The primary objective of this prospective phase 2 study of CPT-11 in adult patients with recurrent temozolomide-refractory anaplastic astrocytoma (AA) was to evaluate 6-month progression-free survival (PFS).
The primary objective of this prospective phase 2 study of CPT-11 in adult patients with recurrent temozolomide-refractory anaplastic astrocytoma (AA) was to evaluate 6-month progression-free survival (PFS).
Forty patients (27 men and 13 women) ages 17 to 58 years (median age, 38 years) with radiographically recurrent AA were treated. All patients had been treated previously with surgery, involved-field radiotherapy, and adjuvant chemotherapy. Fifteen patients were treated at first recurrence with an alternative chemotherapy. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks, which was defined operationally as a single cycle. Neurologic and neuroradiographic evaluations were performed every 9 weeks.
All patients were evaluable for toxicity, and 39 patients were evaluable for response. In total, 302 cycles of CPT-11 (median, 6 cycles; range, 1–22 cycles) were administered. CPT-11-related toxicity included diarrhea (19 cycles), leukopenia (16 cycles), fatigue (11 cycles), anemia (6 cycles), delayed nausea/vomiting (5 cycles), neutropenia (5 cycles), and renal failure (1 patient, 1 toxic death). Two patients (5%) patients required erythrocyte transfusions. Nine patients (23%) demonstrated a radiographic complete response (1 patient) or partial response (8 patients), 16 patients (41%) demonstrated stable disease, and 14 patients (36%) had progressive disease after 3 cycles of CPT-11. The median time to tumor progression was 4.1 month. The median survival was 6.9 months, and the 6-month and 12-month PFS rates were 40% and 5%, respectively.
CPT-11 demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent AA, all of whom had failed on prior temozolomide chemotherapy. Cancer 2008. © 2008 American Cancer Society.
The treatment of recurrent, high-grade glioma (HGG) is problematic, because established therapeutic modalities are only modestly effective. These therapies include chemotherapy, radioactive implants, stereotactic radiotherapies, immunotherapy, and reoperation.1–29 Chemotherapy for recurrent, malignant, primary brain tumors has limited benefit, primarily because response to chemotherapy is of limited duration. In an analysis of 8 institutional Phase II studies of chemotherapy for recurrent HGG, Wong et al. reported that response rates in patients with recurrent anaplastic astrocytoma (AA) were 14%, and the progression-free survival (PFS) rate at 6 months was 31%.13 The most active drugs in use are the nitrosoureas (eg, carmustine and lomustine [CCNU]), temozolomide (TMZ), procarbazine, cis-retinoic acid, and platinum compounds.1–28 Another chemotherapy with purported activity in recurrent HGG is CPT-11 (irinotecan).29–35
The primary objective of this 4-institution, prospective, phase 2 trial was to observe whether CPT-11 given every 3 weeks (dosing: 600 mg/m2 per day for patients on enzyme-inducing anticonvulsant drugs [EIAED] or 350 mg/m2 per day for patients on nonenzyme-inducing anticonvulsant drugs [NEIAED]) could significantly delay progression in patients with neuroradiographically recurrent anaplastic astrocytoma (AA). Forty adult patients with recurrent supratentorial AA previously treated with surgery, radiotherapy and TMZ were entered into study.
The study was performed at the University of Southern California Norris Comprehensive Cancer Center and Hospital, the University of Utah Huntsman Cancer Center, the University of Massachusetts, and the University of South Florida H. Lee Moffitt Cancer Center and Research Institute. The study was activated in January 2000 and closed in January 2007. Approval of the protocol and informed consent by the university Human Investigation Committee was obtained. Informed consent was obtained from each patient.
The 2 primary objectives of this study included determination of efficacy and toxicity of CPT-11 in the treatment of patients with TMZ-refractory, recurrent or progressive AA. The primary response endpoint was PFS at 6 months (6-month PFS). Secondary endpoints included overall survival (OS), time to disease progression, and response. Toxicity was evaluated in all eligible patients who received at least 1 cycle of CPT-11.
Patients were required to have histologically proven, neuroradiologically confirmed, recurrent AA. Patients must have progressed after definitive radiotherapy and TMZ chemotherapy. Patients may have had no more than 2 prior chemotherapy regimens. At least 4 weeks must have elapsed since the last dose of chemotherapy, and patients must have recovered from the adverse effects (AEs) of prior therapy. Patients could not have received prior CPT-11 therapy. Patients were required to have radiographically measurable intracranial disease in which recurrent tumor was measurable bidimensionally (≥1 cm × 1cm) on cranial contrast-enhanced magnetic resonance imaging (MRI) studies. Histologic confirmation of tumor recurrence was not required for entry into the study. Pregnant or lactating women were not permitted to participate. Patients of childbearing potential were required to implement adequate contraceptive measures during participation in this study. Patients were required to have a Karnofsky performance status ≥60 and a life expectancy >3 months.
Adequate hematologic, renal, and hepatic functions were required and were defined as follows: absolute granulocyte count > 1500/dL or white blood cell count > 4000/dL, platelet count > 100,000/dL, total bilirubin level < 1.8 mg/dL, transaminase levels < 4 times the upper limit of normal, and creatinine concentration < 1.8 mg/dL (or creatinine clearance ≥60 mL/m2/1.73).
All patients were aware of the neoplastic nature of their disease and willingly consented to participate after they were informed regarding the procedures to be used, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. Patients with carcinomatous meningitis were not eligible. No serious, concurrent medical illnesses or active infection could be present that would jeopardize the ability of the patient to receive CPT-11 therapy. Patients could not have an active, concomitant malignancy except skin cancer (squamous cell or basal cell). Eligible patients ranged in age from 18 years to 80 years.
CPT-11 (irinotecan; Pfizer Pharmaceuticals, Princeton, NJ) was administered at a dose of 350 mg/m2 to patients on NEIAED or 600 mg/m2 to patients on EIAED. CPT-11 was administered intravenously over 120 minutes on a single day.31 Concurrent dexamethasone was permitted for control of neurologic signs and symptoms. Premedication included antiemetics (ondansetron, granisetron, or dolasetron), dexamethasone (20 mg), and atropine (0.5 mg), all administered intravenously. Prechemotherapy hydration of 0.50 liter of normal saline was given intravenously over 1 hour. No posthydration intravenous fluids were administered.
Postchemotherapy medication included prochlorperazine for nausea or vomiting and loperamide for diarrhea. A cycle of therapy was defined operationally as 21 days during which CPT-11 was administered on Day 1. Treatment with CPT-11 was repeated every 21 days provided that all hematologic toxicity from the previous cycle had resolved to grade 2 or less and that all nonhematologic toxicity had recovered to grade 1 or less. If recovery had not occurred by Day 21, then the subsequent cycle of CPT-11 could be delayed by no more than 2 weeks until these criteria were met. All toxicities because of CPT-11 therapy were rated according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) (version 3.0).
No dose escalations were permitted. The CPT-11 dose was reduced by 25% in patients with Grade ≥3 toxicity. Only 2 dose reductions were allowed. Patients who had grade 3 toxicity of any type after 2 dose reductions were removed from study.
Oral dexamethasone was used concurrently in 26 patients and was increased in 8 patients who had clinical disease progression. The dexamethasone dose was decreased in 6 patients as their clinical status permitted.
Recurrent AA was defined by objective neuroradiographic progression (>25% increase in tumor size) compared with prior baseline neuroradiographic images using the criteria reported by Macdonald et al.36 All neuroradiographic studies were reviewed locally by 2 neuroradiologists who were blinded to treatment and by the principal investigator (M.C.C.). All patients underwent cranial MRI that demonstrated progressive disease within 2 weeks of CPT-11 administration.
Blood counts were obtained weekly, neurologic examinations were performed every 3 weeks, and contrast-enhanced cranial MRI studies were obtained every 9 weeks after every 3 cycles of CPT-11. Neuroradiographic response criteria, as defined by Macdonald et al., were used.36 A complete response (CR) was defined as the disappearance of all enhancing or nonenhancing tumor on consecutive computed tomography (CT) or MRI scans at least 1 month apart with the patient off corticosteroids and neurologically stable or improved. A partial response (PR) was defined as a reduction >50% in tumor size on consecutive CT or MRI scans at least 1 month apart, with the corticosteroid dose stable or decreased and with the patient neurologically stable or improved. Progressive disease (PD) was defined as an increase >25% in tumor size or any new tumor on CT or MRI scans, or if the patient worsened neurologically with a stable or increased corticosteroid dose. Stable disease (SD) was defined as all other situations. A response of SD, similar to CR and PR, required a confirmation MRI scan 1 month after documenting the best response.
In patients with SD, PR, or CR, 3 additional cycles of CPT-11 were administered; then, patients were assessed again as described above. Patients were continued on CPT-11 therapy until documentation of PD, when patients were removed from the study and were either monitored or offered alternative therapy.
PFS and OS were defined as the time from the first day of treatment with CPT-11 until progression or death (PFS) or death (OS). Patients were removed from the study if there was PD, development of unacceptable toxicity, patient refusal, or noncompliance with protocol requirements.
The primary objective was to determine whether CPT-11 significantly delays progression in patients with recurrent AA. Historic values were obtained from analysis of a database of 350 patients with recurrent, HGG (including 125 patients with AA) who were treated on consecutive, prospective, phase 2 trials in which the 6-month PFS rate was 31% for patients with AA.13 The hypotheses tested were H0 (p ≤ p0) versus H1 (p ≥ p1), where p is the probability of remaining alive and progression free at 6-months with a Type I error α ≤ .05 and a Type II error β ≤ .20. For patients with AA, p0 was set at 0.25, and p1 was set at 0.45, and we sought an improvement in the 6-month PFS probability of 14%. The current study was designed to accrue 40 patients with AA. Success was defined as observing that >18 of 40 patients remained alive and progression free at 6 months (yielding α = .03 and β = .21). The associations of OS and PFS with patient's baseline characteristics were evaluated by using the log-rank test.38–43 The Pike estimate of relative risk (RR) based on the log-rank test38 was used to provide a quantitative summary of the data, including 95% confidence intervals (95% CIs).39, 40 Initially, univariate survival analyses were used to evaluate the association of all prognostic factors with OS and the time to progression. The log-rank test was used to test the association of survival or time to progression with all baseline characteristics, adjuvant therapies, and salvage therapies. The median survival, the time to progression, and the associated 95% CIs were computed. Kaplan-Meier plots41 were constructed to display the estimated probabilities of OS and time to progression.
Forty patients (27 men and 13 women) who ranged in age from 17 years to 58 years (median age, 38 years) and who had recurrent AA (original pathology was reviewed and confirmed in all patients by the participating institution) were treated with CPT-11 (Table 1). Patients presented at the time of tumor recurrence with the following signs and symptoms: increased intracranial pressure, as manifested by increasing headache (n = 28 patients; 70%), worsening seizures (n = 14 patients; 35%), altered mental status (n = 6 patients; 15%), progressive hemiparesis (n = 6 patients; 15%), new-onset homonymous hemianopsia (n = 2 patients; 5%), and gait ataxia (n = 2 patients; 5%). Patient performance status using the Karnofsky scale ranged from 70 to 100 (median, 80) at the time of documented tumor recurrence and initiation of CPT-11 therapy. Eight patients were on EIAED, 24 patients were being treated with an NEIAED, and 8 patients were on no antiepileptic drug. Tumor locations, including multilobar tumors, were as follows: frontal lobe, n = 25 tumors (62.5%); temporal lobe, n = 10 tumors (25%); parietal lobe, n = 8 tumors (20%), thalamus, n = 2 tumors (5%), and occipital lobe, n = 1 tumor (2.5%). Twenty-nine patients had lobar tumors, and 11 patients had multilobar tumors. Pathology (reviewed by a panel of 2 neuropathologists at each participating institution) indicate that all tumors were AA according to World Health Organization criteria.
|Factor||No. of patients||%|
|Total no. of patients||40||100|
|Moffitt Cancer Center||17||43|
|Age at diagnosis, y|
|Median [range], y||38 [17–58]|
|Side of tumor|
|Location of tumor|
|Histology of tumor|
|Type of surgery|
|STR and Gliadel||1||3|
|Adjuvant radiotherapy, Gy|
|Median [range], Gy||60 [54–60]|
|TMZ, cRA, and COX2||1||3|
|No. of cycles|
|Median no. of cycles [range]||10 [3–12]|
|Response to adjuvant chemotherapy|
|Resurgery after first recurrence|
|STR and Gliadel||1||5|
|Salvage chemotherapy prior to CPT-11|
|Median no. of cycles [range]||5 [2–12]|
All patients had undergone surgery at diagnosis, and a complete resection was accomplished in 12 patients (resection of all visible, contrast-enhancing tumor confirmed in the immediate postoperative period), a partial resection was accomplished in 14 patients, and 14 patients underwent biopsy only (Table 1). Twenty patients (50%) underwent a second surgery (biopsy in 2 patients, subtotal resection in 18 patients), and 2 patients underwent a third surgery before study entry.
All patients had previously been treated with adjuvant limited-field radiotherapy (Table 1); and, in all patients, conventional fractionated radiotherapy was used in which 1.8 to 2 grays (Gy) were administered daily (median tumor dose, 60 Gy; range, 54–60 Gy). One patient received stereotactic radiotherapy at the time of recurrence before the administration of CPT-11.
All patients were treated with either TMZ29 or carmustine10 chemotherapy after they received radiotherapy (Table 1). TMZ was administered on the standard 5-day schedule. Patients received a median of 10 TMZ cycles of therapy (range, 2–12 cycles). The 10 patients who were treated initially with carmustine received TMZ at first recurrence. Four patients received other chemotherapy (carboplatin in 2 patients, sorafenib and CCNU in 1 patient each) after adjuvant TMZ at the time of first recurrence and before initiating CPT-11. All other patients began CPT-11 immediately after they had documentation of an initial recurrence (except for the 14 patients mentioned above), as demonstrated by neuroradiographic progression (all patients) or clinical disease progression (60% of patients). The median time to initiation of CPT-11 after initial surgery was 35 months (range, 4.4–167 months). In total, 302 cycles of CPT-11 were administered. A minimum of 3 cycles of CPT-11 was administered to each patient with 1 exception (a patient who died after a single course of CPT-11) for a median of 6 cycles (range, 1–22 cycles). CPT-11 was administered at the prescribed dose to all patients. No other antiglioma agents aside from dexamethasone were used during the study.
Toxicity was recorded using the NCI CTC (version 3.0). Table 2 lists all grade 2 through 5 toxicities that were observed: Each number in the table represents the sum of the highest grade of toxicity attained, per toxicity, per cycle for all patients. In total, 302 treatment cycles were administered, during which there were 17 grade 3 AEs (6% of all cycles) in 8 patients (20% of all patients), no grade 4 AEs, and 1 grade 5 AE (diarrhea with dehydration and acute renal failure) in a single patient (2.5% of all patients). Grade 3 or greater AEs that were recorded included diarrhea (4 patients; 10%), delayed vomiting (4 patients; 10%), delayed nausea (2 patients; 5%), fatigue (2 patients; 5%), granulocytopenia (2 patients; 5%), leukopenia (1 patient; 2.5%), thrombophlebitis (1 patient; 2.5%), neutropenic fever (1 patient; 2.5%), and anemia (1 patient; 2.5%). Two patients required transfusion with packed erythrocytes. One patient developed febrile neutropenia with negative body fluid cultures. One treatment-related death occurred related to acute renal failure from dehydration.
|Toxicity*||Grade 2||Grade 3||Grade 4||Grade 5||Total|
All patients were assessable for survival, and 39 patients were assessable for response. After 3 cycles of CPT-11, the first MRI evaluations indicated that 14 patients (35.9.5%) had PD. Fifteen patients (37.5%) received 3 cycles of therapy, and 23 patients (57.5%) received >3 cycles of therapy. Patients who failed to respond to CPT-11 were offered alternative or supportive therapy.
The median time to tumor progression was 4.1 months (95% CI, 2.1–6.2 months). No statistically significant association was observed between OS and patients' baseline characteristics, anticonvulsant type (EIAED or NEIAED), or primary or salvage treatments. The risk of disease progression was greater in men compared with women, but the 95% CI was very wide (RR, 1.57; P = .045; 95%CI, 0.77–3.19). Because only 16 patients (40%) achieved a PFS of at least 6 months, rather than the 18 patients (45%) prespecified in the study design, this trial failed to meet its primary endpoint. The median survival was 6.9 months (95% CI, 5.1–10.8 months). The probability of survival at 12 months (±standard deviation) was 23% ± 8%, and the probabilities of 6-month and 12-month PFS were 40% ± 8% and 5% ± 3%, respectively. One patient (3%) demonstrated a CR; 8 patients (21%) demonstrated a neuroradiographic PR (95% CI, 11%–39%); and 16 patients (41%) demonstrated SD (95% CI, 25%–57%).
There was no association observed between response to CPT-11 and response to the prior regimen of TMZ, however, very few responses to TMZ were observed. No difference was observed in the pretreatment tumor volume in patients with either a PR to CPT-11 or SD as compared with patients who had PD.
In a seminal study on AA, Prados et al. concluded that patients can be expected to have a median survival >3 years; that young age and high Karnofsky performance status have a positive influence on survival; and that salvage therapies may extend survival after the onset of tumor progression for nearly a year.21 In a separate European analysis of anaplastic gliomas (predominantly AA), the median OS was 29 months (with a 5-year probability of survival of 38%.22 In another analysis by Prados et al., the Radiation Therapy Oncology Group database was reviewed and compared patients with newly diagnosed AA who were treated according to protocol with either carmustine or combined procarbazine, CCNU, and vincristine (PCV) adjuvant chemotherapy after surgery and conventional external beam radiotherapy.2 From that retrospective analysis, there did not appear to be any survival benefit to PCV adjuvant chemotherapy. The study also posited that the inclusion of chemotherapy in the treatment of patients with newly diagnosed AA, although it is a common practice, could not be endorsed pending a randomized study. The Medical Research Council Brain Tumor Working Group reported on the largest randomized trial comparing patients who received radiotherapy alone (RT) with patients who received RT and PCV chemotherapy.1 Of 594 eligible patients, 19% (113 patients) had AA histology. There was no difference in median survival (13-month median survival for the RT-only group); however, a trend was reported for improved 2-year survival in the RT and PCV group (2-year survival rate, 37% for RT only vs 42% for RT and PCV). In a recent meta-analysis by the Glioma Meta-Analysis Trialists Group of 12 randomized trials, adjuvant chemotherapy improved 2-year survival by 6% in patients with AA (31% vs 37%).11 The above-mentioned studies suggest a modest benefit for the inclusion of chemotherapy in the adjuvant treatment of AA, although the optimum adjuvant chemotherapy agent remains unsettled. Since the introduction of TMZ into clinical practice in 2000, the established efficacy of TMZ in the treatment of recurrent AA and its modest toxicity have resulted in TMZ supplanting nitrosoureas and other regimens for the treatment of newly diagnosed AA.16 The majority of patients in the current study received TMZ after radiotherapy—an increasingly common neuro-oncology practice that is supported in part by a recent European Organization for Research and Treatment of Cancer trial of adjuvant TMZ for glioblastoma multiforme demonstrating a survival benefit compared with historic controls (15 months vs 12 months).23
The best way to manage recurrent AA remains ill defined notwithstanding a variety of studies. The majority of studies (including the current study) are Phase II, nonrandomized trials comparing patient outcomes with historic controls. In a randomized trial of TMZ versus procarbazine for recurrent AA, Yung et al. demonstrated an advantage to TMZ with a 6-month PFS of 46%, an objective neuroradiographic response rate of 35%, and an OS of 13.6 months.16 In the study by Yung et al., 60% of patients had received adjuvant carmustine, 18% underwent reoperation at the time of recurrence, and the median time to tumor recurrence was 15.2 months. These values are similar to the current findings, except that 100% of our patients received adjuvant chemotherapy, and 50% underwent reoperation at time of tumor recurrence. Brem et al. reported on another randomized trial of patients with recurrent glioma (HGG) and compared surgery with or without placement of biodegradable carmustine polymers (Gliadel).24 Twenty-eight of 88 patients (32%) who were enrolled in that study had AA. The results demonstrated a 35% improvement in OS survival (31 weeks vs 23 weeks) and a 50% increase in 6-month PFS (64% vs 44%). Although 32% of patients entered onto that study had AA, a separate analysis of the group was not reported. These robust results suggest that reoperation is of benefit in patients with AA; and, when a near complete resection can be performed, Gliadel may be an effective therapy. Unfortunately, only a fraction of patients (50% in the current study) with recurrent AA are candidates for reoperation. Therefore, the majority of patients with active disease are offered chemotherapy at progression. Accordingly, Jaeckle et al. recently reported on the combination of TMZ and cis-retinoic acid (Accutane) for patients with recurrent HGG, of whom 22% were chemotherapy naive.25 A 46% 6-month PFS and a 47-week median OS were reported among patients with AA. These are compelling results, although the dataset of patients with AA was small (n = 28). Two other investigational treatments for recurrent HGG, convection-enhanced intratumoral delivery of radiopharmaceutical toxins and molecularly targeted therapies (such as small-molecule inhibitors of receptor tyrosine kinases) currently are under active study.26, 27
The current study was directed at the population of patients with AA who had failed prior TMZ chemotherapy and for whom further treatment appeared to be warranted. The study did not require histologic proof of recurrent AA, and it is possible that a portion of the group had radiation necrosis as opposed to recurrent tumor. This appears to be unlikely for the following reasons: The median time to treatment with CPT-11 was 35 months, a time when issues of pseudoprogression are unlikely.44 Only a single patient received stereotactic radiotherapy, and the risk of radiation necrosis is <5% in patients who receive standard fractionated radiotherapy. Furthermore, 15 patients (37.5%) underwent fluorodeoxyglucose-positron emission tomography studies, and 10 patients (25%) underwent MRI spectroscopy in which recurrent, viable tumor was confirmed radiographically, although the limitations of both types of imaging studies in differentiating necrosis from tumor are well recognized. Finally, 20 patients (50%) who had histopathologically confirmed AA underwent reoperation. The study did not require reexamination of specimens from second surgeries; thus, a proportion of patients who we assumed had AA may have progressed to glioblastoma. Therefore, the study may have evaluated both patients with AA and patients with secondary glioblastoma.
CPT-11 appears to be attractive, because prior single-agent studies have suggested that it has activity against HGG and particularly against AA.29–35 Nonetheless, CPT-11 has been studied primarily in patients with glioblastoma multiforme, and there is a relative dearth of data regarding response in patients with AA. By way of example, Batchelor et al. reported on 5 patients with AA without histology-specific outcome data, Friedman et al. reported on 10 patients with AA (1 patient who achieved a PR and 6 patients with SD), and Prados et al. reported on 13 patients with AA (22% 6-month PFS).29, 33, 35 Furthermore, CPT-11 toxicity is manageable (approximately 25% grade 3–5 toxicity in the current study) and noncumulative, permitting administration without growth factor support. Topoisomerase inhibitors such as CPT-11 do have pharmacodynamically important interactions with EIAED (which are used almost universally in patients with recurrent AA). The induction of cytochrome P450 enzymes by NEIAED such as carbamazepine and phenytoin dramatically reduces the area under the concentration time curve of CPT-11.45 Fortunately, the necessary dosage adjustments for CPT-11 in patients who are receiving such anticonvulsant agents have been defined well by prior studies.36
In conclusion, CPT-11 used at the dose and on the schedule described in this study of patients with previously treated, TMZ-refractory, recurrent AA appears to have modest benefit (6-month PFS, 40%), although the primary response endpoint of our study (a 45% 6-month PFS rate) was not achieved. Outside the setting of a clinical trial, CPT-11 is a reasonable choice for patients with recurrent AA who have previously failed TMZ. Recent data reporting on the use of combination therapy for patients with recurrent, HGG, with CPT-11 given in conjunction with targeted therapies such as bevacizumab or the oral panvascular endothelial growth factor receptor inhibitor AZD2171, appear promising.46, 47 Such regimens may enhance the antiglioma activity of CPT-11 and should be investigated.