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Phase II Trial of Pyrazoloacridine in Patients with Persistent or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study
Gynecologic Oncology 84, 241–244 (2002) doi:10.1006/gyno.2001.6491, available online at http://www.idealibrary.com on
Phase II Trial of Pyrazoloacridine in Patients with Persistent or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study 1 Steven C. Plaxe, M.D.,* John A. Blessing, Ph.D.,† Nader Husseinzadeh, M.D.,‡ Kenneth D. Webster, M.D.,§ Janet S. Rader, M.D., ¶ and Charles J. Dunton, M.D.㛳 *Division of Gynecologic Oncology, University of California at San Diego, San Diego, California 92103; †GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York 14263; ‡Section of Gynecologic Oncology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267; §Section of Gynecologic Oncology, Department of Gynecology, Cleveland Clinic Foundation, Cleveland, Ohio 44195; ¶Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110; and 㛳Division of Gynecologic Oncology, Jefferson Medical College, Philadelphia, Pennsylvania 17107 Received June 13, 2001; published online December 13, 2001
Objectives. The aims of this study were to determine the response rate of pyrazoloacridine (PZA) in patients with recurrent or persistent endometrial carcinoma and to describe the nature and degree of toxicity in this population. Methods. PZA was initially administered at a dose of 750 mg/m 2 intravenously over 3 h every 3 weeks but, due to toxicity, was subsequently reduced to 560 mg/m 2 at the same schedule. Results. Among 23 evaluable patients, 11 of whom had had prior chemotherapy, there was 1 (4.3%) partial response and no complete responses. Forty-eight percent of patients had grade 4 neutropenia. There was 1 treatment-related death, in a patient who had prior chemotherapy and radiotherapy. Conclusion. This dose and schedule of PZA has insignificant activity in this population. The optimal PZA dose appears to vary between different populations and may be related to prior therapy. © 2001 Elsevier Science Key Words: 9-methoxy acridine; noncycling cells.
INTRODUCTION Development of effective systemic therapy for patients with recurrent and metastatic endometrial cancer is an ongoing process [1]. The Gynecologic Oncology Group (GOG) has demonstrated an overall response rate of 18% to 150 mg/m 2 of medroxyprogesterone given daily [2], as well as response rates of 37% for doxorubicin [3] and 20% for cisplatin [4]. Results of treatment of patients with recurrent endometrial cancer with combination chemotherapy consisting of doxorubicin and cisplatin [5], paclitaxel and cisplatin [6], and doxorubicin, paclitaxel, and cisplatin with G-CSF support [7] have been published. Although improved response rates, up to 45% [5, 7], are reported with the use of combinations, better survival has not 1
Please address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107.
been shown to result [6]. Improved survival was not demonstrated in a phase III trial of combination chemotherapy with doxorubicin and cyclophosphamide when compared to treatment with a single agent [8]. In view of the poor prognosis of patients with advanced or recurrent disease, new active agents are being sought. Pyrazoloacridine (PZA) (NSC No. 366140) is a 9-methoxyacridine compound selected for clinical development on the basis of several unusual properties observed during preclinical evaluation [9]. Although the mechanism of action is unknown, acridine compounds cause cytotoxicity through DNA and RNA interactions. PZA inhibits RNA synthesis and, at higher concentrations, inhibits DNA synthesis. Compared to other agents, it demonstrated increased activity against solid tumor lines relative to leukemic tumor lines. It also showed unusual activity against hypoxic cells and plateau-phase (noncycling) cells, which are not commonly targeted by other drugs. With both 1- and 3-h infusions given every 3 weeks, the most common toxicities were emesis, leukopenia, anemia, and neutropenia. Reversible neuromotor and neuropsychiatric disturbances were seen with 1-h infusions, but were eliminated with the 3-h schedule. Myelotoxicity increased with the 3-h infusion [10]. Responses in phase I trials were reported in patients with colon, cervical, and ovarian cancers [10]; however, no significant activity was noted in phase II studies in pancreatic [11] or colorectal [12] carcinomas. A dose of 750 mg/m 2 administered ever 21 days has been used, and tolerated, in phase II trials in pancreatic cancer [11], colorectal cancer [12], squamous carcinoma of the cervix [13], transitional cell carcinoma [14], and ovarian cancer [15]; however, lower doses have been prescribed in other populations. In a phase II study of patients with cisplatin-refractory germ cell tumors, 600 mg/m 2 was given every 3 weeks and 46% of patients experi-
241
0090-8258/01 $35.00 © 2001 Elsevier Science All rights reserved.
242
PLAXE ET AL.
enced grade 3 or 4 neutropenia [16]. Neutropenia was a predominant toxicity in each of these trials [11–16]. The Gynecologic Oncology Group initiated a phase II clinical trial to determine the response rate of pyrazoloacridine in patients with recurrent or persistent endometrial carcinoma and to describe the nature and degree of toxicity in this population. The phase II dose of 750 mg/m 2 given every 3 weeks appeared tolerable for most populations and was chosen for the present investigation. MATERIALS AND METHODS Women with recurrent or persistent endometrial carcinoma were enrolled on a GOG phase II study of pyrazoloacridine. Patients with uterine sarcomas were not eligible for this clinical trial. All patients had disease progression after primary treatment and were allowed only one prior chemotherapy regimen. Patients had measurable disease, GOG performance status of 0 –2, and adequate hematologic, hepatic, and renal function. Patients with preexisting compromised neurologic function were eligible; however, the neurologic deficit must have been limited to paresthesia and decreased vibratory sense without motor weakness. All patients were required to be able to function independently and be without delirium, confusion, suicidal ideation, or untreated depression. The initial starting dose of pyrazoloacridine was 750 mg/m 2 in 500 cc of D 5W over 3 h; however, this was decreased to 560 mg/m 2 after the first 10 patients were treated because of an unexpectedly high frequency of myelotoxicity. Patients were retreated every 3 weeks. All patients received antiemetics. Patients who received one or more courses of treatment and who survived at least 3 weeks were evaluable for response. Patients who received one or more courses were evaluable for toxicity. Granulocytes ⬎1500/l, platelets ⬎100,000/l, creatinine ⱕ1.5 mg%, bilirubin ⱕ1.5 mg/dl, and recovery from all other toxicities to ⱕGOG grade 1 were required for retreatment. If toxicity persisted, treatment delay to a maximum of 14 days was permitted to meet the above criteria. If toxicity had not resolved to permit treatment within 14 days from the planned treatment, the patient was removed from study. Dose reductions to 75 and 50% and escalation to 125% of the starting dose were required, based on tolerance of the prior course. One dose level reduction was required for any of the following: febrile neutropenia or uncomplicated grade 4 neutropenia (absolute neutrophils ⬍500/l), platelet transfusion or grade 4 thrombocytopenia (platelets ⬍25,000/l), or nonhematologic toxicity ⱖgrade 2 (except nausea or vomiting). Two dose reductions were permitted for each patient. Myelosuppression was initially managed by dose delay and/or dose reduction without use of G-CSF or other hematopoietic growth factors. At the discretion of the treating physician, management of recurrent myelosuppression with G-CSF, rather than a second dose reduction, was permitted. One dose level escalation
was required if all of the following were met on the previous course: no treatment delay for recovery of toxicity, no hematologic toxicity ⱖgrade 2, no nausea or vomiting ⱖgrade 3, and no other nonhematologic toxicity ⱖgrade 1. Patients were assessed prior to each course of treatment and disease measured only by scan was assessed after every second course of treatment. Response was defined using standard Gynecologic Oncology Group criteria. Treatment was continued until disease progression or the patient became unable to tolerate 50% of their original starting dose. Written informed consent fulfilling all institutional, state, and federal regulations was obtained from all patients prior to entry on study. The study was approved by the Institutional Review Board of all participating institutions. RESULTS Patient characteristics. Twenty-eight patients were enrolled. Two patients (7.1%) were ineligible, 1 due to incorrect cell type and another because of inadequate pathologic material. One patient (3.6%) was eligible, but inevaluable, because she was never treated with pyrazoloacridine, and 2 patients (7.1%) were evaluable for toxicity, but not for response. The remaining 23 patients (82.1%) were evaluable for both response and toxicity. Of the 25 evaluable patients, 16 (64%) were enrolled at 560 mg/m 2 and 9 (36%) were enrolled at 750 mg/m 2. The median age of patients was 61 years, with a range of 46 to 80. Thirteen patients had performance status of 0 and 10 had performance status of 1. Tumor grade was as follows: 5 patients had grade 1, 5 had grade 2, and 13 had grade 3. In terms of prior treatment, 23 patients had received radiation therapy, 11 chemotherapy, and 5 hormonal therapy. The median number of courses administered was 2, with a range of 1 to 14. Response. There were no complete responses. There was 1 partial response, lasting 5 months, in a patient with multiple pulmonary metastases. Seven patients (30.4%) had stable disease, and the remaining 15 evaluable patients (65.3%) experienced increasing disease. The total response rate in this study was, therefore, 4.3%. Adverse effects. Adverse effects are summarized in Table 1. The predominant toxicities of pyrazoloacridine in this population were hematologic. A total of 12 patients experienced grade 4 myelotoxicity: 6 (24.0%) leukopenia, 12 (48.0%) granulocytopenia, and 3 (12.0%) thrombocytopenia. Of the 6 grade 4 leukopenias, 4 occurred at a dose of 560 mg/m 2 and 2 at 750 mg/m 2. Of the 3 grade 4 thrombocytopenias, 1 occurred at a dose of 560 mg/m 2 and 2 at 750 mg/m 2. For patients who experienced at least grade 1 leukopenia, the median leukocyte count was 1925/l (range 300 –3000/l) for those enrolled at 560 mg/m 2 and 1650/l (range: 200 –2800/l) for those enrolled at 750 mg/m 2. Of the 12 grade 4 granulocytopenias, 9 occurred at a dose of 560 mg/m 2 and 3 at 750 mg/m 2. The
PZA OF LIMITED VALUE FOR RECURRENT ENDOMETRIAL CANCER
TABLE 1 Adverse Effects Grade Adverse effect
0
1
2
3
4
Leukopenia Neutropenia Thrombocytopenia Anemia Fever Nausea/vomiting Dry mouth Weight loss GI Alopecia Dermatologic GU BUN Creatinine Alkaline phosphatase Metabolic Fatigue Shortness of breath Dyspnea Cough Cardiovascular Edema Leg swelling DVT Neurotoxicity Visual disturbances
3 2 15 11 19 14 24 24 16 21 20 23 23 22 24 24 22 22 22 24 24 24 24 24 16 24
1 4 5 3 1 2 1 1 4 2 3 1 0 3 1 0 0 0 0 0 0 0 1 0 1 1
8 2 1 6 5 4 0 0 2 2 2 0 1 0 0 0 3 0 1 0 0 0 0 1 5 0
7 5 1 5 0 2 0 0 3 0 0 1 1 0 0 1 0 2 0 1 0 1 0 0 3 0
6 12 3 0 0 3 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0
243
population, all of whom had received prior chemotherapy and radiation therapy. The 750 mg/m 2 dose has been used, and tolerated, in phase II trials in other diseases [13–16]; however, lower doses have been employed as well [17]. Our experience in this trial and review of the literature suggests that individualized dosing of PZA is important and that tolerable doses differ between populations. It is possible that prior therapy may play a role and that administration of higher doses may be feasible in less heavily pretreated cohorts. With 24% of patients experiencing grade 4 neutropenia, 560 mg/m 2 may be the maximum tolerated starting dose for the population studied in the present investigation. ACKNOWLEDGMENTS This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Group Statistical Office (CA 37517). The following are Gynecologic Oncology Group institutions that participated in this study: Duke University Medical Center, Abington Memorial Hospital, Emory University Clinic, University of Mississippi Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of lowa Hospitals and Clinics, University of Texas/Southwestern Medical Center at Dallas, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts–New England Medical Center, Rush–Presbyterian–St. Luke’s Medical Center, SUNY Downstate Medical Center, Community Clinical Oncology Program, The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, Washington University School of Medicine, University of Chicago, Thomas Jefferson University Hospital, Case Western Reserve University.
REFERENCES median nadir leukocyte count for all 22 patients with leukopenia was 1750/l, with a range of 200/l–3000/l. The median nadir platelet count for all 10 patients with thrombocytopenia was 91,000/l; the range was 3000/l–134,000/l. The single treatment-related death occurred in a 78-year-old patient with recurrent, metastatic papillary serous cancer who had prior treatment with whole abdominal radiation in addition to combination chemotherapy with doxorubicin and cisplatin. She was treated at a dose of 750 mg/m 2 and had rapid disease progression, which required hospital admission on day 5 posttreatment. Increasing ascites, pleural effusion, small bowel obstruction, and new onset of atrial fibrillation were complicated by neutropenia and thrombocytopenia on day 10 posttreatment. She continued to deteriorate, developed multiorgan system failure, and expired. The starting dose of PZA was reduced to 560 mg/m 2 for patients subsequently enrolled. DISCUSSION Pyrazoloacridine at the reduced dose and schedule is relatively well tolerated, although it shows limited activity in patients with recurrent or persistent endometrial carcinoma. It is noteworthy that significant, unexpected toxicity accompanied the original starting dose of 750 mg/m 2 in this patient
1. Moore TD, Phillips PH, Nerenstone SR, Cheson BD. Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions. J Clin Oncol 1991;9:1071– 88. 2. Thigpen JT, Blessing JA, DiSaia PJ, et al. Oral medroxyprogesterone acetate in advanced or recurrent endometrial carcinoma—results of therapy and correlation with estrogen and progesterone receptor levels: the Gynecologic Oncology Group experience. In: Bailieu EE, Iacobelli S, McGuire WL, editors. Endocrinology and malignancy: proceedings of the First International Congress on Cancer and Hormones. Park Ridge, NJ: Parthenon, 1986:446 –54. 3. Thigpen JT, Buchsbaum HJ, Mangan C, Blessing JA. Phase II trial of Adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep 1979;63:21–7. 4. Thigpen JT, Blessing JA, Homesley HD, et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 1989; 33:68 –70. 5. Thigpen T, Blessing J, Homesley H, Malfetano J, DiSaia P, Yordan E. Phase III trial of doxorubicin ⫾ cisplatin in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 1993;12:261, (abstract 830). 6. Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Persistent chemosensitivity to platinum and/or paclitaxel in metastatic endometrial cancer. Gynecol Oncol 1999;73:422–3. 7. Fleming GF, Fowler JM, Waggoner SE, Copeland LLLJ, Greer BE, Horowitz I, Sutton G, Schilder RJ, Fracasso PM, Ball HG, McGuire WP. Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gy-
244
8.
9. 10.
11.
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necologic malignancies: a Gynecologic Oncology Group study. J Clin Oncol 2001;19:1021–9. Thigpen JT, Blessing JA, DiSaia PJ, Yordan E, Carson LF, Evers C. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1994;12(7):1408 –14. Annual report to the Food and Drug Administration: Pyrazoloacridine NSC No. 366140, IND No. 36325, 1993. Rowinsky EK, Noe DA, Grochow LB, Sartorious SE, Bowling MK, Chen TL, Lubejko BG, Kaufmann SH. Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules. J Clin Oncol 1995;13:1975– 84. Zalupski MM, Shields AF, Philip PA, Kraut M, LoRusso P, Heilbrun LK, Vaitkevicius V: Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma. Invest New Drugs 1998;16:93– 6.
12. Zalupski MM, Philip PA, LoRusso P, Shields AF: Phase II study of pyrazoloacridine in patients with advanced colorectal carcinoma. Cancer Chemother Pharmacol 1997;40:225–7. 13. Plaxe SC, Blessing JA, Lucci JA, Hurteau JA. A phase II trial of pyrazoloacridine (PZA) in squamous carcinoma of the cervix: a Gynecologic Group study. Invest New Drugs 2001;19:77– 80. 14. Dodd PM, McCaffrey JA, Mazumdar M, Icasaino E, Higgins G, Herr H, Bajorin D. Phase II trial of pyrazoloacridine as second-line therapy for patients with unresectable or metastatic transitional cell carcinoma. Invest New Drugs 2000;18:247–51. 15. Plaxe SC, Blessing JA, Bookman MA, Creasman WT. Phase II trial of pyrazoloacridine (PZA) in recurrent platinum sensitive ovarian cancer: a Gynecologic Group study. Gynecol Oncol, in press. 16. Vuky J, McCaffrey J, Ginsburg M, Mariani T, Bajorin DF, Bosl GJ, Motzer RJ. Phase II trial of pyrazoloacridine in patients with cisplatinrefractory germ cell tumors. Invest New Drugs 2000;18:265–7.
Phase II Trial of Pyrazoloacridine in Patients with Persistent or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study 1 Steven C. Plaxe, M.D.,* John A. Blessing, Ph.D.,† Nader Husseinzadeh, M.D.,‡ Kenneth D. Webster, M.D.,§ Janet S. Rader, M.D., ¶ and Charles J. Dunton, M.D.㛳 *Division of Gynecologic Oncology, University of California at San Diego, San Diego, California 92103; †GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York 14263; ‡Section of Gynecologic Oncology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267; §Section of Gynecologic Oncology, Department of Gynecology, Cleveland Clinic Foundation, Cleveland, Ohio 44195; ¶Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110; and 㛳Division of Gynecologic Oncology, Jefferson Medical College, Philadelphia, Pennsylvania 17107 Received June 13, 2001; published online December 13, 2001
Objectives. The aims of this study were to determine the response rate of pyrazoloacridine (PZA) in patients with recurrent or persistent endometrial carcinoma and to describe the nature and degree of toxicity in this population. Methods. PZA was initially administered at a dose of 750 mg/m 2 intravenously over 3 h every 3 weeks but, due to toxicity, was subsequently reduced to 560 mg/m 2 at the same schedule. Results. Among 23 evaluable patients, 11 of whom had had prior chemotherapy, there was 1 (4.3%) partial response and no complete responses. Forty-eight percent of patients had grade 4 neutropenia. There was 1 treatment-related death, in a patient who had prior chemotherapy and radiotherapy. Conclusion. This dose and schedule of PZA has insignificant activity in this population. The optimal PZA dose appears to vary between different populations and may be related to prior therapy. © 2001 Elsevier Science Key Words: 9-methoxy acridine; noncycling cells.
INTRODUCTION Development of effective systemic therapy for patients with recurrent and metastatic endometrial cancer is an ongoing process [1]. The Gynecologic Oncology Group (GOG) has demonstrated an overall response rate of 18% to 150 mg/m 2 of medroxyprogesterone given daily [2], as well as response rates of 37% for doxorubicin [3] and 20% for cisplatin [4]. Results of treatment of patients with recurrent endometrial cancer with combination chemotherapy consisting of doxorubicin and cisplatin [5], paclitaxel and cisplatin [6], and doxorubicin, paclitaxel, and cisplatin with G-CSF support [7] have been published. Although improved response rates, up to 45% [5, 7], are reported with the use of combinations, better survival has not 1
Please address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107.
been shown to result [6]. Improved survival was not demonstrated in a phase III trial of combination chemotherapy with doxorubicin and cyclophosphamide when compared to treatment with a single agent [8]. In view of the poor prognosis of patients with advanced or recurrent disease, new active agents are being sought. Pyrazoloacridine (PZA) (NSC No. 366140) is a 9-methoxyacridine compound selected for clinical development on the basis of several unusual properties observed during preclinical evaluation [9]. Although the mechanism of action is unknown, acridine compounds cause cytotoxicity through DNA and RNA interactions. PZA inhibits RNA synthesis and, at higher concentrations, inhibits DNA synthesis. Compared to other agents, it demonstrated increased activity against solid tumor lines relative to leukemic tumor lines. It also showed unusual activity against hypoxic cells and plateau-phase (noncycling) cells, which are not commonly targeted by other drugs. With both 1- and 3-h infusions given every 3 weeks, the most common toxicities were emesis, leukopenia, anemia, and neutropenia. Reversible neuromotor and neuropsychiatric disturbances were seen with 1-h infusions, but were eliminated with the 3-h schedule. Myelotoxicity increased with the 3-h infusion [10]. Responses in phase I trials were reported in patients with colon, cervical, and ovarian cancers [10]; however, no significant activity was noted in phase II studies in pancreatic [11] or colorectal [12] carcinomas. A dose of 750 mg/m 2 administered ever 21 days has been used, and tolerated, in phase II trials in pancreatic cancer [11], colorectal cancer [12], squamous carcinoma of the cervix [13], transitional cell carcinoma [14], and ovarian cancer [15]; however, lower doses have been prescribed in other populations. In a phase II study of patients with cisplatin-refractory germ cell tumors, 600 mg/m 2 was given every 3 weeks and 46% of patients experi-
241
0090-8258/01 $35.00 © 2001 Elsevier Science All rights reserved.
242
PLAXE ET AL.
enced grade 3 or 4 neutropenia [16]. Neutropenia was a predominant toxicity in each of these trials [11–16]. The Gynecologic Oncology Group initiated a phase II clinical trial to determine the response rate of pyrazoloacridine in patients with recurrent or persistent endometrial carcinoma and to describe the nature and degree of toxicity in this population. The phase II dose of 750 mg/m 2 given every 3 weeks appeared tolerable for most populations and was chosen for the present investigation. MATERIALS AND METHODS Women with recurrent or persistent endometrial carcinoma were enrolled on a GOG phase II study of pyrazoloacridine. Patients with uterine sarcomas were not eligible for this clinical trial. All patients had disease progression after primary treatment and were allowed only one prior chemotherapy regimen. Patients had measurable disease, GOG performance status of 0 –2, and adequate hematologic, hepatic, and renal function. Patients with preexisting compromised neurologic function were eligible; however, the neurologic deficit must have been limited to paresthesia and decreased vibratory sense without motor weakness. All patients were required to be able to function independently and be without delirium, confusion, suicidal ideation, or untreated depression. The initial starting dose of pyrazoloacridine was 750 mg/m 2 in 500 cc of D 5W over 3 h; however, this was decreased to 560 mg/m 2 after the first 10 patients were treated because of an unexpectedly high frequency of myelotoxicity. Patients were retreated every 3 weeks. All patients received antiemetics. Patients who received one or more courses of treatment and who survived at least 3 weeks were evaluable for response. Patients who received one or more courses were evaluable for toxicity. Granulocytes ⬎1500/l, platelets ⬎100,000/l, creatinine ⱕ1.5 mg%, bilirubin ⱕ1.5 mg/dl, and recovery from all other toxicities to ⱕGOG grade 1 were required for retreatment. If toxicity persisted, treatment delay to a maximum of 14 days was permitted to meet the above criteria. If toxicity had not resolved to permit treatment within 14 days from the planned treatment, the patient was removed from study. Dose reductions to 75 and 50% and escalation to 125% of the starting dose were required, based on tolerance of the prior course. One dose level reduction was required for any of the following: febrile neutropenia or uncomplicated grade 4 neutropenia (absolute neutrophils ⬍500/l), platelet transfusion or grade 4 thrombocytopenia (platelets ⬍25,000/l), or nonhematologic toxicity ⱖgrade 2 (except nausea or vomiting). Two dose reductions were permitted for each patient. Myelosuppression was initially managed by dose delay and/or dose reduction without use of G-CSF or other hematopoietic growth factors. At the discretion of the treating physician, management of recurrent myelosuppression with G-CSF, rather than a second dose reduction, was permitted. One dose level escalation
was required if all of the following were met on the previous course: no treatment delay for recovery of toxicity, no hematologic toxicity ⱖgrade 2, no nausea or vomiting ⱖgrade 3, and no other nonhematologic toxicity ⱖgrade 1. Patients were assessed prior to each course of treatment and disease measured only by scan was assessed after every second course of treatment. Response was defined using standard Gynecologic Oncology Group criteria. Treatment was continued until disease progression or the patient became unable to tolerate 50% of their original starting dose. Written informed consent fulfilling all institutional, state, and federal regulations was obtained from all patients prior to entry on study. The study was approved by the Institutional Review Board of all participating institutions. RESULTS Patient characteristics. Twenty-eight patients were enrolled. Two patients (7.1%) were ineligible, 1 due to incorrect cell type and another because of inadequate pathologic material. One patient (3.6%) was eligible, but inevaluable, because she was never treated with pyrazoloacridine, and 2 patients (7.1%) were evaluable for toxicity, but not for response. The remaining 23 patients (82.1%) were evaluable for both response and toxicity. Of the 25 evaluable patients, 16 (64%) were enrolled at 560 mg/m 2 and 9 (36%) were enrolled at 750 mg/m 2. The median age of patients was 61 years, with a range of 46 to 80. Thirteen patients had performance status of 0 and 10 had performance status of 1. Tumor grade was as follows: 5 patients had grade 1, 5 had grade 2, and 13 had grade 3. In terms of prior treatment, 23 patients had received radiation therapy, 11 chemotherapy, and 5 hormonal therapy. The median number of courses administered was 2, with a range of 1 to 14. Response. There were no complete responses. There was 1 partial response, lasting 5 months, in a patient with multiple pulmonary metastases. Seven patients (30.4%) had stable disease, and the remaining 15 evaluable patients (65.3%) experienced increasing disease. The total response rate in this study was, therefore, 4.3%. Adverse effects. Adverse effects are summarized in Table 1. The predominant toxicities of pyrazoloacridine in this population were hematologic. A total of 12 patients experienced grade 4 myelotoxicity: 6 (24.0%) leukopenia, 12 (48.0%) granulocytopenia, and 3 (12.0%) thrombocytopenia. Of the 6 grade 4 leukopenias, 4 occurred at a dose of 560 mg/m 2 and 2 at 750 mg/m 2. Of the 3 grade 4 thrombocytopenias, 1 occurred at a dose of 560 mg/m 2 and 2 at 750 mg/m 2. For patients who experienced at least grade 1 leukopenia, the median leukocyte count was 1925/l (range 300 –3000/l) for those enrolled at 560 mg/m 2 and 1650/l (range: 200 –2800/l) for those enrolled at 750 mg/m 2. Of the 12 grade 4 granulocytopenias, 9 occurred at a dose of 560 mg/m 2 and 3 at 750 mg/m 2. The
PZA OF LIMITED VALUE FOR RECURRENT ENDOMETRIAL CANCER
TABLE 1 Adverse Effects Grade Adverse effect
0
1
2
3
4
Leukopenia Neutropenia Thrombocytopenia Anemia Fever Nausea/vomiting Dry mouth Weight loss GI Alopecia Dermatologic GU BUN Creatinine Alkaline phosphatase Metabolic Fatigue Shortness of breath Dyspnea Cough Cardiovascular Edema Leg swelling DVT Neurotoxicity Visual disturbances
3 2 15 11 19 14 24 24 16 21 20 23 23 22 24 24 22 22 22 24 24 24 24 24 16 24
1 4 5 3 1 2 1 1 4 2 3 1 0 3 1 0 0 0 0 0 0 0 1 0 1 1
8 2 1 6 5 4 0 0 2 2 2 0 1 0 0 0 3 0 1 0 0 0 0 1 5 0
7 5 1 5 0 2 0 0 3 0 0 1 1 0 0 1 0 2 0 1 0 1 0 0 3 0
6 12 3 0 0 3 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0
243
population, all of whom had received prior chemotherapy and radiation therapy. The 750 mg/m 2 dose has been used, and tolerated, in phase II trials in other diseases [13–16]; however, lower doses have been employed as well [17]. Our experience in this trial and review of the literature suggests that individualized dosing of PZA is important and that tolerable doses differ between populations. It is possible that prior therapy may play a role and that administration of higher doses may be feasible in less heavily pretreated cohorts. With 24% of patients experiencing grade 4 neutropenia, 560 mg/m 2 may be the maximum tolerated starting dose for the population studied in the present investigation. ACKNOWLEDGMENTS This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Group Statistical Office (CA 37517). The following are Gynecologic Oncology Group institutions that participated in this study: Duke University Medical Center, Abington Memorial Hospital, Emory University Clinic, University of Mississippi Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of lowa Hospitals and Clinics, University of Texas/Southwestern Medical Center at Dallas, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts–New England Medical Center, Rush–Presbyterian–St. Luke’s Medical Center, SUNY Downstate Medical Center, Community Clinical Oncology Program, The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, Washington University School of Medicine, University of Chicago, Thomas Jefferson University Hospital, Case Western Reserve University.
REFERENCES median nadir leukocyte count for all 22 patients with leukopenia was 1750/l, with a range of 200/l–3000/l. The median nadir platelet count for all 10 patients with thrombocytopenia was 91,000/l; the range was 3000/l–134,000/l. The single treatment-related death occurred in a 78-year-old patient with recurrent, metastatic papillary serous cancer who had prior treatment with whole abdominal radiation in addition to combination chemotherapy with doxorubicin and cisplatin. She was treated at a dose of 750 mg/m 2 and had rapid disease progression, which required hospital admission on day 5 posttreatment. Increasing ascites, pleural effusion, small bowel obstruction, and new onset of atrial fibrillation were complicated by neutropenia and thrombocytopenia on day 10 posttreatment. She continued to deteriorate, developed multiorgan system failure, and expired. The starting dose of PZA was reduced to 560 mg/m 2 for patients subsequently enrolled. DISCUSSION Pyrazoloacridine at the reduced dose and schedule is relatively well tolerated, although it shows limited activity in patients with recurrent or persistent endometrial carcinoma. It is noteworthy that significant, unexpected toxicity accompanied the original starting dose of 750 mg/m 2 in this patient
1. Moore TD, Phillips PH, Nerenstone SR, Cheson BD. Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions. J Clin Oncol 1991;9:1071– 88. 2. Thigpen JT, Blessing JA, DiSaia PJ, et al. Oral medroxyprogesterone acetate in advanced or recurrent endometrial carcinoma—results of therapy and correlation with estrogen and progesterone receptor levels: the Gynecologic Oncology Group experience. In: Bailieu EE, Iacobelli S, McGuire WL, editors. Endocrinology and malignancy: proceedings of the First International Congress on Cancer and Hormones. Park Ridge, NJ: Parthenon, 1986:446 –54. 3. Thigpen JT, Buchsbaum HJ, Mangan C, Blessing JA. Phase II trial of Adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep 1979;63:21–7. 4. Thigpen JT, Blessing JA, Homesley HD, et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 1989; 33:68 –70. 5. Thigpen T, Blessing J, Homesley H, Malfetano J, DiSaia P, Yordan E. Phase III trial of doxorubicin ⫾ cisplatin in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 1993;12:261, (abstract 830). 6. Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Persistent chemosensitivity to platinum and/or paclitaxel in metastatic endometrial cancer. Gynecol Oncol 1999;73:422–3. 7. Fleming GF, Fowler JM, Waggoner SE, Copeland LLLJ, Greer BE, Horowitz I, Sutton G, Schilder RJ, Fracasso PM, Ball HG, McGuire WP. Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gy-
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