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Phase II Study of Oxaliplatin in Platinum-Resistant and Refractory Ovarian Cancer: A Gynecologic Group Study By Paula M. Fracasso, John A. Blessing, Mark A. Morgan, Anil K. Sood, and James S. Hoffman Purpose: A phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with platinumresistant or refractory epithelial ovarian carcinoma. Materials and Methods: Eligible patients were to receive oxaliplatin 130 mg/m2 intravenously over 2 hours, every 21 days, until progression of disease or adverse effects prohibited further therapy. Results: Of 25 patients entered onto the study, 23 were eligible and assessable. There were no patients with complete response. One patient (4.3%) achieved a partial response, with a response duration of 6.4 months. Nine patients (39.1%) experienced stable disease, with a median duration of 5.6ⴙ months (range, 1.8 to 13.1months). The most frequently reported drug-related toxicities were hematologic, gastrointestinal, and neurologic. Conclusion: Oxaliplatin as a single agent has minimal activity in patients with platinum-resistant or refractory ovarian cancer at the dosage and schedule tested. However, future studies of oxaliplatin combined with other active agents in women with platinum-naı̈ve or platinumsensitive epithelial ovarian carcinoma may be indicated. J Clin Oncol 21:2856-2859. © 2003 by American Society of Clinical Oncology. E this has limited the use of carboplatin in combination with other myelosuppressive drugs. Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatin; Eloxatine, Sanofi, Paris, France) is a novel diaminocyclohexane platinum derivative with a wide range of activity against human and murine tumor cell lines, including cisplatinresistant cell lines.5 The mechanism of action of oxaliplatin is thought to be similar to that of other platinum derivatives that exert cytotoxic effects through the formation of DNA adducts, with subsequent impairment of DNA replication and transcription and resultant cell death. Preclinical data indicate, however, that the platinum-DNA adducts formed by oxaliplatin may be responsible for its unique cytotoxic activity as compared with that of cisplatin. In particular, the 1,2diaminocyclohexane-platinum (dach-PT) adducts formed from oxaliplatin may be more effective in DNA synthesis inhibition than the cis-diamine-PT adducts formed from cisplatin, and DNA mismatch-repair complexes do not recognize dach-PT adducts.5 Phase I studies of oxaliplatin have demonstrated a favorable safety profile.6 The dose-limiting toxicity was a cumulative peripheral sensory neuropathy often exacerbated by cold. Nausea and vomiting were noted but, unlike cisplatin or carboplatin, renal toxicity, ototoxicity, and significant hematologic toxicity were absent for oxaliplatin. The recommended phase II dosage was 125 to 130 mg/m2 every 3 weeks or 85 m/m2 every 2 weeks. Efficacy was noted in phase II and III studies using oxaliplatin for treatment of advanced colon cancer, both as a single agent and in combination with fluorouracil and leucovorin. As a result, oxaliplatin in combination with fluorouracil and leucovorin has been approved for the treatment of colon cancer in Asia, Latin America, and Europe. Recently, the United States Food and Drug Administration approved oxaliplatin in combination with fluorouracil and leucovorin as second-line treatment of patients with advanced colorectal carcinoma. PITHELIAL OVARIAN carcinoma is the fifth most frequent type of cancer in American women, accounting for 23,300 new diagnoses and 13,900 deaths in 2002.1 Most patients present with advanced disease and are treated with cytoreductive surgery, followed by platinum-based combination chemotherapy. Although most of these women initially respond to treatment, most patients with advanced disease experience its recurrence and eventually die as a result of resistant disease.2 cis-Diamminedichloroplatinum (cisplatin), one of the most active single agents in ovarian carcinoma, has been widely used in combination with paclitaxel for the treatment of advanced disease.3 Despite the activity of cisplatin in ovarian cancer, its continued use may be limited by acute dose-related renal toxicity and chronic neurotoxicity.4 Different analogs have been prepared to combat these toxicities. Carboplatin, a bidentate dicarboxylate analog of cisplatin, has a therapeutic spectrum similar to cisplatin and is less nephrotoxic. However, carboplatin is more myelosuppressive than cisplatin, and From the Washington University School of Medicine, St Louis, MO; Gynecologic Oncology Group Statistical and Data Cancer; Roswell Park Cancer Institute, Buffalo, NY; Department of Gynecologic Oncology, University of Pennsylvania Cancer Center, Philadelphia, PA; Division of Gynecologic Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA; and Division of Gynecologic Oncology, University of Connecticut School of Medicine, Farmington, CT. Submitted March 12, 2003; accepted May 5, 2003. Supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517), and a Clinical Oncology Career Development Award from the American Cancer Society to P.M.F. Address reprint requests to Paula M. Fracasso, MD, PhD, Washington University School of Medicine, Campus Box 8056, 660 South Euclid, St Louis, MO 63130; email: [email protected]. © 2003 by American Society of Clinical Oncology. 0732-183X/03/2115-2856/$20.00 2856 Journal of Clinical Oncology, Vol 21, No 15 (August 1), 2003: pp 2856-2859 DOI: 10.1200/JCO.2003.03.077 Downloaded from jco.ascopubs.org on April 20, 2008 . For personal use only. No other uses without permission. Copyright © 2003 by the American Society of Clinical Oncology. All rights reserved. 2857 OXALIPLATIN FOR OVARIAN CARCINOMA Phase II studies with oxaliplatin have also demonstrated its activity in women with previously treated ovarian carcinoma when oxaliplatin is used as a single agent or in combination.7-15 Given the activity and low levels of renal, hematologic, and ototoxicity seen with single-agent oxaliplatin for ovarian carcinoma, this phase II study was designed to investigate its activity and toxicity in women with platinum-resistant and refractory ovarian carcinoma. MATERIALS AND METHODS Eligible patients with epithelial ovarian carcinoma were required to have had one previous platinum-based chemotherapeutic regimen and be platinum-resistant or refractory. Platinum resistance was defined as having had a treatment-free interval of less than 6 months after platinum treatment. Patients who were refractory to treatment with platinum were defined as having had progressive disease during platinum-based therapy. Patients with a known allergy to platinum compounds or who had undergone prior therapy with oxaliplatin were ineligible. Patients were required to have had measurable disease and a Gynecologic Oncology Group (GOG) performance status of 0 to 2. Laboratory criteria for eligibility included absolute neutrophil count ⱖ 1,500/L, platelets at least the institutional lower limit of normal, creatinine ⱕ 1.5 times the institutional upper limit of normal, bilirubin ⱕ 1.5 times the institutional upper limit of normal, and AST and alkaline phosphatase ⱕ 2.5 times the institutional upper limit of normal. No chemotherapy or radiotherapy was permitted within 3 weeks before study entry. Patients with other malignancies during the previous 5 years (with the exception of nonmelanoma skin cancers) were ineligible. Patients with significant comorbid conditions (including active infection, symptomatic congestive heart failure, unstable angina pectoris, and cardiac arrhythmias) or brain metastases were ineligible, as were patients with evidence of preexisting peripheral neuropathy greater than grade 1. All patients provided signed informed consent consistent with all federal, state, and local requirements before entering onto the study. Treatment cycles were every 21 days, with oxaliplatin 130 mg/m2 administered by 2-hour continuous intravenous infusion. Premedication with dexamethasone and 5-hydroxytryptamine-3 antagonists was recommended before and after each dose of oxaliplatin. Patients were counseled to avoid cold drinks and exposure to cold water and air to avoid cold-induced sensory neuropathy. Subsequent courses of oxaliplatin were administered if hematologic parameters had returned to the following status: neutrophils ⱖ 1,500/L and platelets ⱖ 100,000/L. The oxaliplatin dosage was to be reduced by 25% if the absolute neutrophil count nadir in the previous course was ⱕ 1,000/L, if the platelet nadir was less than 50,000/L, or if the hemoglobin nadir was less than 8.0 g/dL. Before each course, complete resolution of stomatitis or pharyngitis and diarrhea was required. The oxaliplatin dosage was to be reduced by 25% for grade 3 or 4 stomatitis or pharyngitis, as well as for grade 3 or 4 diarrhea. Patients were monitored for neurotoxicity before each course, with treatment given only if paresthesia or dysesthesia was grade 2 or less. In the event grade 2 paresthesia or dysesthesia had not resolved by the beginning of the next course, the dose of oxaliplatin was to be reduced by 25%. Grade 3 paresthesia ordysesthesia that had not resolved by the beginning of the next course required discontinuation of treatment. A 25% dosage reduction was allowed for grade 3 paresthesia or dysesthesia that resolved before the start of the next course. Any grade 4 paresthesia or dysesthesia required discontinuation of oxaliplatin treatment. If the patient had pharyngolaryngeal dysesthesia with prior cycles, the duration of the oxaliplatin infusion was to be increased from 2 to 6 hours. Eligible patients were to receive six courses of oxaliplatin, unless evidence of disease progression or toxicity prohibited further therapy. Those still receiving clinical benefit after six courses of treatment could continue therapy for an additional three courses. Response to therapy was evaluated after the second course of therapy. Patients who received one or more course(s) of drug were assessable for toxicity, and those who received one or more course(s) and whose disease was reassessed were assessable for response. Response was defined according to standard GOG criteria, as follows: complete response is the disappearance of all gross evidence of disease for a duration of at least 4 weeks; partial response is a 50% or greater reduction in the product obtained from measurement of each lesion for at least 4 weeks and no appearance of new lesions; increasing disease is a 50% or greater increase in the product from any lesion documented within 2 months of study entry or the appearance of any new lesion within 8 weeks of study entry; and stable disease is any condition not meeting those criteria. This study used a two-stage accrual design with an early stopping rule in the event that the treatment demonstrated insufficient activity. During the first stage of accrual, 22 to 29 patients were to be entered and evaluated. If at least four responses were observed among the first 22 to 24 patients, or five responses were observed among 25 to 29 patients, a second phase of accrual was to be initiated, which would increase accrual to 53 to 60 patients. The regimen would be considered active if at least 11 responses were observed among 53 patients, at least 12 responses were observed among 54 to 57 patients, or at least 13 responses were observed among 58 to 60 patients. If the true probability of response was only 15%, the study design provided a 90% chance of correctly classifying the treatment as inactive. Conversely, if the true response rate was 30%, then the probability of correctly classifying the treatment as active was 90%. RESULTS Between February and June 2000, member institutions of the GOG entered 25 patients with ovarian carcinoma onto GOG Protocol 126-K to evaluate the efficacy of oxaliplatin. Two patients were found, on central pathology review, not to have epithelial ovarian carcinoma and were thus ineligible. The characteristics of the 23 eligible patients are presented in Table 1. All patients had epithelial ovarian carcinoma and were resistant or refractory to platinum chemotherapy as defined above. The median age was 60 years, and the majority of patients had GOG performance status of 0. Table 1. Patient Characteristics (n ⴝ 23) Characteristic Age, years Median Range GOG performance status 0 1 Histology Serous adenocarcinoma Endometrial adenocarcinoma Clear-cell carcinoma Transitional-cell carcinoma Mixed epithelial carcinoma Grade 1 2 3 Unspecified Site of disease Pelvic Extrapelvic Prior chemotherapy Prior platinum therapy Prior radiotherapy No. of Patients 60 43 to 78 Abbreviation: GOG, Gynecologic Oncology Group. Downloaded from jco.ascopubs.org on April 20, 2008 . For personal use only. No other uses without permission. Copyright © 2003 by the American Society of Clinical Oncology. All rights reserved. 14 9 17 2 2 1 1 1 8 13 1 12 11 23 23 2 2858 FRACASSO ET AL Table 2. Adverse Effects Associated With Oxaliplatin (n ⴝ 23) Table 3. No. of Patients by Grade Adverse Effect Hematologic Neutropenia Leukopenia Anemia Thrombocytopenia Other Neurotoxicity Sensory Pharyngolaryngeal dysesthesia Gastrointestinal Nausea or vomiting Other Allergy Cardiovascular Constitutional Dermatologic Genitourinary or renal Hepatic Infection Metabolic Myalgia or arthralgia Ocular Pain Pulmonary 1 2 3 4 3 7 9 7 1 1 2 9 0 1 3 0 0 6 4 0 0 0 0 0 10 7 6 0 1 0 0 0 8 8 0 2 7 0 2 5 2 2 0 1 5 3 5 3 0 3 9 1 0 1 0 1 1 1 7 3 3 1 1 0 2 1 0 1 1 1 1 0 3 1 0 3 0 0 0 0 0 0 0 2 0 0 0 0 All eligible patients were assessable for response. A total of 97 courses of oxaliplatin were administered, with a median of three courses (range, 1 to 13 courses) per patient. Five patients received dosage reductions because of hematologic toxicity; none had the oxaliplatin dosage reduced because of paresthesia or dysesthesia, and study therapy was not discontinued because of neurotoxicity. Adverse effects associated with oxaliplatin are displayed in Table 2. Neurotoxicity was the most frequent adverse effect and could be divided into sensory neurotoxicity (paresthesia or dysesthesia) and pharyngolaryngeal dysesthesia. Paresthesia or dysesthesia was most common and occurred in 17 patients, although grade 3 toxicity occurred in only one patient (4.3%). Similarly, pharyngolaryngeal dysesthesia occurred in seven patients. There was no grade 4 neurotoxicity reported. Gastrointestinal toxicity, including nausea and vomiting, was common, and required intravenous hydration in two patients. Grade 4 disease-related ileus occurred in three patients. Three patients had grade 3 or 4 metabolic adverse effects: In two patients, hyponatremia was due to dehydration; in the third patient, hypokalemia was secondary to diuretics. One patient experienced grade 3 infection, and two patients had grade 1 infection, all without neutropenia. Grade 3 myelosuppression was infrequent and occurred in 13% of patients. RBC transfusions were required in three patients. There were no treatmentrelated deaths. Response to treatment is summarized in Table 3. One of 23 patients (4.3%) achieved a partial response, with a response duration of 6.4 months. Nine patients (39.1%) had stable disease, with a median duration of 5.6⫹ months (range, 1.8 to 13.1 months). Thirteen patients experienced increasing disease. Response to Treatment With Oxaliplatin (n ⴝ 23) Clinical Response No. of Patients % Partial response Stable disease Increasing disease 1 9 13 4.3 39.1 56.6 DISCUSSION Oxaliplatin, a novel platinum derivative, is more potent than cisplatin in vitro, and requires fewer platinum adducts to achieve an equal level of cytotoxicity.5 In addition, oxaliplatin demonstrated greater efficacy in preclinical studies against many tumor cell lines, including a cisplatin-resistant ovarian cancer cell line.16 As a result, oxaliplatin has been evaluated as a single agent and in combination regimens in women with ovarian carcinoma. Several trials have evaluated the activity of oxaliplatin in women with ovarian carcinoma who had been previously treated with platinum. In 1991, a trial of 15 women resistant to platinum compounds revealed activity of oxaliplatin in four patients.7 Four larger trials confirmed this activity. In the first of these trials, 35 women were treated with varying doses of oxaliplatin (58 to 130 mg/m2) every 3 weeks.8 An overall response rate of 29% was observed in 34 assessable patients. Partial responses were noted in six of 13 women (46%) and in three of 18 women (17%) who were platinum-sensitive and platinum-refractory (defined as having had platinum-free, progression-free intervals of ⬍ 6 months), respectively. A second study, conducted by the European Organization for Research and Treatment of Cancer, involved patients with advanced ovarian cancer who were previously treated with platinum therapy and then randomly assigned to receive either paclitaxel or oxaliplatin.9 A total of 86 patients were enrolled; 45 patients received oxaliplatin and 41 patients received paclitaxel. The overall response rate was 16% in the oxaliplatin arm and 17% in the paclitaxel arm. In women treated with oxaliplatin, response was seen in five of 13 patients (38%) and in two of 32 patients (6%) with platinum-free, progression-free intervals of 6 to 12 months, versus less than 6 months, respectively. Among the platinum-refractory women treated with paclitaxel, only five of 31 (16%) responded. In a third study, 42 assessable women were treated with oxaliplatin 130 mg/m2 every 3 weeks. An overall response rate of 26% was reported, with responses observed in seven of 17 patients (41%), three of nine patients (33%), and one of 14 patients (7%) with platinum-free, progression-free intervals of more than 12 months, 6 to 12 months, and less than 6 months, respectively.10 Finally, a fourth study was reported at the 37th Annual Meeting of the American Society of Clinical Oncology. One hundred fifty-six women were enrolled onto this study, with 78 patients receiving either single-agent oxaliplatin or topotecan. The overall response rate was 11.4% in the oxaliplatin arm and 8.9% in the topotecan arm. In women with platinum-free, progressionfree intervals of less than 6 months, the response rate was 3.9% (two of 51 patients) and 5.7% (three of 53 patients) for those treated with oxaliplatin and topotecan, respectively.11 The tox- Downloaded from jco.ascopubs.org on April 20, 2008 . For personal use only. No other uses without permission. Copyright © 2003 by the American Society of Clinical Oncology. All rights reserved. 2859 OXALIPLATIN FOR OVARIAN CARCINOMA icity profile for oxaliplatin in these four studies was acceptable, with infrequent incidence of grade 3 or 4 hematologic toxicity. Nausea, vomiting, and peripheral neuropathy occurred at tolerable levels. Given that single-agent oxaliplatin has demonstrated activity in advanced ovarian cancer with little hematologic and no renal toxicity, we proposed a phase II study of this agent in women with advanced ovarian carcinoma who were previously treated with platinum. The majority of patients enrolled onto this trial developed peripheral sensory neuropathy, although only one had grade 3 toxicity that interfered with daily activities. Acute, self-limited pharyngolaryngeal dysesthesia was also reported within hours after the oxaliplatin infusion and was observed in approximately one third of patients on this trial. Other common side effects included nausea, vomiting, anemia, and constitutional symptoms. Drugrelated renal toxicity was not observed. In addition, no treatmentrelated alopecia or clinical ototoxicity was reported. In our study, all patients were required to have received at least one platinum-based chemotherapy and be resistant or refractory to platinum, as defined by a treatment-free interval of less than 6 months after platinum treatment, or have documented progressive disease during platinum-based therapy. Among the 23 assessable women, no complete response occurred. One woman (4.3%) achieved a partial response to therapy, with a duration of 6.4 months. Nine patients (39.1%) experienced stable disease, with a median duration of 5.6 months. This response rate is consistent with previously published studies of refractory disease and demonstrates that, in women with platinum-refractory advanced ovarian carcinoma, oxaliplatin has minimal activity as a single agent.8-11 Given its tolerable toxicity profile, future studies with oxaliplatin in combination with other active agents in women with platinum-naı̈ve or platinum-sensitive epithelial ovarian carcinoma may be indicated. The role of oxaliplatin as an active chemotherapeutic agent has been demonstrated when it is used alone for treatment of platinum-sensitive disease or is combined with other medications in women with advanced ovarian carcinoma.12-15 ACKNOWLEDGMENT We thank the following individuals for their contributions to this study: S. Percy Ivy, MD, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, for her assistance in the development and execution of this study; Teresa J. Vietti, MD, and Sherry A. Goodner, RN, MA, for editorial assistance; Suzanne Baskerville, GOG Statistical and Data Center, for data collection and analysis; and Kia Neff and Meg Colahan, GOG Administrative Office, for their contributions to protocol management. APPENDIX The appendix is included in the full text version of this article only, available on-line at www.jco.org. It is not included in the PDF version. REFERENCES 1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23-47, 2002 2. Cannistra SA: Cancer of the ovary. N Engl J Med 329:1550-1559, 1993 3. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage II and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996 4. Patton TF, Repta AJ, Sternson LA: Clinical pharmacology of cisplatin, in Ames MM, Powis G, Kovach JS (eds): Pharmacokinetics of Anticancer Agents in Humans. Amsterdam, the Netherlands, Elsevier, 1983 5. Mani S, Graham MA, Bregman DB, et al: Oxaliplatin: A review of evolving concepts. Cancer Invest 20:246-263, 2002 6. Extra JM, Marty M, Brienza S, et al: Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 25:13-22, 1998 7. Misset JL, Kidani Y, Gastiaburu J, et al: Oxaliplatin (L-OHP): Experimental and clinical studies, in Howell SB (ed): Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy. New York, NY, Plenum Press, 1991, p 374 8. Chollet P, Bensmaı̈ne MA, Brienza S, et al: Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol 7:1065-1070, 1996 9. Piccart MJ, Green JA, Jimenez Lacave A, et al: Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol 18:1193-1202, 2000 10. Dieras V, Bougnoux P, Petit T, et al: Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin ⫾ taxane-pretreated ovarian cancer patients. Ann Oncol 13:258-266, 2002 11. Vermorken J, Gore M, Perren T, et al: Multicenter randomized phase II study of oxaliplatin (OXA) or topotecan (TOPO) in platinum-pretreated epithelial ovarian cancer (EOC) patients (pts). Proc Am Soc Clin Oncol 20:212a, 2001 (abstract 847) 12. Soulié P, Bensmaı̈ne A, Garrino C, et al: Oxaliplatin/cisplatin (LOHP/CDDP) combination in heavily pretreated ovarian cancer. Eur J Cancer 33:1400-1406, 1997 13. Faivre S, Kalla S, Cvitkovic E, et al: Oxaliplatin and paclitaxel combination in patients with platinum-pretreated ovarian carcinoma: An investigatororiginated compassionate-use experience. Ann Oncol 10:1125-1128, 1999 14. Delaloge S, Laadem A, Taamma A, et al: Pilot study of the paclitaxel, oxaliplatin, and cisplatin combination in patients with advanced/recurrent ovarian cancer. Am J Clin Oncol 23:569-574, 2000 15. Misset J-L, Vennin P, Chollet P, et al: Multicenter phase II-III study of oxaliplatin plus cyclophosphamide vs. cisplatin plus cyclophosphamide in chemonaı̈ve advanced ovarian cancer patients. Ann Oncol 12:1411-1415, 2001 16. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institutes Anticancer Drug Screen Panel. Biochem Pharmacol 52:1855-1865, 1996 Downloaded from jco.ascopubs.org on April 20, 2008 . For personal use only. No other uses without permission. Copyright © 2003 by the American Society of Clinical Oncology. All rights reserved.