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Results of a European Organization for Research and Treatment of Cancer/Early Clinical Studies Group Phase II Trial of First-Line Irinotecan in Patients With Advanced or Recurrent Squamous Cell Carcinoma of the Cervix

From the Institut G. Roussy and Hôpital P. Brousse, Villejuif; Centre R. Gauducheau, Nantes; Centre J.F. Leclerc, Dijon; Centre A. Vautrin, Nancy; Institut Curie, Paris; Fondation Bergonié, Bordeaux; Centre O. Lambret, Lille; Centre L. Bérard, Lyon; Centre C. Regaud, Toulouse; Laboratoires Rhône-Poulenc Rorer, Montrouge; Centre H. Becquerel, Rouen, France; and European Organization for Research and Treatment of Cancer, Brussels, Belgium.

Address reprint requests to Catherine Lhommé, MD, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; email lhomme{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the efficacy and tolerability of irinotecan (CPT-11) in advanced or recurrent cervical carcinoma.

PATIENTS AND METHODS: Eligible patients had histologically confirmed, inoperable, progressive, metastatic or recurrent squamous cell cervical carcinoma and had received no radiotherapy in the preceding 3 months and had never received chemotherapy. The initial irinotecan dosage of 350 mg/m² every 3 weeks was modifiable according to toxicity. Treatment continued for six cycles after complete response, or until disease progression or excessive toxicity after partial response, or for three additional cycles in the case of stable disease. Patients were stratified into group A ( one measurable lesion in a previously unirradiated area, with or without progressive disease in irradiated fields) or group B (measurable new lesion[s] in an irradiated field).

RESULTS: Fifty-one of 55 enrolled patients were eligible for inclusion (median age, 47 years; range, 30 to 71 years). The response rate was 15.7% (95% confidence interval [CI], 7.0% to 28.6%) overall, 23.5% (95% CI, 10.7% to 41.2%) for group A (complete response, 2.9%), and zero for group B. The median time to progression and median survival were 4.0 and 8.2 months for group A and 2.5 and 4.2 months for group B, respectively. The major grade 3/4 toxicities for groups A and B were diarrhea (24.3% and 55.5%, respectively) and neutropenia (24.3% and 33.3%, respectively). There were four toxicity-related deaths, three in group B. Patients with no prior external pelvic irradiation experienced fewer grade 3 and 4 adverse events.

CONCLUSION: Irinotecan is effective in treating cervical squamous cell carcinoma if disease is located in an unirradiated area. Because of toxicity, a reduced dose is advised for patients previously treated with external pelvic irradiation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CANCER OF THE UTERINE cervix is the main cause of death from gynecologic cancer in emerging countries. In the developed world, a third of women with cervical cancer die from uncontrolled disease, because of either presentation with primary extrapelvic disease or persistent or recurrent disease after surgery and/or radiotherapy.¹ In such patients, most active single chemotherapeutic agents show overall response rates of 15% to 35%, although this figure is dramatically reduced if the tumor is in an irradiated area. Unfortunately, responses are mainly partial and of only a few months duration,^1,2 with little beneficial impact on the median duration of survival. Thus, there is a clear need for new active agents to treat patients with cervical cancer.

Irinotecan (CPT-11) is a camptothecin derivative³ that inhibits DNA topoisomerase I, a nuclear enzyme that modulates the topologic structure of DNA.^4-6 It exerts an antitumoral activity through its active metabolite SN-38, which is 100- to 1,000-fold more active than the parent compound.⁷ Preclinical investigations have shown irinotecan to have activity against a wide variety of solid tumors, to an equivalent or greater extent than that observed with the most active available anticancer agents.⁸ Irinotecan is internationally approved for use in metastatic colorectal cancer after failure of fluorouracil treatment; in Japan, irinotecan is indicated for the treatment of other malignancies, including lymphoma and cancer of the lung, stomach, breast, larynx, and cervix.

The limiting toxicities of single-agent irinotecan are delayed diarrhea (grade 3/4 observed in 34% of patients in earliest phase II studies) and neutropenia (grade 3/4 in 40% of patients).⁹ Concomitant occurrence of grade 4 neutropenia with grade 3/4 delayed diarrhea can be life-threatening and requires aggressive supportive care.¹⁰ The other most frequently observed toxicities are acute cholinergic syndrome (which can be easily managed or prevented with atropine), nausea/vomiting, fatigue, and alopecia.

A variety of schedules have been recommended for phase II studies, including irinotecan 100 mg/m²/wk in Japan¹¹ and 125 mg/m²/wk for 4 weeks followed by 2 weeks of rest in the United States.¹² In Europe, after phase I trials, the recommended schedule is 350 mg/m² as a 30- to 60 min intravenous infusion every 3 weeks.^10,13 In colorectal cancer, the efficacy and safety results have been shown to be consistent and reproducible, irrespective of the schedule used.^9,12,14

Initial results from a Japanese study of irinotecan in patients with cervical carcinoma who were pretreated or not pretreated with chemotherapy indicated a 24% objective response rate.¹⁵ To further characterize these encouraging observations, the European Organization for Research and Treatment of Cancer/Early Clinical Studies Group conducted this open, multicenter phase II study of irinotecan in chemotherapy-naive patients with progressive advanced or recurrent cervical squamous cell carcinoma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligible patients (18 to 75 years old) were required to fulfill the following criteria: histologically proven, infiltrative squamous cell carcinoma of the uterine cervix; no previous chemotherapy (even as a radiation sensitizer); inoperable, metastatic, or recurrent progressive disease, with or without previous pelvic radiotherapy; presence of at least one bidimensionally measurable lesion 2.5 cm (2 cm for lung metastases); no radiotherapy in the 3 months before study entry; World Health Organization (WHO) performance status of 0 to 2 with life expectancy greater than 3 months; adequate bone marrow function (neutrophil count 2,000/µL, platelet count 100,000/µL), renal function (creatinine level 130 µmol/L), and hepatic function (in the absence of hepatic metastases, serum bilirubin level 1.25 times and AST, ALT, and alkaline phosphatase levels two times the institutional upper limit of normal; if hepatic malignant infiltration, serum bilirubin level 1.5 times and AST, ALT, gamma-glutamyl transferase, and alkaline phosphatase levels four times the institutional upper limit of normal), and written, informed consent of the patient according to the local and institutional regulatory requirements.

Patients were excluded if they met the following criteria: anticipated difficulty in follow-up because of psychiatric disorders or geography; previous or concurrent malignancy, excluding adequately treated basal or squamous cell carcinoma of the skin; significant risk of uncontrolled infection; pulmonary or cardiac dysfunction; chronic enteropathy (Crohn's disease, ulcerative colitis), or significant diarrhea. Sclerotic bone metastases, serous effusions, or bone lesions only detectable by bone scan were not acceptable as the only tumor-response parameter.

Treatment
Irinotecan was provided by the Laboratoires Rhône-Poulenc Rorer, Montrouge, France. Treatment consisted of an intravenous infusion of irinotecan 350 mg/m² in 250 mL of physiologic saline over 30 minutes every 3 weeks. In the event of gastrointestinal toxicity (diarrhea grade 3) during or after treatment administration, the infusion time was extended to 90 minutes for the next infusion.

The dose and treatment schedule could be modified according to hematologic toxicity and diarrhea. In all cases, at least 3,000 leukocytes/µL, or 1,500 neutrophils/µL, and 100,000 platelets/µL were required for the subsequent infusion. If these criteria were not met, treatment was delayed for 1 week without dose reduction and then for 2 weeks with a 15% dose reduction for the subsequent infusion. If toxicity persisted for up to 5 weeks without recovery, the patient was removed from the study. In all cases, if grade 4 neutropenia (with or without sepsis) or thrombocytopenia occurred, the next dose of irinotecan was reduced by 15% (ie, to 300 mg/m²); only two dose reductions were permitted.

Antiemetics were administered according to the physician's discretion. If acute diarrhea developed during the first infusion of irinotecan, premedication with subcutaneous atropine (0.25 mg 15 min before infusion) or oral loperamide (4 mg) was permitted before subsequent infusions. If diarrhea occurred between two infusions, treatment with oral loperamide 4 mg was started immediately and continued every 6 hours until recovery (12 hours after the last liquid stool); if needed, antidiarrheal therapy was subsequently continued with other agents.

Treatment was discontinued in the case of progressive disease, excessive toxicity, or patient request. Irinotecan was continued for six courses after the first observation of complete response or until excessive toxicity or disease progression occurred after a partial response, and treatment was allowed for three further courses in the case of stable disease.

Assessments
Pretreatment evaluation included medical history, assessment of performance status, complete physical examination, complete and differential blood counts, creatinine, bilirubin, AST, ALT, alkaline phosphatase, chest x-ray, pelvic-abdominal CT-scan, and any imaging studies necessary to assess the indicator lesion(s). The same clinical and biologic examinations were repeated before each irinotecan infusion. Complete and differential blood counts, and creatinine assays in the event of diarrhea, were performed weekly. Acute toxicities were measured using the WHO scale of adverse events, and diarrhea was assessed using the National Cancer Institute Common Toxicity Criteria grade.¹⁶ All treated patients were evaluated for toxicity.

Responses for all patients were evaluated according to the WHO criteria¹⁷ and reassessed by an independent review panel. Follow-up continued every three cycles until the disease progressed, the study ended, or another treatment was started. Time to progression was measured from the start of treatment until disease progression. The duration of responses and overall survival was evaluated by the Kaplan-Meier method.¹⁸

The trial population was stratified into two groups: group A patients had at least one measurable lesion outside previously irradiated areas (with or without progressive disease in previously irradiated areas), and group B patients had a recent measurable lesion(s) inside a previously irradiated area. The Gehan two-stage sampling plan design was used for each group of patients according to the eligibility criteria.¹⁹ In the first stage, 14 assessable patients were to be registered in each group, and the trial was to be stopped if no complete or partial responses were observed (as determined by an independent review panel). This ensured that, if the treatment was active in 20% of cases, the probability of erroneously rejecting the treatment was less than .05. If one, two, three, or four or more responses were observed in a group, one, six, nine, or 11 additional patients, respectively, were to be enrolled; this ensured that the SE of the observed response rate would be .10.

The protocol was approved by the main investigator's national ethics committee and the European Organization for Research and Treatment of Cancer Protocol Review Committee.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Of 55 patients recruited from 15 centers, 51 (93%) were eligible for response assessment, 34 in group A (recruited in two stages) and 17 in group B (recruited in one stage) (Table 1). The reasons for exclusion were no measurable target lesion (two patients, group A), prior chemotherapy (one patient, group A), and the single target lesion (primary tumor recurrence) was preirradiated (one patient, group B). The median WHO/Eastern Cooperative Oncology Group performance status (PS) was 1 (range, 0 to 2). In Group A, 94% of patients had received prior radiotherapy (of whom 68% had received external pelvic radiation and 82% had received brachytherapy). In accordance with the protocol, all patients in group B had received previous radiation (76% had received external pelvic radiation and 24% had received brachytherapy alone). Two of these patients had nonmeasurable disease outside prior irradiated fields. At initial diagnosis, 53% of patients in group A and 47% of group B had local advanced disease (stage III or IV_A); only nine patients (16%) had stage I disease. Therefore, in accordance with our local protocols, the majority of patients received prior radiotherapy (external and/or brachytherapy). The number and location of assessable tumor sites are shown in Table 2.

A total of 226 cycles of therapy (172 in group A and 54 in group B) were administered to the 55 entered patients. The median number of treatment cycles per patient was four (range, one to 10) in group A and three (range, one to seven) in group B. The mean administered dose-intensity was 0.97 (range, 0.67 to 1.03) of the planned dose. The 51 eligible patients received 211 cycles (161 in group A and 50 in group B).

Response to Therapy
The overall response rate observed in the eligible population was 15.7% (95% confidence interval, 7.0% to 28.6%).

In group A, one complete response (CR) (para-aortic lymph nodes) and seven partial responses (PRs) (20.6%) were observed, giving an overall response rate of 23.5% (95% confidence interval, 10.7% to 41.2%). The duration of the CR was 33 weeks, and the median duration of the PR was 24 weeks (range, 15 to 66 weeks). Median times to progression and survival were 4.0 and 8.2 months, respectively. In group B, no response was reported in any of the 17 eligible patients. Median times to progression and survival were 2.5 and 4.2 months, respectively.

Some patients had more than one target site. Table 3 shows site-specific responses classified by site and status of prior irradiation, pooling the data from both groups. Of these site-specific responses, only two PRs were observed in previously irradiated areas, whereas three CRs (lymph nodes) and nine PRs were achieved in previously unirradiated sites.

Tolerability
All 55 treated patients were evaluated for toxicity (Table 4). With respect to hematologic toxicity, 27% of patients experienced grade 3 or 4 neutropenia in at least one cycle, and febrile neutropenia occurred in five patients (9%). Thrombocytopenia was generally mild, with 7% of patients experiencing grade 3 or 4 toxicity. Grade 3 or 4 anemia was observed in 29% of patients. The major nonhematologic side effect was gastrointestinal disturbance, with grade 3 or 4 diarrhea reported in 34% of patients. Grade 3 or 4 nausea and vomiting occurred in 29% of patients; grade 3 alopecia was observed in 21 patients (38%) and grade 3 mucositis in one patient.

The most frequent toxicities were analyzed according to previous irradiation of the main hematopoietic area (Table 5). Grade 3 or 4 neutropenia occurred in 43% of patients who had received prior external pelvic irradiation, compared with 15% of patients without external irradiation; grade 3 or 4 diarrhea occurred in 46% and 22%, respectively.

Four toxic deaths occurred. In group A, one toxic death was reported at day 18 of the first cycle due to septicemia after aplasia recovery. This 66-year-old patient had previously had a right colectomy and prior external radiotherapy and had bulky disease (parietal involvement) at inclusion; on day 15, fistula and skin necroses were observed. Three toxic deaths occurred in group B (17%): one patient had grade 4 neutropenia after one cycle (PS = 1), one patient with a prior history of hydronephrosis developed febrile neutropenia and grade 4 diarrhea and died of toxic hepatitis after two cycles, and one patient developed febrile neutropenia and grade 4 diarrhea after three cycles (PS = 2).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The prognosis for patients with previously irradiated inoperable recurrent or persistent cervical cancer remains poor, and there is an urgent need for novel therapeutic agents. Our study was designed to determine the efficacy and tolerability of irinotecan in a clinical setting of patients who had received no previous chemotherapy. Irinotecan was administered every 3 weeks on the basis of the results of earlier French phase I studies.^10,13 This schedule was recommended for future phase II and III studies, and is the currently approved schedule for irinotecan monotherapy. The overall response rate achieved in our study was 15.7%, with grade 3 or 4 anemia, neutropenia, and diarrhea/vomiting each occurring in about one third of patients.

The most extensively studied agent in the treatment of cervical squamous cell cancer to date is cisplatin, which has been used both as a single agent and in combination treatment regimens. In one randomized study involving 119 patients with advanced cervical cancer and no prior chemotherapy, three (33%) of 11 patients responded to cisplatin monotherapy, which compared favorably with cisplatin combined with mitomycin (25%) or a cisplatin, mitomycin, vincristine, and bleomycin combination (22%).²⁰ Although greater response rates have been observed with cisplatin combinations in other trials, most patients experienced only partial tumor regression, and the duration of survival achieved with single and combination cisplatin therapy seems to be similar.²¹

Several novel agents have also been tested recently in previously untreated patients with squamous cell cervical carcinoma.¹ Paclitaxel, a taxane extracted from the Pacific yew tree, achieved response rates of 17%²² and 25%²³ (Table 6). The dose-limiting toxicity seemed to be neutropenia. In the two studies, dose reductions were necessary in 28% of patients²² and 21% of courses.²³ Vinorelbine has shown similar activity, achieving a response rate of 18%, although necessitating dose reductions in only four (11%) of 35 patients.²⁴

A number of studies have demonstrated the efficacy of irinotecan in cervical cancer (Table 6). A preliminary study of 66 patients with advanced cervical carcinoma who were treated with irinotecan 100 mg/m²/wk or 150 mg/m² every 2 weeks demonstrated a response rate of 24%.¹⁵ Verschraegen et al²⁵ reported a 21% response rate with a schedule of 125 mg/m²/wk for 4 weeks with a 2-week rest, in 42 assessable patients with prior chemotherapy (mainly cisplatin)–treated cervical carcinoma, 88% of whom had received prior radiotherapy.²⁵ The major grade 3 or 4 toxicities were nausea and vomiting and anemia. Diarrhea was dose-limiting in 10 patients, and dose was reduced in 77% of patients because of toxicity (48% of patients had a PS of 2 at baseline). With the same schedule, the Gynecologic Oncology Group recently reported a 13% response rate in 45 patients, but dose reductions were required in 65% of patients.²⁶ However, other investigators have obtained disappointing results, with no objective responses in 14 assessable patients with cisplatin-resistant cervical carcinoma, 81% of whom had received prior pelvic/abdominal radiotherapy.²⁷ This result was possibly related to significant toxicity resulting in a low median dose-intensity (only 71% of that originally planned, compared with 97% in our study).

In our study, responses to therapy were considerably greater in the subgroup with disease that was outside any previously irradiated areas; no objective response was noted in any of the 17 patients whose lesions had previously been irradiated. The high rate of external radiotherapy with or without brachytherapy was due to a high proportion of patients with initial advanced disease, or high-risk localized cervical cancer. Those with less advanced disease received brachytherapy initially. Similar results have been obtained in a retrospective study of 168 patients with chemotherapy-naive, recurrent, inoperable cervical carcinoma, who were treated with 14 different chemotherapeutic protocols.²⁸ Although a response rate of 25.2% was obtained when there was recurrent disease outside the irradiated field, this figure fell to only 5.3% when recurrent disease was in the irradiated field only (P = .008). As in the current study, all CRs observed occurred in patients with previously unirradiated tumors. Similarly, in a study of cisplatin/fluorouracil therapy in patients with recurrent carcinoma, 68% of patients with previously unirradiated recurrent disease responded, compared with only 15% of patients with disease limited to an irradiated area.²⁹ However, it is notable that, in the Verschraegen study, the one CR observed was in a woman who had previously received chemotherapy, radiotherapy, and immunotherapy for persistent disease; the response was maintained for 12 weeks.²⁵

At the time of initiation of this study, guidelines concerning the management of expected side effects of irinotecan were not well established, and this is reflected in the incidence of diarrhea, which occurred in approximately one third of patients. Whereas occurrence of grade 3 or 4 diarrhea with irinotecan treatment seems to be dose-related, this does not seem to be the case for granulocytopenia in the Vershraegen study. In our study, the major hematologic toxicity observed was neutropenia. It is notable that, except for grade 3/4 neutropenia, the incidence of most hematologic (including febrile neutropenia) and nonhematological grade 3 or 4 adverse events was markedly greater in group B than in group A patients. In addition, three of the four toxicity-related deaths were in group B. In view of both the toxicity and response rates obtained, therefore, we would not recommend the use of irinotecan for such patients.

The results reported from this and other studies of irinotecan monotherapy for cervical carcinoma are encouraging and merit further analysis. However, a number of studies have indicated that combination chemotherapy regimens may offer improved efficacy in patients with cervical cancer.^1,30 For example, against tumors located in previously unirradiated areas, a bleomycin/vindesine/mitomycin/cisplatin combination was more effective (44.4% response rate) than cisplatin alone (30.3% response rate).³¹ In vitro evidence indicates that irinotecan and cisplatin operate by synergistic mechanisms,³² and this combination has been shown to be effective against murine squamous cell cervical carcinoma.³³ In one preliminary study, cisplatin plus irinotecan achieved an overall response rate of 40%, with two of the 25 patients achieving a CR.³⁴ Therefore, as the next stage of our investigations, we propose to examine a combination of cisplatin and irinotecan using the every-3-weeks schedule, in a larger phase II/III study of cervical carcinoma therapy in chemotherapy-naive patients.

	ACKNOWLEDGMENTS

 
Supported by Laboratoires Rhône-Poulenc Rorer, Montrouge, France

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Omura GA: Chemotherapy for cervix cancer. Semin Oncol21:54-62, 1994

2. Thigpen JT, Vance R, Puneky L, et al: Chemotherapy as a palliative treatment in carcinoma of the uterine cervix. Semin Oncol22:16-24, 1995 (2 suppl 3)[Medline]

3. Kanzawa F, Sugimoto Y, Minato K, et al: Establishment of a camptothecine analogue (CPT-11) resistant cell line of human non small cell lung cancer: Characterization and mechanism of resistance. Cancer Res50:5919-5924, 1990[Abstract/Free Full Text]

4. Wall ME, Want MC, Cook CE, et al: Plant antitumour agents: I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc88:3888-3890, 1996

5. Kohn KW, Ewing RAG, Erickson LC, et al: Measurement of strand breaks and cross links by alkaline elution, in Friedberg EC, Hanawalt PC (eds): DNA Repair: A Laboratory Manual of Research Techniques. New York, NY, Marcel Dekker, 1981, pp 379-401

6. Kubota N, Kanzawa F, Nishio K, et al: Detection of topoisomerase I gene point mutation in CPT-11 resistant lung cancer cell line. Biochem Biophys Res Commun188:571-577, 1992[Medline]

7. Rowinsky EK, Grochow LB, Ettinger DS, et al: Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-(4(1-piperidino)-1piperidino)carbonyloxy camptothecin (CPT11) administered as ninety-minute infusion every 3 weeks. Cancer Res54:427-436, 1994[Abstract/Free Full Text]

8. Tsuruo T, Masuzaki T, Matsushita M, et al: Antitumour effect of CPT-11, a new derivative of camptothecine, against pleiotropic drug resistant tumours in vitro and in vivo. Cancer Chemother Pharmacol21:71-74, 1988[Medline]

9. Rougier P, Bugat R, Douillard JY, et al: A phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil based chemotherapy. J Clin Oncol15:251-260, 1997[Abstract/Free Full Text]

10. Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol13:210-221, 1995[Abstract/Free Full Text]

11. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst83:1164-1168, 1991[Abstract/Free Full Text]

12. Rothenberg ML, Kuhn JG, Burris HA III, et al: Phase I and pharmacokinetic trial of weekly CPT11. J Clin Oncol11:2194-2204, 1993[Abstract/Free Full Text]

13. De Forni M, Bugat R, Chabot GG, et al: Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. Cancer Res54:4347-4354, 1994[Abstract/Free Full Text]

14. Suminaga M, Furue H, Taguchi T, et al: Phase I study of CPT11, a derivative of camptothecin. Presented at 16th Int Congress Chemotherapy (ICC), Jerusalem, Israel, June 11-16 1989 (abstr p 51)

15. Takeuchi S, Noda K, Yakushiji M: Late phase II study of CPT 11, a topoisomerase I inhibitor, in advanced cervical carcinoma. Proc Am Soc Clin Oncol11:224, 1992 (abstr 708)

16. National Cancer Institute: Guidelines for the Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988

17. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer47:207-214, 1981[Medline]

18. Kaplan EL, Meier P: Non-parametric estimation from incomplete data. J Am Stat Assoc53:457-481, 1958

19. Gehan EA: The determination of the number of patients required in a preliminary and follow-up trial of a new chemotherapeutic agent. J Chronic Dis13:346-353, 1961[Medline]

20. Alberts DS, Kronmal R, Baker LH, et al: Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: A Southwest Oncology Group study. J Clin Oncol5:1791-1795, 1987[Abstract/Free Full Text]

21. Alberts DS, Garcia D, Mason-Liddil N, et al: Cisplatin in advanced cancer of the cervix: An update. Semin Oncol1:1811-1824, 1991 (suppl 3)

22. McGuire WP, Blessing JA, Moore D, et al: Paclitaxel has moderate activity in squamous cervix cancer: A Gynecologic Oncology Group study. J Clin Oncol14:792-795, 1996[Abstract/Free Full Text]

23. Kudelka AP, Winn R, Edwards CL, et al: An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Anticancer Drugs8:657-661, 1997[Medline]

24. Morris M, Brader KR, Levenback C, et al: Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol16:1094-1098, 1998[Abstract]

25. Verschraegen CF, Levy T, Kudelka AP, et al: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol15:625-631, 1997[Abstract/Free Full Text]

26. Look KY, Blessing JA, Levenback C, et al: A phase II trial of CPT-11 in recurrent squamous carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol70:334-338, 1998[Medline]

27. Irvin WP, Price FV, Bailey H, et al: A phase II study of irinotecan (CPT-11) in patients with advanced squamous cell carcinoma of the cervix. Cancer82:328-333, 1998[Medline]

28. Brader KR, Morris M, Levenback C, et al: Chemotherapy for cervical carcinoma: Factors determining response and implications for clinical trial design. J Clin Oncol16:1879-1884, 1998[Abstract]

29. Kaern J, Trope C, Abeler V, et al: A phase II study of 5-fluorouracil/cisplatinum in recurrent cervical cancer. Acta Oncol29:25-28, 1990[Medline]

30. Rothenberg ML: CPT-11: An original spectrum of clinical activity. Semin Oncol23:21-26, 1996 (1 suppl 3)[Medline]

31. Vermorken JB, Zanetta G, De Oliviera CF, et al: Cisplatin-based combination chemotherapy (BEMP) versus single agent cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix (SCUCC): Mature data EORTC protocol 55863. Ann Oncol7:67, 1996 (suppl 5, abstr 318)

32. Kano Y, Suzuki K, Akutsu M, et al: Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer50:604-610, 1992[Medline]

33. Fushiki H, Hidaka T, Hori S, et al: Evaluation of a new anti-cancer drug regimen against uterine cervical cancer in nude mice [in Japanese]. Gan To Kagaku Ryoho24:1981-1985, 1997[Medline]

34. Sugiyama T, Noda K, Yakushiji M, et al: Multicentric phase II trial of irinotecan (CPT-11) and cisplatin as first line chemotherapy in recurrent or advanced cervical cancer: Japan CPT-11 study group trial. Proc Am Soc Clin Oncol17:352, 1998 (abstr 1360)

Submitted January 20, 1999; accepted May 28, 1999.

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