent glioblastoma,^2–4 is spontaneously converted to monomethyl-triazenoimidazole carbaxamide, which methylates DNA at the O⁶ position of guanine. This lesion can be repaired by O⁶-alkylguanine DNA-alkyl transferase (AGAT), which is responsible for conferring resistance to TMZ. Given that AGAT removes alkyl adducts from DNA via a suicide mechanism, it has been suggested that protracted exposure to an alkylating agent may not only saturate the enzyme copies available within cancer cells, but may also inactivate the new molecules while they are being synthesized, thus leading to AGAT "depletion" that should enhance the cytotoxicity of the drug itself.⁵ Spiro et al⁶ administered TMZ twice daily (200 mg/m² bolus followed by 9 doses at 90 mg/m² every 12 hours) and demonstrated that an AGAT depletion of 90% can be achieved in peripheral WBCs. Platinum compounds were long considered active agents for the treatment of gliomas besides nitrosoureas,⁷ with reported response rates (RR) of approximately 15%.⁸ Cisplatin was shown to reduce AGAT activity in vitro,⁹ suggesting that it could enhance the single-agent activity of TMZ. Moreover, the rationale for this combination derives from the demonstration that cisplatin has a synergic interaction with TMZ in preclinical models,¹⁰ with no overlapping profiles of toxicity, thus allowing the administration of a full dose of both drugs in phase II trials.¹¹

We therefore started a multicenter phase II study in patients with GBM recurrent after surgery plus radiotherapy in order to evaluate PFS-6, response, toxicity, and survival following the administration of cisplatin followed by fractionated TMZ.

	PATIENTS AND METHODS

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Eligibility
Criteria for eligibility were histologic diagnosis of GBM, age 18 years and 70 years, Karnofsky performance status (KPS) 60, normal baseline counts for neutrophils ( 1,500/µL) and platelets ( 100,000/µL), transaminases and alkaline phosphatase levels 1.5 times the upper normal limits, bilirubin and creatinine levels 1.25 times the upper normal limits, and previous surgery followed by standard radiotherapy (60 Gy/30 fractions). Unequivocal evidence of recurrence or progression of disease at neuroimaging with gadolinium-enhanced magnetic resonance imaging (MRI) was also required. Only patients showing disease progression in two subsequent MRI scans separated by at least 1 month, with at least one enhancing measurable lesion of 2 cm in diameter, were accrued in the present study. For patients who underwent intervention for the recurrence, brain imaging performed within 2 days after surgery showing residual disease with the previously described characteristics was mandatory. All patients accrued had been on a stable dose of corticosteroids for at least 2 weeks before initiation of therapy. Patients with childbearing potential had to use effective contraception, and a normal beta-human chorionic gonadotropin level was required for fertile females. Patients who were pregnant or breast-feeding were considered ineligible, as were patients who had previously received any type of cytotoxic therapy, had presented active infection or other uncontrolled diseases, had psychiatric disturbances, or had a history of cancer other than resected nonmelanoma skin cancer or carcinoma-in-situ of the uterine cervix. All patients signed a form giving their fully informed consent to take part in the study, which was approved by the Institutional Review Board of Padova University Hospital, Italy, and was conducted according to the principles of the Declaration of Helsinki and the rules of Good Clinical Practice.

Treatment Regimen
Cisplatin (75 mg/m² over 1 hour intravenous [IV] infusion) was administered on day 1, with 1,500 mL hydration of saline solution with 30 mEq KCl, 20 mEq MgSO₄, 150 mL mannitol 18%, and 20 mg furosemide. Antiemetic prophylaxis consisted of granisetron 3 mg plus dexamethazone 8 mg. Hydration with 1,000 mL of saline solution was repeated on day 2, when the first TMZ bolus (130 mg/m²) was administered orally, followed by nine doses every 12 hours (days 2 to 6), at a cumulative dose of 750 mg/m² (Table 1). Patients were required to fast for at least 2 hours before and after each TMZ dose. Unless the patient experienced nausea or vomiting, 3 mg granisetron was administered only once in the morning on days 2 to 6. In the absence of hematologic toxicity G2 after the first cycle, TMZ was escalated to 1,000 mg/m² and proportionately divided into 10 doses (Table 1). Each dose was rounded to the nearest 20 mg, but the total dose over the 5 days remained fixed. Chemotherapy was repeated after 4 weeks, for a maximum of eight cycles. Subsequently, patients with tumor response or stable disease continued chemotherapy with TMZ alone, with the same fractionated schedule, for up to 1 year. The use of growth factors to maintain high blood counts and to administer chemotherapy at fixed intervals was proscribed.

Cisplatin was discontinued also in cases of G2 nephrotoxicity, with creatinine levels 3 times the upper normal limit for at least 2 weeks, or in cases of G3 neurotoxicity or ototoxicity, whereas TMZ administration could be prosecuted. Patients were kept at the lowest corticosteroid dosage allowed by their neurologic status.

Efficacy Measures
Time to progression (TTP) was evaluated from the start of chemotherapy to progression or exit from the study for any reason; median survival time (MST) was calculated from the time of start of chemotherapy to death for any reason. Data on all 50 patients were included in the statistical analysis. TTP, PFS-6, and MST were calculated using the Kaplan-Meier method;¹³ differences in progression and overall survival were evaluated by the log-rank test for statistical significance.

Patients were evaluated for response according to clinical and neurologic examinations (performed monthly before each cycle) and MRI or computed tomography neuroimaging performed every two cycles, or earlier if clinically indicated, according to Macdonald's criteria.¹⁴

Neurologic status was assessed considering signs and symptoms that might be correlated with tumor progression, as compared with the previous examination; each variation in the daily dosage of corticosteroids was recorded.

Responses were confirmed as complete or partial only if they were constant on successive scans taken at least 4 weeks apart from each other. An independent central review of computed tomography and MRI scans was made for patients achieving complete (CR) or partial (PR) response or disease stabilization (SD), evaluated by local investigators. Patients were withdrawn from the study if they had progressive disease, unacceptable toxicity, or retracted their consent. Patients who interrupted treatment before the first radiologic evaluation were considered assessable for toxicity but not for response.

Statistical Analysis
The primary end point of the present study was to determine PFS-6. Historical values were obtained from the analysis of a database containing information on 225 patients with recurrent GBM treated in eight consecutive prospective trials, in which PFS-6 was 15%.¹ The hypotheses to be tested were H0: p < p0 versus H1: p > p1, where p was the probability of remaining alive and free from disease progression at 6 months. Alpha (false-positive rate) was taken to be 10% and beta (false-negative rate) to be 5%. p0 was set to 10% and p1 to 30% (looking for an improvement of 0.2). A study with 50 patients was expected to yield acceptable error rates for testing our hypothesis and precision for estimation. To declare success, 15 responses (patients alive and progression free at 6 months) among 50 patients (our target of 30%) were needed (the 95% CI on the true response proportion ranges from 17% to 43%).¹⁵

TTP, PFS-6, and overall survival were calculated according to the Kaplan-Meier method using S-PLUS software (NathSoft Inc, Seattle, WA), and differences in progression and survival according to prognostic factors were evaluated with the log-rank test. Parameters possibly correlated with disease progression and survival were age, KPS, and time interval between end of radiotherapy and recurrence.

Multivariate analysis with the Cox model¹⁶ was used to assess truly independent prognostic factors and was performed only on variables with P < .05 at univariate analysis.

	RESULTS

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Patient Characteristics
From February 2001 to November 2002, 50 patients (24 males) were enrolled onto the study. Although all patients were assessable for toxicity, 49 were assessable for response because one patient died as a result of pulmonary embolism before the assessment was performed. The demographic and clinical characteristics of patients are outlined in Table 2. The median age was 51 years (range, 27 to 70 years), and the median KPS was 80 (range, 60 to 100). Forty-five patients had undergone one surgical procedure, and five had undergone more than one. Last surgery was considered macroscopically radical in 18 patients (36%) on the basis of either the neurosurgeon's impression or findings at postoperative neuroimaging. All patients had received full dose radiotherapy, but none had been treated with cytotoxic drugs. All patients were on antiepileptic prophylaxis enzyme-inducing drugs (phenobarbital, 68%; phenytoin, 18%; or carbamazepine, 14%). The median follow-up period was 14.35 months (range, 2.3 to 24.8 months).

View larger version (15K): [in this window] [in a new window]   Fig 1. Progression-free survival (three censored patients; thin line), and median survival time (15 censored patients; thick line) in the study population.

Response
In the 49 assessable patients, one CR (2%; Fig 2) and nine PRs (18.4%) were obtained, with an overall RR of 20.4% (95% CI, 7.7% to 33.0%). All radiologic responses were confirmed by an independent centralized review, and stable or decreased steroid dosage was confirmed in all patients at the time of recording response. Interestingly, all responses but two (80%) were identified after the second cycle. The median duration of CR + PR was 26.5 weeks (range, 10 to 74 weeks). The median duration of disease stabilization, achieved in 23 patients (46.9%; 95% CI, 31% to 63%), was 24 weeks (range, 10 to 73.9 weeks).

View larger version (142K): [in this window] [in a new window]   Fig 2. Complete tumor response: a 50-year-old patient before (A) and after (B) eight cycles of chemotherapy.

Toxicity
All toxicities were recorded and graded according to the common toxicity criteria of the National Cancer Institute, version 2.0.¹² A total of 203 treatment cycles were given to 50 patients; the number of cycles per patient ranged from one to eight, with a mean of four cycles per patient. The following toxicities were observed: neutropenia, grade 1 to 2 in nine patients (18%); neutropenia, grade 3 to 4 in seven patients (14%); thrombocytopenia, grade 1 to 2 in eight patients (16%), and grade 3 to 4 in five patients (10%). One patient developed G3 anemia and required therapy with erythropoietin alpha. G3-4 hematologic toxicity did not appear to be cumulative (Table 3). Eleven patients (22%) had mild to moderate nausea or vomiting, nine patients (18%) reported constipation, and one patient (2%) experienced grade 2 hepatic toxicity. Chemotherapy was withdrawn for 1 month because of acute cholecystitis requiring surgery in one patient and then resumed because the patient had a good radiologic response (Fig 2). There were no relevant episodes of nephrotoxicity, but cumulative G3 ototoxicity and G3 neurotoxicity attributable to cisplatin was experienced by one and three patients, respectively (Table 4). Chemotherapy was interrupted in four cases because of toxicity (one thrombocytopenia at cycle 4, one neurologic toxicity at cycle 6, one irreversible heart failure at cycle 2, and one arterial embolism with leg amputation at cycle 2). One patient developed pulmonary embolism after one cycle and died before the first evaluation of disease. Dose reduction was required in seven cases (14%): hematologic toxicity occurred in four cases (8%) and concomitant hematologic and neurologic toxicity in three cases (6%). Forty cycles (20%) were delayed for a mean of 1.67 weeks because of reversible hematologic toxicity.

	DISCUSSION

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TMZ is currently the object of numerous clinical trials aiming to improve on the results of standard schedule, to combine the drug with other cytotoxic or cytostatic agents, or to explore new modalities to overcome chemoresistance. Groves et al¹⁷ and Jaeckle et al¹⁸ reported similar results in their group of patients, of whom some were pretreated, with TMZ in combination regimens. TMZ plus marimastat administration was followed by a PFS-6 of 39%, (95% CI, 24% to 54%), with a median PFS of 17 weeks (95% CI, 13 to 26 weeks); TMZ plus 13-cis-retinoic acid resulted in a PFS-6 of 32% (95% CI, 21% to 51%), with a median PFS of 16 weeks (95% CI, 9 to 26 weeks).

Given that the chemoresistance of gliomas is not overcome by dose escalation, even at myeloablative levels,¹⁹ alternative strategies should be developed to increase the cytocidal potential of currently available cytotoxic agents. Alkylation on the O⁶ position of guanine is the critical (although not unique) lesion caused by this drug, and high levels of AGAT in malignant gliomas correlate with lower RR to TMZ and a shorter survival.²⁰ As AGAT removes alkyl adducts from DNA with a suicide mechanism, it has been speculated that a bid administration of TMZ may progressively deplete all the copies of enzyme in cancer cells, thus improving the therapeutic index. Samplings of peripheral mononuclear cells (PBMC) were used to obtain in vivo sequential measurements of AGAT inhibition, with mean activity levels decreasing by up to 95% when a bid TMZ regimen was applied for 5 days.⁶ Comparisons made between AGAT levels in PBMC and tumor biopsies taken from patients with solid tumors showed that the enzyme inhibition in tumor cells is extremely heterogeneous, slower than, and usually inferior to that found in PBMC.⁶ Differences in exposure to TMZ metabolites (expectedly more homogeneous in circulating blood than in tumor microcirculation) and the presence of necrotic, inflammatory, or fibrous cells in tumor biopsies have been proposed as explanations for this lack of correlation. As PBMC AGAT levels are considered a poor surrogate for tumor enzyme depletion, only surgical specimens collected after a neoadjuvant chemotherapy cycle²¹ are likely to allow a reliable and objective in vivo measurement of AGAT inhibition within GBM cells and to provide evidence that enhanced AGAT inhibition obtained by bid TMZ schedule correlates with higher tumor control rates.

In our trial, a bid regimen of TMZ was preceded by a single dose of cisplatin, which has been shown to have some activity in gliomas as a single agent,⁸ has a low myelotoxicity and, above all, can inhibit AGAT through alternative molecular interactions.⁹ When this combination was administered to chemotherapy-naive GBM patients, a PFS-6 of 34% (95% CI, 23% to 50%) and a PFS-12 of 4% (95% CI, 0.3% to 16%) were obtained, with a median PFS of 18.4 weeks (95% CI, 13 to 25.9 weeks). Cisplatin-related adverse events were mild, with no nephrotoxicity, and there were only three cases of cumulative G3 neuro- or otoxicity (6%) after the fourth cycle.

These results appear better than those obtained with a standard schedule of TMZ alone and comparable to those obtained using TMZ combined with other drugs. (Table 5). However, adjustments for distribution of known prognostic factors cannot be performed in nonrandomized studies. Moreover, previous chemotherapy exposure might have decreased chemosensitivity and PFS-6 in the trials cited.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

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

	REFERENCES

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Submitted November 5, 2003; accepted February 20, 2004.

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