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© 2003 American Society for Clinical Oncology Limited Access Trial Using Amifostine for Protection Against Cisplatin- and Three-Hour Paclitaxel–Induced Neurotoxicity: A Phase II Study of the Gynecologic Oncology Group
From the Department of Obstetrics/Gynecology, Indiana University School of Medicine, Indianapolis, IN; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo; Department of Gynecologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; Cancer Center, Franklin Square Hospital, Baltimore, MD; Institute for Health Services Research and Policy Studies, Northwestern University, Evanston; Division of Obstetrics and Gynecology, University of Chicago, Chicago, IL; and Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, Washington University School of Medicine, St Louis, MO. Address reprint requests to Denise Mackey, Gynecologic Oncology Group, Four Penn Center, 1600 JFK Blvd, Suite 1020, Philadelphia, PA 19103.
Purpose: The purpose of this study was to determine whether amifostine (WR-2721) prevents or ameliorates clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy. Materials and Methods: The chemotherapy program consisted of intravenous paclitaxel 175 mg/m2 over 3 hours followed by amifostine 740 mg/m2 and cisplatin 75 mg/m2 administered over 90 minutes beginning 15 minutes after amifostine administration. At baseline, before each treatment cycle, and for 3 months after completing chemotherapy, patients were evaluated for evidence of neurotoxicity and other treatment-related adverse effects using three methods: standard clinical evaluation (National Cancer Institute common toxicity criteria [CTC] grading), a neurotoxicity questionnaire to assess symptoms and limitations imposed by peripheral neuropathy, and vibration perception threshold (VPT) testing. Results: Four of 27 assessable patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. This number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed. Conclusion: Amifostine’s level of activity in this trial was insufficient to warrant further study in a phase III trial. Based on the receiver operating characteristic analysis, it would appear that VPT measurements are less sensitive to the development of peripheral neuropathy than the neurotoxicity questionnaire. The questionnaire, referred to as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity, may be used instead of VPT measurements in future studies of chemotherapy-induced peripheral neuropathy.
SINCE ITS introduction two decades ago, platinum-based chemotherapy has become the standard treatment for epithelial ovarian cancer.1 Prospective controlled trials have confirmed the superiority of cisplatin-containing regimens over drug combinations that do not contain cisplatin.2–4 Paclitaxel was identified as a drug with significant activity against epithelial ovarian cancer approximately 15 years ago.5 Scarce supply initially hampered its clinical development, but after this supply problem was alleviated, the National Cancer Institute (NCI) initiated a trial of paclitaxel as salvage treatment for patients with platinum-refractory ovarian cancer. Among more than 1,000 patients who participated in this important study, objective responses were reported in 22% of patients (4% complete response; 18% partial response).6 Cisplatin and paclitaxel were successfully combined in a phase I trial in which paclitaxel was given as a 24-hour infusion, preferably before cisplatin administration.7 Subsequently, the Gynecologic Oncology Group (GOG) completed a phase III trial of cisplatin plus paclitaxel versus cisplatin plus cyclophosphamide in patients with suboptimal stage III/IV ovarian cancer. The paclitaxel-containing regimen yielded superior objective response rates (73% v 60%), progression-free survival (median, 18 v 13 months), and overall survival (median, 38 v 24 months).8 Paclitaxel has subsequently been combined with both cisplatin and carboplatin at various dose schedules and infusion rates. Pending results from ongoing and planned phase III investigations, a paclitaxel plus platinum combination is considered the preferred treatment for epithelial ovarian cancer. One of the dose-limiting side effects of cisplatin chemotherapy is peripheral neuropathy manifested by paresthesias, loss of deep tendon reflexes, and decreased sensory capabilities (fine touch, vibration perception, proprioception). Lo Monaco et al9 conducted prospective neurophysiologic investigations in patients undergoing cisplatin chemotherapy. Study patients underwent serial electromyography assessments of distal limb muscles and motor and sensory nerve conduction studies. The incidence of polyneuropathy was 44% at a cumulative cisplatin dose of 400 mg/m2 and 88% at a cumulative dose of 600 mg/m2. At 3 months posttreatment, all patients had evidence of peripheral neuropathy. One patient experienced grade 1 and the remainder had grade 2 to 4 neurotoxicity.9 Paclitaxel may also induce a peripheral neuropathy characterized by numbness and paresthesias in a stocking-glove distribution.10 In a phase I study of paclitaxel with granulocyte colony-stimulating factor support, peripheral neurotoxicity was the dose-limiting toxicity.11 At conventional doses, the neurotoxicity of paclitaxel is believed to be rare. The GOG reported that peripheral neuropathy was more common in the cisplatin plus paclitaxel (v cyclophosphamide) arm but was generally mild.8 When cisplatin was combined with paclitaxel (135 or 175 mg/m2) administered as a 3-hour infusion, Markman et al12 noted a high incidence of neurotoxicity, with 16 (42%) of 38 patients experiencing grade 2 or worse peripheral neuropathy. This was similar to the findings of the NCI of Canada Clinical Trials Group, which reported a 49% incidence of neurosensory toxicity with 3-hour paclitaxel in a cohort of patients with recurrent ovarian cancer after one or two prior platinum-containing regimens.13 Piccart et al14 reported the results of a randomized trial of cisplatin plus paclitaxel versus cisplatin plus cyclophosphamide that was conducted as an intergroup collaboration between European and Canadian investigators. Paclitaxel was given at a dose of 175 mg/m2 over 3 hours and followed by cisplatin 75 mg/m2. During the first six treatment cycles, 14% of patients who received the paclitaxel-containing regimen experienced grade 3 to 4 neurosensory toxicity. Amifostine (WR-2721) is an organic thiophosphate that was originally developed as a radioprotective compound. It is dephosphorylated in tissues to an active free thiol metabolite that has been shown to reduce the toxic effects of cisplatin.15 Animal and clinical studies have suggested that amifostine can reduce the neurotoxicity of cisplatin chemotherapy.16,17 In a randomized, controlled trial of cisplatin plus cyclophosphamide with or without amifostine, Rose et al18 reported a significant reduction in peripheral neuropathy and a 43% reduction in ototoxicity in the amifostine-treated group. Side effects associated with amifostine administration include transient hypotension during drug infusion, nausea and emesis, hypocalcemia, and (rarely) allergic reactions. Patients should be adequately hydrated before amifostine infusion, and frequent blood pressure monitoring is advised. Spurred by the current push toward outpatient treatment, the 3-hour infusion of paclitaxel has become increasingly popular. It is the purpose of this study to determine whether amifostine can reduce the potential for clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy to 5% from an anticipated frequency of 15%.
Patients This phase II study (Protocol 9805) was conducted by selected GOG institutions and their affiliates. Eligible patients included women with epithelial ovarian, primary peritoneal, fallopian tube, endometrial, or cervical carcinoma or uterine sarcoma for whom the proposed treatment was cisplatin plus paclitaxel chemotherapy. Potential study participants were counseled regarding the possible adverse effects of the proposed protocol therapy, as well as the availability of alternative treatments, including carboplatin-containing regimens. Patients could not be eligible for a higher priority GOG study and were ineligible if they had previously received radiation therapy or chemotherapy. All patients had a GOG performance status of 0 to 2, adequate bone marrow function (WBC  3,000/µL, granulocyte count 1,500/µL, platelet count 100,000/µL), renal function (serum creatinine  2.0 mg/dL), and hepatic function (bilirubin 1.5 times institutional normal, AST and alkaline phosphatase three times institutional normal), with no history of neuropathy, and without evidence of significant infection. Patients with a prior history of malignancy were eligible if they had received no radiation therapy or chemotherapy and were without evidence of recurrent cancer for a minimum of 12 months subsequent to diagnosis. The protocol was reviewed and approved by respective institutional review boards (or equivalent), and all study participants provided signed informed consent satisfying national, state, and local guidelines before the initiation of protocol treatment.
Treatment
At baseline, before each treatment cycle, and 3 months after completing treatment, patients were evaluated by three methods for evidence of neurotoxicity and other treatment-related adverse effects. A clinical evaluation for neuropathic sensory toxicity was conducted and graded, using the NCI common toxicity criteria (CTC) scale. Patient-reported neurotoxicity symptoms were further assessed using the neurotoxicity subscale of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx), version 4.19 The FACT/GOG-Ntx is a 39-item self-report questionnaire that contains two components: a general measure of quality of life (FACT-G) plus a neurotoxicity (Ntx) subscale.20,21 Only the neurotoxicity subscale was used in the present study. The Ntx subscale is a validated, 11-item questionnaire designed to assess neuropathic side effects of platinum- and taxane-containing systemic chemotherapy experienced during the prior week (Fig 1
Statistical Considerations The primary goal of this study was to determine the proportion of patients treated with amifostine plus cisplatin and 3-hour paclitaxel chemotherapy who experience significant treatment-induced peripheral neuropathy. Grade 4 neurotoxicity constituting permanent sensory loss was not anticipated, given eligibility criteria, specified monitoring, and treatment modifications during therapy. For evaluation purposes, either of the following occurrences at any assessment point during the six-cycle treatment program was considered a significant event: grade 3 neuropathic-sensory toxicity or persistent grade 2 neuropathic-sensory toxicity requiring a dose reduction. If the event rate was 15%, then the proportion of patients treated with amifostine who experienced significant peripheral neuropathy while on the study regimen was considered too large to warrant further investigation. Alternatively, an event rate 5% would indicate that the proportion of patients treated with amifostine who experienced significant peripheral neuropathy is small enough to warrant further investigation in a phase III trial. The anticipated annual accrual to this study was 20 patients. The study used a two-stage group sequential design. Twenty-nine patients were to be entered onto the first stage of the trial. If there were fewer than four events within the first 29 patients treated, then an additional 30 patients would be entered. At the conclusion of the second stage, if there were fewer than six events, then further investigation of amifostine in a phase III trial would be warranted. If the true event rate for this regimen is 5%, this design provides a 90% chance of concluding the regimen warrants further investigation at the end of the trial. If the true event rate for this regimen is 15%, then this design provides a 91% chance of concluding the regimen does not warrant further investigation at the end of the trial and a 65% chance of reaching this conclusion at the end of the first stage of accrual.
Five institutions participated in this limited access GOG study. The study opened in December 1998, and the first stage of accrual ended May 2000. Twenty-nine patients were enrolled, and all were subsequently confirmed eligible by central data and pathology committee review. Two patients prematurely discontinued chemotherapy because of medical complications, thus 27 patients were assessable for response and toxicity. The mean age of the study population was 61 years (range, 32 to 83 years). There were 18 patients with epithelial ovarian cancer, four patients with primary peritoneal carcinoma, two patients each with endometrial or fallopian tube carcinoma, and one patient with cervical carcinoma. Performance status in 10 patients was 0, in 16 patients was 1, and in one patient was 2. Twenty-one patients completed all six cycles of cisplatin plus 3-hour paclitaxel chemotherapy and 3 months of clinical follow-up. Four patients completed the prescribed six cycles of chemotherapy but, at the time of analysis, 3 months of follow-up were not yet available. One patient had completed five cycles of chemotherapy and another had received two cycles of chemotherapy at the time the trial was suspended.
Four patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. Three patients experienced grade 3 peripheral neuropathy, and one patient experienced persistent grade 2 peripheral neuropathy despite reductions in chemotherapy dose. Because the number of neuropathic events exceeded the predetermined threshold for a second stage of accrual, the study was closed. The risk for chemotherapy-induced peripheral neuropathy was significantly greater among older patients (Fig 2
The neurotoxicity analysis was formulated from data obtained at the time of the last patient assessment, using all three tools: CTC grading, FACT/GOG-Ntx questionnaire, and Vibratron II VPT measurements. A comparison between index finger VPT, great toe VPT, and Ntx scores for patients who did (n = 4) versus those who did not (n = 23) experience clinically significant neurotoxicity is displayed in Table 1  . There was no significant difference between mean VPT scores from either the index finger or great toe among patients who did versus did not experience grade 2 peripheral neuropathy. However, the difference in mean Ntx scores for patients who did versus those who did not experience grade 2 peripheral neuropathy was significant (P = .02). All four patients with dose-limiting neurotoxicity had Ntx scores less than 25.
To determine the predictive utility of VPT measurements and Ntx scores, a receiver operating characteristic (ROC) analysis was performed, and curves for all three measures are displayed in Fig 3 . The analysis was conducted with the SPSS statistical package (Release 11.0.1; SPSS Inc, Chicago, IL). The diagonal line represents the null hypothesis that the signal detection of the instrument is equal to chance. The area under the curve for finger VPT, toe VPT, and FACT/GOG-Ntx measures is 0.57, 0.49, and 0.86, respectively, with only the FACT/GOG-Ntx area under the curve reaching statistical significance (P = .02). Given these data, it would seem that VPT measurements are less sensitive to the development of peripheral neuropathy than the FACT/GOG-Ntx subscale. The ROC analysis suggests that the Ntx subscale is an accurate indicator of the development of peripheral neuropathy, with sensitivity and specificity superior to an objective measure. Pending replication, this finding may be particularly notable because the criterion in the study was not a chronic, hardened neuropathy, but an emerging condition.
In Fig 4 , the 95% confidence intervals for the FACT/GOG-Ntx means of patients who continued and discontinued the trial are shown. If clinical significance as defined by our CTC criterion is used as a gold standard, then a cutoff of 25 on the FACT/GOG-Ntx seems to be reasonably effective in discriminating significant neurotoxicity. In the present data, a score of 25 on the FACT/GOG-Ntx produces a sensitivity of 1 and a specificity of 0.85 with regard to trial completion. The correlation between the full CTC scale (grades 0 to 4) and the FACT/GOG-Ntx was as follows: Spearman’s rho = -0.59 (P = .001), and examination of the plot of these scores showed a clear linear relationship.
Hay22 conducted a MEDLINE search and found that only two studies (of 884 relevant study references) systematically evaluated the utility loss associated with severe chemotherapy-induced neuropathy. He further scrutinized data from 1,073 patients who participated in the Scottish Randomised Trial in Ovarian Cancer clinical trial of docetaxel plus carboplatin versus paclitaxel plus carboplatin. Severe neuropathy was associated with a 15% to 20% reduction in patient quality of life. The use of less neurotoxic regimens of otherwise equivalent effectiveness could therefore lead to improvements in patient-assessed health status and quality of life.23 Several clinical trials have suggested that amifostine (WR-2721) may protect against cisplatin-induced peripheral neuropathy. Glover et al24 reported results from a phase I trial of cisplatin plus WR-2721 in which cisplatin doses were increased from 50 mg/m2 to 150 mg/m2, and escalating doses of WR-2721 were administered 15 minutes before the cisplatin infusion. Grade 1 to 2 neuropathies developed in 26% of patients after a median cumulative cisplatin dose of 725 mg/m2. These investigators subsequently conducted another phase I trial of escalating doses of cisplatin (60 to 150 mg/m2) plus a fixed dose of amifostine (740 mg/m2). Among 52 assessable patients, there were seven patients (13%) who developed mild to moderate peripheral neuropathy after a median cumulative cisplatin dose of 870 mg/m2.25 Mollman et al17 reported results from a prospective study of cisplatin, alone or in combination with other chemotherapeutic agents. The overall incidence of neuropathy was 49%; however, among patients who also received WR-2721, the incidence of neurotoxicity was 25%. Furthermore, the mean dose at the onset of neuropathy was 635 mg/m2 for patients who did, versus 383 mg/m2 for patients who did not, receive WR-2721. In a prospective study of high-dose cisplatin plus WR-2721 for treatment of metastatic malignant melanoma, Glover et al26 reported that nine (25%) of 36 assessable patients developed peripheral neuropathy at a median cumulative cisplatin dose of 670 mg/m2. Kemp et al27 reported the results from a phase III trial of cisplatin 100 mg/m2 plus cyclophosphamide 1,000 mg/m2 with or without amifostine for treatment of epithelial ovarian cancer, in which 242 patients received six treatment cycles. There was no significant difference between the two arms in the incidence of ototoxicity. The overall incidence of grade 3 neuropathy was low (only 24 patients); nonetheless, there was a significantly lower incidence of peripheral neuropathy among patients who did versus those who did not receive amifostine (nine v 15; P = .029). Reasons for the lack of demonstrated effectiveness in this amifostine trial are not clear, but there are four plausible explanations for this observation. First, in comparison with other published series, this study required a more rigorous surveillance program to assess for chemotherapy-induced peripheral neuropathy; therefore, our results may represent a detection bias. Second, the underlying mechanism of paclitaxel chemotherapy–induced peripheral neuropathy may be different from that of cisplatin-induced peripheral neuropathy and not amenable to amifostine neuroprotection. Third, the statistical design set stringent criteria to determine effectiveness, such that a modest effect of amifostine may have been missed, resulting in a false-negative study. Last, it may be that amifostine is not effective in preventing the development of peripheral neurotoxicity in patients receiving cytotoxic chemotherapy. The prescribed chemotherapy regimen of cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 administered over 3 hours was useful for the study of amifostine neuroprotection because of its associated high incidence of peripheral neuropathy. However, carboplatin has largely replaced cisplatin as the preferred platinum analog for treatment of ovarian cancer because of its perceived equivalent cytotoxicity and more favorable toxicity profile, including less severe nausea, emesis, nephrotoxicity, and neurotoxicity. Also, although paclitaxel is still the favored taxane in most clinical trials, docetaxel seems to be a suitable alternative, with less neurotoxicity, more myelosuppression, and no substantial difference in activity.23
At baseline, before each treatment cycle, and 3 months after completing treatment, a clinical evaluation for neuropathic sensory toxicity was conducted and graded using the NCI CTC scale. Patients also completed the Ntx subscale questionnaire and underwent VPT testing. Postma et al28 studied the CTC system for grading chemotherapy-induced peripheral neuropathy. For all grades of neurotoxicity, the inter-observer agreement using the CTC scale was 46%. The inter-observer agreement for neurotoxicity grade Although VPT testing is considered to be the gold standard, it is not without inaccuracies. Ideally, patients should undergo VPT testing under identical circumstances: time of day, nondistracting environment, room location, and ambient temperature. Skewed results may occur if the same finger and toe are not used at each testing procedure, the patient comes into contact with the metal casing of the vibrating rods, or the patient is not prevented from viewing the instrument settings or data sheet during the testing procedure. Devices used for VPT testing are not inexpensive and must be calibrated every 6 months.
An important finding in this trial was the clinical validation of the FACT/GOG-Ntx subscale. Neurotoxicity evaluations by physicians are notoriously inconsistent, and a validated, patient-reported scale is an important contribution to the future study of chemotherapy-induced peripheral neuropathy. Other validated neurotoxicity questionnaires exist and have been used by clinical trials groups.29 All four patients with dose-limiting ( Amifostine’s level of activity in this trial was insufficient to warrant further study in a phase III trial. Glutamine has been reported to decrease the potential for paclitaxel-induced neuropathies.30 Future clinical strategies to reduce the incidence of chemotherapy-induced neuropathy should investigate glutamine or one of the other emerging neuroprotectors.
The following member institutions participated in this study: University of North Carolina School of Medicine, Chapel Hill, NC;Indiana University Medical Center, Indianapolis, IN; University of California Medical Center at Irvine, Irvine, CA; Washington University School of Medicine, St Louis, MO; and University of Chicago, Chicago, IL.
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. Acted as a consultant within the last 2 years: David H. Moore, Lilly Oncology, Schering-Plough, GlaxoSmithKline.
Supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (grant no. CA 27469), Philadelphia, PA, and the Gynecologic Oncology Group Statistical Office (grant no. CA 37517), Buffalo, NY.
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14. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699–708, 2000 15. Yuhas JM, Culo F: Selective inhibition of the nephrotoxicity of cis-DDP by WR-2721 without altering its antitumor properties. Cancer Treat Rep 64:57–64, 1980[Medline]
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28. Postma TH, Heimans JJ, Muller MJ, et al: Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol 9:739–744, 1998 29. Cassidy J, Paul J, Soukop M, et al: Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin. Cancer Chemother Pharmacol 41:161–166, 1998[CrossRef][Medline] 30. Peltier AC, Russell JW: Recent advances in drug-induced neuropathies. Curr Opin Neurol 15:633–638, 2002[CrossRef][Medline] Submitted February 19, 2003; accepted August 26, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
