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Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4779-4786 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.06.181 Second-Line Chemotherapy With Irinotecan Plus Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)From the Departments of Medical Oncology, Neuroradiology, Radiotherapy, Neurological Sciences, University Hospital of Padova, Department of Radiochemotherapy, San Raffaele Hospital, Milan, Department of Medical Oncology, Ospedale S. Chiara, Trento, Italy Address reprint requests to Alba A. Brandes, MD, Department of Medical Oncology, University Hospital, Via Gattamelata 64, Padova, Italy; e-mail: aabrandes{at}unipd.it
PURPOSE: Glioblastoma multiforme (GBM), the most frequent brain tumor in adults, is not considered chemosensitive. Nevertheless, there is widespread use of first-line chemotherapy, often with temozolomide, as a therapeutic option in patients with progressive disease after surgery and radiotherapy. However, at the time of second recurrence and/or progression, active and noncross-resistant chemotherapy regimens are required. The aim of the present multicenter phase II trial, therefore, was to ascertain the efficacy of second-line carmustine (BCNU) and irinotecan chemotherapy. PATIENTS AND METHODS: Patients with histologically confirmed GBM, recurring or progressing after surgery, standard radiotherapy and a first-line temozolomide-based chemotherapy, were considered eligible. The primary end-point was progression-free survival at 6 months (PFS-6), and secondary end-points included response rate, toxicity, and survival. All patients were on enzyme-inducing antiepileptic prophylaxis. Chemotherapy consisted of BCNU (100 mg/m2 on day 1) plus irinotecan (175 mg/m2/weekly for 4 weeks), every 6 weeks, for a maximum of eight cycles. In the absence of grade 2 toxicity, the irinotecan dose was increased to 200 mg/m2. RESULTS: A total of 42 patients (median age, 53.4 years; median Karnofsky performance status, 80; range, 60 to 90) were included in the study. PFS-6 was 30.3% (95% CI, 18.5% to 49.7%). Median time to progression was 17 weeks (95% CI, 11.9 to 23.9). Nine partial responses (21.4%; 95% CI, 9% to 34%) were obtained. Toxicity was manageable. CONCLUSION: The BCNU plus irinotecan regimen seems active and non–cross-resistant in patients with GBM with recurrence after temozolomide-based chemotherapy.
Glioblastoma multiforme (GBM) was long considered chemoresistant, with a median life expectancy of less than 12 months after diagnosis.1 However, findings in a recent meta-analysis2 demonstrated that nitrosourea-based regimens in an adjuvant setting can significantly prolong survival (absolute gains of 6% and 4% at 1 and 2 years, respectively). Moreover, a body of evidence demonstrates that chemotherapy can ameliorate the neurological status, thus influencing quality of life.3 Most GBM patients currently receive temozolomide as a first-line chemotherapy regimen, either concomitantly with standard radiotherapy4 or at first relapse,5,6 even though no formal randomized study has yet been conducted to compare the efficacy of temozolomide with that of nitrosoureas in this setting. Of the several potentially noncross-resistant drugs studied, none has been demonstrated to obtain a substantial impact on delaying disease progression.1 New agents, or novel synergic combinations, are therefore required. In animal studies, the topoisomerase-I inhibitor, irinotecan, has displayed a marked antitumoral activity against a broad panel of subcutaneous and intracranial human GBM, ependymoma, and medulloblastoma xenografts.7,8 After intravenous (IV) injection, irinotecan is metabolized in the liver into the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which has a low molecular weight and lipophilic properties, enabling it to cross the blood-brain barrier.9 Alkylating agents are ideal candidates for combination chemotherapy with irinotecan because they have different mechanisms of action and different organ toxicities. Carmustine (BCNU) exerts its cytotoxic activity primarily by covalently adding a chloroethyl group to the O6 position of guanine, resulting in cross-linking between DNA strands, and DNA duplication and transcription impairment.10 Its main toxicities are cumulative myelosuppression and pulmonary toxicity. Irinotecan and BCNU appear to act synergistically against CNS tumor cell lines.8-11 On administering irinotecan and BCNU, supra-additive effects have been observed without there being a consistent increase in toxicity; maximal activity was achieved when BCNU was administered on day 1 and irinotecan was administered on days 1 to 5 and 8 to 12.11 These findings suggest that the presence of BCNU-induced adducts or crosslinks to DNA before irinotecan administration is critical to the enhanced antitumoral activity of this combination.11 A substantial body of clinical evidence demonstrates that the concurrent administration of enzyme-inducing anticonvulsants (EIA) alters the hepatic metabolism of irinotecan and reduces the area under the plasma concentration curve of the active metabolite SN-38.9 Therefore, irinotecan dosages must be adjusted according to the type of antiepileptic drug taken by patients. A phase I study was performed using combined BCNU 100 mg/m2 (day 1) and irinotecan (weekly, on days 1, 8, 15, and 22), starting with 125 mg/m2, every 6 weeks, in patients either taking or not taking EIAs. Dose-limiting toxicity was mainly hematologic, the maximum-tolerated dose for irinotecan being 225 mg/m2 or 125 mg/m2 in patients on, and not on, EIA, respectively.12 The present multicenter phase II study was conducted to evaluate the efficacy and clinical tolerability of BCNU plus weekly irinotecan, given every 6 weeks to patients with recurrent GBM after previous exposure to temozolomide-based chemotherapy.
Eligibility Criteria for eligibility were: presence of GBM (confirmed by a centralized pathology review) that recurred or progressed after surgery and radiotherapy (60 Gy/30 fractions on limited fields) completed at least 3 months before enrolment and previous temozolomide-based chemotherapy (delivered at first relapse/disease progression); age  18 years; Karnofsky performance status (KPS) 60; unequivocal evidence of recurrence or disease progression at neuroimaging with Gadolinium-enhanced magnetic resonance imaging (MRI). If radiation necrosis was suspected, spectroscopic MRI was performed to confirm the presence of viable tumor cells. For patients who underwent repeat surgery for recurrence, brain imaging within 2 days after surgery showing residual measurable disease was mandatory. All patients had been on a stable dose of corticosteroids for at least 2 weeks before baseline imaging and initiation of chemotherapy, and they were required to start chemotherapy within 3 days after enrolment.
Adequate hematologic, renal, hepatic, and pulmonary function (absolute neutrophil count
Treatment Regimen
Dose Modifications
Supportive Care
Efficacy Measures Before each cycle, patients were evaluated for response with a clinical and neurological examination plus MRI neuroimaging, performed every 6 weeks or earlier if clinically indicated, according to Macdonald's criteria.17 Neurological status was assessed by 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. MRI scans from all patients without disease progression were sent by the local investigator to the coordinating center (Padova) for independent central review. The scans were evaluated by a multidisciplinary team consisting of a neurosurgeon, a neuroradiologist, a neuro-oncologist, and a radiotherapist.
Statistical Analysis
Patient Characteristics From August 2001 to October 2003, 42 patients (29 men, 13 women; median age, 53.4 years; age range, 26.9 to 71.3 years; median KPS, 80; KPS range, 60 to 100) were enrolled in the study; all started chemotherapy within 3 days from enrollment, and all were assessable for both response and toxicity. The median follow-up period was 5.7 months. The demographic and clinical characteristics of patients are outlined in Table 1. Twenty-five patients (59.5%) had undergone one surgical procedure and 17 (40.5%) had undergone more than one. All patients had received full-dose radiotherapy (60 Gy/30 F) and were treated at second relapse or disease progression after first-line chemotherapy with a temozolomide-based regimen: 26 patients (61.9%) had been treated with temozolomide alone, and 16 with temozolomide plus cisplatin (38.1%) within a former trial conducted by Gruppo Italiano Cooperativo Neuro-Oncologico.6 Outcomes following first-line chemotherapy were classified as complete (CR; 1 patient; 2.4%; 95% CI, 0.1% to 7%), or partial response (PR; 11 patients; 26.2%; 95% CI, 13% to 39.5%), disease stabilization (SD; 14 patients; 33.3%; 95% CI, 19% to 47.5%) and disease progression (PD; 16 patients; 38.1%; 95% CI, 23.3% to 52.7%).
Disease Progression Considering all 42 patients, median TTP was 17 weeks (95% CI, 11.9% to 23.9%); median TTP was 35.3 weeks (95% CI, 34.1% to not assessable) in patients with PR, and 22 weeks (95% CI, 17% to not assessable) in those with SD (P = .03). PFS-6 was 30.3% (95% CI, 18.5% to 49.7%; Fig 1). At log-rank test evaluation, no significant correlation was found between TTP and KPS, type of surgery, or time from end of radiotherapy to chemotherapy, whereas age  45 years (P = .024) and response to therapy (P < .000001) were significant prognostic factors. At multivariate analysis, only response to therapy retained significance (P < .000001).
Overall Survival The MST was 11.7 months (95% CI, 9.5 to not assessable); 71% (95% CI, 57.7% to 88.3%), and 44.1% (95% CI, 26.4 to 73.6%) of the patients were alive at 6 and 12 months, respectively (Fig 1).
At univariate analysis, age
Response The characteristics of responders are listed in Table 2 and the more relevant tumor responses are shown in Figure 2.
Toxicity A total of 130 treatment cycles were given to 42 patients; the number of cycles per patient ranged from 1 to 8, with a mean of 3.1 cycles per patient. The irinotecan dose was increased to 200 mg/m2 in 26 cycles (20%) and reduced by 25% in 22 cycles (17%) because of grade 3 diarrhea or grade 3 vomiting, and by 15% in 12 cycles (9.2%) because of cholinergic syndrome refractive to atropine. Sixteen cycles (12.3%) were delayed for a median time of 1.4 weeks (range, 1 to 2 weeks) due to neutropenia (3 cycles) or diarrhea (13 cycles). The following toxicities were observed at nadir: neutropenia grade 1 to grade 2 in 11 patients (26%); neutropenia grade 3 in one patient (2.4%); thrombocytopenia grade 1 to 2 in four patients (9.5%), and anemia grade 1 to 2 in three patients (7.1%). Nausea and/or vomiting was grade 1 to grade 2 in 12 patients (28.6%) and grade 3 in four patients (9.5%). Diarrhea was grade 1 to 2 in 29 patients (69%), and grade 3 in three (7.1%). Four patients (9.5%) had the cholinergic syndrome. The series were not large enough for any correlation to be found between type of EIAD and toxicity. Four patients had thromboembolic events: grade 2 in one, grade 3 in two, and grade 4 in one. Dose reduction of both irinotecan and BCNU was required in one patient (2.4%) due to grade 3 diarrhea and grade 3 neutropenia. Chemotherapy was interrupted in two responding patients (4.8%) due to toxicity: DLCO impairment (at third cycle) and pulmonary embolism (at second cycle), respectively (Table 3).
The role of chemotherapy in the management of GBM has long been questioned because of the frequently disappointing results reported in previous clinical trials. The response rate is no longer considered a valid end-point for chemotherapy activity in patients with glioma, because it may be influenced by confounding factors, such as steroid dosage and radiation necrosis, and it is not a reliable predictor of TTP or survival. Delayed progression appears to be a more appropriate end-point for phase II trials in neuro-oncology.20 A re-evaluation of eight phase II trials with cytotoxic and/or cytostatic drugs involving 225 recurrent GBM patients showed a median PFS-6 of 15% (95% CI, 10% to 19%).18 Kappelle et al21 recently reported a PFS-6 of 29% in patients given procarbazine, vincristine, and lomustine (PCV) chemotherapy, while a PFS-6 of 27% (95% CI, 15.9 to 45.9%) was obtained in a phase II trial of BCNU plus daily thalidomide.22 PFS-6 values for temozolomide have been promising, ranging from 21% (95% CI, 13% to 29%)5 to 24% (95% CI, 14% to 42%)23 when used alone, and from 32% (95% CI, 21% to 51%),24 to 34% (95% CI, 23% to 50%),6 up to 39% (95% CI, 24% to 54%)25 when combined with other drugs (Table 4). In view of the above data, and the optimal clinical tolerability of temozolomide, and despite the absence of randomized comparisons with nitrosourea-based regimens, most GBM patients are given temozolomide (alone or in combination) as a first-line chemotherapy regimen in current clinical practice. However, local recurrence is almost inevitable in GBM patients, second-line chemotherapy with nitrosoureas or with experimental drugs being the most widely used therapeutic option in such cases.
After preliminary observations concerning irinotecan activity in glioma cells lines, pilot studies reported conflicting results, with high response rates reported in adult26 and pediatric27 patients, and, conversely, absence of any activity in other series.28 The present multicenter phase II study, therefore, was performed to assess the efficacy of a combination of BCNU and weekly irinotecan in a homogeneous cohort of patients with GBM recurring or progressing after temozolomide-based chemotherapy administered at first relapse. BCNU was associated with irinotecan in view of experimental evidence of the antitumoral synergy between these drugs, and in order not to deprive patients of the possibility of being exposed to a standard nitrosourea in the course of their disease. The PFS-6 of 30.3% (95% CI, 18.5% to 49.7%) is appreciable compared with that of other experimental regimens recently tested in recurrent GBM patients, such as pegylated liposomal doxorubicin plus tamoxifen (7.1%)29 or the epidermal growth factor receptor (EGFR) inhibitor (Iressa; AstraZeneca, Wilmington, DE; 13%).30 None of our patients was chemonaïive, while approximately one-third5 to two-thirds21 of the patients in trials reported by other authors had never been exposed to chemotherapy. In our trial, age younger than 45 years was the only independent prognostic factor for both response and survival, unlike KPS, response to previous chemotherapy, and time interval from end of radiotherapy. The median age of our patients was equivalent to,5,25 or slightly higher than, that in other series.23,24 However, adjustments for other known prognostic factors cannot be made when comparing findings from different phase II studies, and the selection bias of patients maintaining a good KPS after first progression, which enables them to receive second-line chemotherapy, must be considered when interpreting our results. Although MST was not a primary end-point of the present study, the 11.2-month median survival of patients starting second-line chemotherapy was somewhat surprising in patients with GBM, which has such a dismal prognosis. In the present trial, we also recorded the rate of centrally confirmed radiographic responses in 42 assessable patients. SD was obtained in 10 (60%) of the 16 patients who had PD after first-line chemotherapy; of the remaining six patients, 25% had a partial remission and only two underwent progression. Of 11 patients with partial response after previous chemotherapy, 3 (28%) achieved a second response and four (36%) SD, which suggests that the BCNU plus irinotecan regimen may represent a true second-line chemotherapy, noncross-resistant with temozolomide. In the present series, toxicity was moderate, except for irinotecan-induced diarrhea, which frequently required supportive medication with loperamide and called for a delay in the administration of chemotherapy (10% of cycles delayed because of persistently loose stools) or dosage reduction (26.2% of cycles). The high incidence of diarrhea (grade 1 to grade 2 in 69% of patients and grade 3 in 7.1% of patients) justified our choice not to exceed the weekly dosage of irinotecan to > 200 mg/m2. Only two patients discontinued treatment early during response, because of partially reversible interstitial pneumonitis or pulmonary thromboembolism requiring hospitalization. In conclusion, the present study is, to our knowledge, the first report to appear on a second-line regimen given to a homogeneous cohort of GBM patients with disease recurrence and/or progression after temozolomide-based chemotherapy given at first relapse. The association of irinotecan plus BCNU proved active, and noncross-resistant with temozolomide, incurring only marginal pulmonary or hematologic toxicity and manageable diarrhea. With this regimen, the survival of younger patients who do not respond to temozolomide can exceed 15 months. Moreover, to date, no single agent salvage therapy has yielded comparable results.1 Findings from a randomized study might definitively establish whether this apparently promising outcome is attributable to BCNU and irinotecan combined, or to either drug alone. However, in view of the large number of patients required, this type of trial does not currently appear feasible.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Silvio Monfardini, Eli Lilly. Honoraria: Alba A. Brandes, Schering-Plough. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.
We thank Dr Valeria Blatt for her data management and help in the preparation of the manuscript.
Presented in part at the Poster Discussion Session of the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, June 5-8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Brandes AA, Basso U, Pasetto LM, et al: New strategy developments in brain tumor therapy. Curr Pharm Des 7:1553-1580, 2001[CrossRef][Medline] 2. Stewart LA: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011-1018, 2002[CrossRef][Medline]
3. Osoba D, Brada M, Yung WK: Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme, J Clin Oncol 18:1481-1491, 2000
4. Stupp R, Dietrich PY, Kraljevic SO, et al: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375-1382, 2002 5. Yung A, Albright R, 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]
6. Brandes AA, Basso U, Reni M, et al: First line chemotherapy with cisplatin plus fractionated temozolomide (bid) in recurrent glioblastoma multiforme: A phase II study of the Gruppo Italiano Cooperativo Neuro-Oncologia (GICNO). J Clin Oncol 22:1598-1604, 2004 7. Hare CB, Elion GB, Houghton PJ, et al: Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonylohy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 39:187-191, 1997[CrossRef][Medline] 8. Coggins CA, Elion GB, Houghton PJ, et al: Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol 41:485-490, 1998[CrossRef][Medline] 9. Gupta E, Mick R, Ramirez J, et al: Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 15:1502-1510, 1997[Abstract] 10. Erickson LC, Laurent G, Sharkey NA, Kohn KW: DNA-cross-linking and monoadduct repair in nitrosourea-treated human tumor cells. Nature 288:727-729, 1980[CrossRef][Medline] 11. Friedman HS, Castellino RC, Elion GB, et al: Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts. Cancer Chemother Pharmacol 45:345-349, 2000[CrossRef][Medline] 12. Quinn JA, Reardon DA, Friedmann AH, et al: Phase I trial of irinotecan plus BCNU in patients with progressing or recurrent malignant glioma. Neurooncol 6:145-153, 2004[Abstract] 13. Buckner J, Reid J, Shaaf L, et al: A phase II trial of Irinotecan (CPT-11) in recurrent glioma. Proc Am Soc Clin Oncol 19:175a, 2000 (abstr 679) 14. Gilbert M, Supko J, Grossman S, et al: Dose requirements, pharmacology and activity of CPT-11 in patients with recurrent high grade glioma: A NABTT CNS Consortium Trial. Proc Am Soc Clin Oncol 19:161a, 2000 (abstr 622) 15. National Cancer Institute: Reporting Guidelines, Common Toxicity Criteria V2.0 (CTC). http://ctep.cancer.gov/reporting/CTC-3.html 16. Kaplan EL, Meier P: Non parametric estimation for incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef] 17. Macdonald DR, Cascino TL, Schold SC Jr., et al: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277-1280, 1990[Abstract]
18. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999 19. Cox DR: Regression models and life tables. J R Stat Soc 34:187-202, 1972
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22. Fine HA, Wen PY, Maher EA, et al: Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol 21:2299-2304, 2003 23. Brandes AA, Ermani M, Basso U, et al: Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: A phase II study. Oncology 63:38-41, 2002[CrossRef][Medline]
24. Jackle KA, Hess KR, Yung A, et al: Phase II evaluation of temozolomide and 13-cis retinoic acid for the treatment of recurrent and progressive malignant glioma: A North American Brain Tumor Consortium Study. J Clin Oncol 21:2305-2311, 2003
25. Groves MD, Puduvalli VK, Hess KR, et al: Phase II trial of temozolomide plus matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J Clin Oncol 20:1383-1388, 2002
26. Jaeckle KA, Hess KR, Yung WK, et al: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17:1516-1525, 1999 27. Turner CD, Gururangan S, Eastwood J, et al: Phase II study of irinotecan (CPT11) in children with high-risk malignant brain tumors: The Duke Experience. Neuro-Oncology 4:102-110, 2002[Abstract] 28. Chamberlain MC: Salvage chemotherapy with CPT-11 for recurrent glioblastoma multiforme. J Neurooncol 56:183-188, 2002[CrossRef][Medline] 29. Hau P, Fabel K, Baumgart U, et al: Pehylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer 100:1199-1207, 2004[CrossRef][Medline]
30. Rich JN, Reardon DA, Peery T, et al: Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133-142, 2004 Submitted June 23, 2004; accepted September 17, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
(false-positive rate) was taken as 10% and ß (false-negative rate), as 5%, and P0 was set at 10% to avoid using a regimen that yielded values significantly worse than the aggregate value from the eight negative trials; P1 was set at 30%, to search for an improvement of 0.2. Based on these figures, it was postulated that a single-stage study with 42 patients would yield acceptable error rates for testing the hypothesis and achieving precision for estimation (success 30% with 95% CI on the true response proportion ranging from 16% to 44%). TTP, PFS-6, and MST were calculated according to the Kaplan-Meier method using S-PLUS software, and differences in progression and survival in relation to prognostic factors were evaluated with the log-rank test. Parameters considered possibly correlated with disease progression and survival were age, KPS (
2, P = .58). 
