Cisplatin and Pentoxifylline in Advanced or Recurrent Squamous Cell Carcinoma of the Cervix: A Phase II Trial of the Gynecologic Oncology Group

Gynecologic Oncology 79, 64 – 66 (2000) doi:10.1006/gyno.2000.5874, available online at http://www.idealibrary.com on

Cisplatin and Pentoxifylline in Advanced or Recurrent Squamous Cell Carcinoma of the Cervix: A Phase II Trial of the Gynecologic Oncology Group 1 Robert S. Mannel, M.D.,* John A. Blessing, Ph.D.,† and Guy Boike, M.D.‡ *Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190; †Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, New York 14263; and ‡Gynecologic Oncology, Michigan State University College of Human Medicine, Hurley Medical Center, Flint, Michigan 48503 Received January 18, 2000

cent in vitro studies have demonstrated a reversal of cisplatin resistance using pentoxifylline to inhibit DNA repair [4]. Pentoxifylline is a methylxanthine which has been reported to enhance the in vitro cytotoxicity of cisplatin against cervical, ovarian, breast, and lung cancer cell lines [5–7]. Initial in vivo studies combining pentoxifylline with alkylating agents such as thiotepa and nitrogen mustard showed enhanced activity in breast and bladder cancer [8]. A subsequent Phase I dose escalation trial in recurrent gynecologic cancers established a maximum tolerated dose of 1600 mg every 8 h starting 1 h before cisplatin infusion and continuing for a total of nine doses [9]. Of the 22 patients in the study, 13 had recurrent cervical cancer with 2 complete responders and 4 partial responders for an objective response rate of 46.1% [10]. This encouraging response rate forms the basis of the current Phase II trial.

Objective. The aim of this study was to determine the antitumor activity and toxicity of cisplatin and pentoxifylline in previously treated patients with squamous cell carcinoma of the cervix. Methods. A Gynecologic Oncology Group (GOG) Phase II trial of recurrent squamous cell cervical cancer using standard GOG response and toxicity criteria was performed. Results. A total of 47 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered. The starting dose was 75 mg/m 2 of cisplatin every 21 days and 1600 mg of pentoxifylline PO every 8 h for nine doses during each course. Forty patients were evaluable for response and 44 were evaluable for toxicity. Of the 40 evaluable patients, 37 had received prior radiotherapy and 35 had received prior chemotherapy. A median of three courses were given (range: 1–7). Among evaluable patients, 1 had a complete response (2.5%) and 3 had a partial response (7.5%) for an overall objective response rate of 10%. The complete responder had not previously had chemotherapy. Grade 3 or 4 toxicity was predominantly nausea and vomiting (32%) and hematologic toxicity (23%). Conclusions. The combination of cisplatin and pentoxifylline at the dose and schedule tested has limited activity in previously treated advanced or recurrent cervical cancer. © 2000 Academic Press

MATERIALS AND METHODS Patients were eligible if they had histologically confirmed advanced or recurrent squamous cell carcinoma of the cervix deemed not curative by surgery or radiation. Patients could not have received more than one prior cytotoxic drug treatment and could not have been eligible for a higher priority GOG protocol. The tumor had to be bidimensionally measurable by physical examination or radiographic study. A pretreatment leukocyte count greater than or equal to 3000/mm 3, platelet count greater than or equal to 100,000/mm 3, a granulocyte count greater than or equal to 1500/mm 3, creatinine less than or equal to 2.0 mg%, bilirubin less than or equal to 1.5⫻ institutional normal, and serum glutamic– oxalocetic transaminase (SGOT) and alkaline phosphatase less than or equal to 3⫻ institutional normal were required. Patients were also required to have no history of other malignancy and a GOG performance status of 3 or better, and at least 3 weeks must have elapsed since any prior therapy. All patients signed an informed consent approved by the Institutional Review Boards of participating

INTRODUCTION Patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix not treatable by radiation therapy or surgery are usually treated with cisplatin chemotherapy. Cisplatin has been extensively studied by the Gynecologic Oncology Group (GOG) for this group of patients with objective response rates of 21–33% [1–3]. The documented high treatment failure rate and short response duration suggest tumor cell resistance to cisplatin. Mechanisms of resistance include alterations in cellular transport, enhanced DNA repair, and activation of intracellular detoxification systems [4]. Re1

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institutions and fulfilling all institutional, state, and federal regulations prior to study entry. Cisplatin was to be administered at a dosage of 75 mg/m 2 every 21 days. Pentoxifylline (1600 mg PO every 8 h for nine doses) was administered beginning 1 h prior to cisplatin infusion. Pretreatment evaluation included tumor measurement, creatinine, SGOT, alkaline phosphatase, bilirubin, calcium, phosphorous, magnesium, and electrolytes. A weekly complete blood count with differential was obtained. Treatment was modified for adverse renal effects as follows: a serum creatinine level of greater than or equal to 1.5 mg% but less than 2.0 mg% required a reduction of the cisplatin dose to 50 mg/m 2. If serum creatinine rose to more than 2.0 mg% a creatinine clearance (CCR) was obtained. If the CCR was ⱖ50 ml/min, treatment was continued at a reduced cisplatin dose of 50 mg/m 2. If the CCR was ⬍50 ml/min treatment was held until CCR rose to ⱖ50 ml/min or the serum creatinine fell to ⱕ2.0 mg%, at which time therapy was resumed. If there was persistence of CCR ⬍50 or serum creatinine ⬎2 mg% for more than 4 weeks, the patient was removed from the study. The dose modification for hematologic toxicity was as follows: for white blood cell count nadir ⬍2000/␮l, or platelet nadir ⬍50,000/␮l, the cisplatin was reduced by 25 mg/m 2. If the patient had a dose modification for hematologic toxicity, that dose remained the standard dose for subsequent courses with the same modifications for additional toxicity. If the patient had persistent leukopenia or thrombocytopenia despite dose modification, the patient was removed from study. Grade 3 or 4 peripheral neuropathy required interruption of cisplatin therapy until resolution of adverse effects. If 6 weeks or more elapsed since the prior dose, the patient was removed from the study. Grade 2 neurotoxicity required a dose reduction to 50 mg/m 2 of cisplatin. If the adverse effects resolved, the patient was dose-escalated to the original dose of cisplatin of 75 mg/m 2. Audiography was required prior to initiation of therapy. Symptomatic hearing loss and tinnitus required a cisplatin dose reduction to 50 mg/m 2. If these adverse effects resolved, the cisplatin dose was escalated to 75 mg/m 2. The pentoxifylline dose was modified as follows: grade 3 vomiting required the pentoxifylline dose level to be reduced to 1200 mg PO every 8 h times nine doses for all subsequent treatment cycles. Grade 4 gastrointestinal toxicity required removal of the patient from study. There were no dose modifications of pentoxifylline for hematologic toxicity. Therapy was continued until disease progression or adverse effects prohibited further therapy. Response, performance status, and grades of toxicity were defined by standard GOG criteria. Patients who received one or more courses of therapy were evaluable for response. RESULTS Between July and December of 1993, 30 patients were entered into this trial. Based upon the response rate observed in

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the first stage of accrual, the study was reopened in June 1994 to a second stage accrual in accordance with the study design. The study was closed in November of 1994 after a total of 47 patients were entered. Forty patients were evaluable for response and 44 for toxicity. The median age was 50 years (range: 23– 81) and 93% had a grade 0 or 1 performance status. Recurrent disease was present in the pelvis in 15 (38%) and extrapelvic in 25 (62%). Thirty-seven had received prior radiotherapy and 35 prior chemotherapy (including 33 cisplatin) with 33 patients receiving both radiation and chemotherapy. A median of three courses of study treatment were given (range: 1–7). One patient had a complete response (2.5%) and three had partial responses (7.5%), for an overall objective response of 10%. The patient with the complete response had no prior chemotherapy. One of the partial responders had previous ifosfamide therapy. The remaining two partial responders had previous cisplatin-based therapy. Median response time was 4.3 months. Fifty-five percent of the patients had stable disease for a median duration of 3.7 months. The most common toxicity was nausea and vomiting occurring in 70% of patients (grade 1—9%; grade 2—30%; grade 3—18%; grade 4 —14%). Myelosuppression was seen with grade 3 thrombocytopenia in 9%, grade 3 anemia in 9%, grade 4 anemia in 2%, and grade 3 leukopenia and neutropenia in 5%. The median white blood count nadir for 17 patients who experienced leukopenia was 2500 (range: 1200 –3500). The median platelet nadir for eight patients experiencing thrombocytopenia was 66,000 (range: 27,000 –138,000). Neurologic toxicity was grade 2 in 9%, grade 3 in 5%, and grade 4 in 2% of patients. One patient developed grade 3 ototoxicity. Renal toxicity was grade 2 in 12% and grade 3 in 5%. DISCUSSION The management of recurrent cervical cancer patients not treatable with surgery or radiation continues to have only limited success. Multiple Phase II and III trials have shown cisplatin to be the most active single agent in this disease process with objective response rates ranging from 21 to 33% [1–3]. This is the standard against which Phase II trials in this disease must be measured. Combining cisplatin with other cytotoxic agents, such as ifosfamide, has yielded significantly improved objective response rates but no prolongation in survival [3]. These marginal improvements have come at the cost of a significant increase in toxicity, bringing into question the value of using objective response as the sole criteria for choosing the best agent for the treatment of recurrent cervical cancer. The use of noncytotoxic chemical modifiers, such as pentoxifylline, has been shown to enhance cisplatin activity in vitro and in vivo in a number of tumors [5– 8, 10]. Recent in vitro studies have indicated that pentoxifylline may work through reversal of de novo or acquired cisplatin resistance

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by inhibition of DNA repair. A previous single institution Phase I trial combining cisplatin with pentoxifylline reported a 46% objective response rate in 13 patients with recurrent cervical cancer [10]. Two of the six responders in this trial had previously received and were thought to be refractory to cisplatin. Their response to further cisplatin therapy, with the addition of pentoxifylline, supports previous in vitro observations. In the current trial, of the four responders, two had received prior cisplatin therapy, but may not have been cisplatin-resistant. Even if they were, in fact, platinum-resistant, the infrequency of overcoming resistance by the pentoxifylline strategy would not seem to warrant further study in this patient population.

ACKNOWLEDGMENTS This study was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517). The following Gynecologic Oncology Group institutions participated in this study. Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Army Medical Center, University of Minnesota Medical School, University of Mississippi Medical Center, The Milton S. Hershey School of Medicine of the Pennsylvania State University, Georgetown University Hospital, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, Tufts New England Medical Center, Rush–Presbyterian–St. Lukes Medical Center, Stanford University Medical Center, Cleveland Clinic Foundation, Washington University School of Medicine, Cooper Hospital University Medical Center, Columbus Cancer Council, University of Massachusetts Medical Center, Medical University of South Carolina, University of Oklahoma Health Sciences Center, Thomas Jefferson University Hospital, and Case Western Reserve University.

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