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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3113-3119 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.170 Phase III Study of Cisplatin With or Without Paclitaxel in Stage IVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group StudyFrom the Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Psychiatry and Behavioral Science, Institute for Health Services Research and Policy Studies, Northwestern University; Center on Outcomes, Research and Education, Evanston Northwestern Healthcare, Evanston, IL; Department of Pathology and Obstetrics and Gynecology, University of Iowa, Iowa City, IA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Gynecology, Milton S. Hershey Medical Center/Pennsylvania State University School of Medicine, Hershey; Division of Gynecologic Oncology, Thomas Jefferson University Hospital, Philadelphia, PA; and Division of Gynecologic Oncology, Robert Wood Johnson Medical School at Camden, Camden, NJ Address reprint requests to David H. Moore, MD, Indiana University School of Medicine, 3535 Barnhill Dr, RT433, Indianapolis, IN 46202-5274; e-mail: dhmoore{at}uipui.edu
PURPOSE: To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Eligible patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. RESULTS: Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n= 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION: C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.
The prognosis is bleak for patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix that is no longer amenable to surgical resection or radiation therapy. Median survival for these patients is poor; fewer than 20% survive 1 year. The need for effective chemotherapy in this clinical setting is well recognized, and optimal treatment has yet to be defined. Systemic therapy for cervical cancer at this time may be considered experimental.1 For a number of years, cisplatin has been considered the most active drug for the treatment of cervical cancer, with initial response rates as high as 50%.2 More recent trials with larger numbers of patients have reported response rates in the 20% to 30% range. Striving to improve on these marginal results, a number of studies have been conducted in an attempt to identify other active agents to be used alone or in combination with cisplatin. The Gynecologic Oncology Group (GOG) conducted a phase II trial of two platinum analogs and noted response rates of only 15% and 11% for carboplatin and iproplatin, respectively.3 However, the GOG conducted a phase II study of mitolactol (dibromodulcitol), resulting in a 29% response rate.4 Ifosfamide has also been identified as an active agent for squamous cell carcinoma of the cervix, with response rates of 16% to 40%.5-7 After subsequent feasibility studies of these agents in combination with cisplatin, the GOG conducted a randomized phase III trial of cisplatin versus cisplatin plus dibromodulcitol versus cisplatin plus ifosfamide. Compared with cisplatin alone, cisplatin plus ifosfamide had a significantly higher response rate (33% v 19%) and progression-free survival (PFS; 4.6 v 3.2 months), with no significant difference in survival. Furthermore, adverse side effects such as leukopenia, nephrotoxicity, and central and peripheral neurotoxicity were substantially increased in the ifosfamide-containing arm.8 Paclitaxel is a diterpenoid compound extracted from the bark of the Pacific yew (Taxus brevifolia). Its cytotoxicity is believed to be exerted via stabilization of tubulin polymer bundles, thus interfering with microtubular assembly and cell replication. Clinical research with paclitaxel was difficult until initial supply problems were resolved. It has broad activity against a number of solid tumors, including cancers of the ovary, breast, and endometrium. The GOG reported a 17% response rate using single-agent paclitaxel for advanced squamous cell carcinoma of the cervix.9 The combination of cisplatin plus paclitaxel (C + P) has been used for the treatment of cervical carcinoma and in phase II trials yielded objective response rates of 46%.10,11 The GOG initiated this randomized phase III trial of cisplatin versus C+P to determine whether the combination arm improved the response rate, PFS, or survival in patients with advanced squamous cell carcinoma of the cervix compared with treatment with cisplatin alone. Secondary objectives of this study included a comparison of the treatment arms with respect to treatment-related toxicity, health-related quality of life (QOL), and pain during the chemotherapy treatment period.
Patients Patients were accrued from August 1997 to March 1999 at GOG member institutions and their affiliates. The protocol was approved by respective institutional review boards, and patients provided written informed consent consistent with institutional, state, and federal regulations before study entry.
All patients had squamous cell carcinoma of the cervix confirmed by GOG central Pathology Committee review. Patients were eligible if they had International Federation of Gynecology and Obstetrics stage IVB, recurrent, or persistent disease that was not amenable to curative treatment with surgery or radiation therapy. Patients were required to have bidimensional tumor measurable by physical examination, radiography, computed tomography (CT), or magnetic resonance imaging (MRI). Measurable disease by CT or MRI was accepted without biopsy confirmation in the appropriate clinical setting if the lesion measured 3 cm or more and was well defined. Smaller lesions required pathologic or cytologic confirmation. Eligible patients also had adequate bone marrow function, absolute neutrophil count greater than 1,500/mL, platelets Single-agent cisplatin was administered at an intravenous (IV) dose of 50 mg/m2 at the rate of 1 mg/min. Patients randomly assigned to the combination arm (C+P) received paclitaxel at an IV dose of 135 mg/m2 as a 24-hour infusion followed immediately by cisplatin at a dose of 50 mg/m2. Patients who received paclitaxel were premedicated with dexamethasone, diphenhydramine, and an H2 receptor antagonist (eg, cimetidine or ranitidine). A prophylactic antiemetic regimen based on ondansetron or granisetron was administered to all patients, along with adequate IV hydration and electrolyte replacement. Treatment cycles were repeated at 21-day intervals for a total of six cycles unless disease progression or toxicity prohibited further therapy. Patients who continued to respond to treatment were permitted to continue on study beyond six treatment courses with the consent of the study chair. Cisplatin dose level reductions to 37.5 mg/m2 (level 1) or 25 mg/m2 (level 2) were prescribed for specific adverse effects. There were no cisplatin dose modifications for hematologic toxicity or prior radiation therapy. A one-dose-level reduction was required for grade 4 nausea and vomiting, and a two-dose-level reduction was required for grade 2 neurotoxicity (peripheral neuropathy or ototoxicity). Cisplatin was discontinued in the event of grade 3 to 4 neurotoxicity. A persistent elevation of serum creatinine to greater than 2.0 mg/dL required withholding treatment. If this creatinine elevation persisted for more than 6 weeks after a previous dose, then further treatment with cisplatin was discontinued. Paclitaxel dose level reductions to 110 mg/m2 (level 1) or 90 mg/m2 (level 2) were prescribed for specific adverse effects. A one-dose-level reduction was required for grade 3 to 4 neutropenic fever or grade 4 thrombocytopenia, and a two-dose-level reduction was required for grade 2 peripheral neuropathy. Treatment with paclitaxel was discontinued for grade 3 to 4 peripheral neuropathy or hepatotoxicity.
Patients who were hospitalized for fever with either grade 3 or 4 neutropenia were permitted treatment with granulocyte colony-stimulating factor 5 mg/kg/d during the episode. In addition to a one-dose-level reduction of paclitaxel with the next treatment course, it was suggested that patients who experienced febrile neutropenia receive prophylactic granulocyte colony-stimulating factor 5 mg/kg/d subcutaneously, starting 24 to 48 hours after the completion of the subsequent chemotherapy course and continuing until the WBC is The pretreatment clinical evaluation was repeated before each treatment cycle with the exception of radiography or CT/MRI imaging, which were repeated at least every other treatment cycle. Treatment was continued until disease progression or adverse effects precluded further therapy. Response to treatment, in terms of the best response achieved in a given patient, was assessed using standard clinical criteria. Complete response was defined as disappearance of all gross evidence of disease for at least 4 weeks. Partial response was defined as a greater than 50% reduction in the product of perpendicular diameters obtained from measurement of each lesion, sustained for at least 4 weeks. Increasing disease was defined as a greater than 50% increase in the product of perpendicular diameters of any lesion documented within 2 months of study entry or the appearance of any new lesion within 8 weeks of study entry. Stable disease was any condition not meeting any of the above three criteria. Survival was measured as observed length of life from protocol entry to death or (for living patients) date of last contact. PFS was measured from the date of protocol entry to first progression or death or to date of last contact for patients who are alive and progression-free. QOL assessments were obtained at baseline and at each successive cycle of chemotherapy, for a total of four assessments. The self-reporting instruments included the Functional Assessment of Cancer Therapy (FACT-G), a cervix cancer–specific subscale (FACT-Cx), a neurotoxicity subscale, and the Brief Pain Inventory (BPI).12 The FACT-G version 3 is a 29-item QOL measure that was developed and validated with cancer patients and designed for clinical trials13 and includes five subscales (physical well-being, social/family well-being, relationship with doctor, emotional well-being, and functional well-being). Each scale produces a separate score that can be summed into one total QOL score. The FACT-Cx consists of 15 items developed by experts and patients with cervical cancer. In addition, six items measuring neurotoxicity were included to address potential side effects that could result from paclitaxel and/or cisplatin chemotherapy, as well as the 14-item BPI designed to assess pain in patients with cancer and other diseases.14 The BPI has demonstrated reliability and validity across cultures and languages and has been used to study the effectiveness of pain treatment by measuring pain intensity (sensory dimension, six items) and pain interference in the patient's life (reactive dimension, seven items) and includes one medication question. Of primary clinical interest were those subscale items (FACT physical well-being, family well-being, and Cx subscale) that we identified as having particular relevance to cervical cancer treatment. These we defined as the Treatment Outcome Index. Patients were classified as either QOL completers or drop-outs. Completers were defined as patients who completed the questionnaire at the fourth time point, and drop-outs were those who did not; this was without regard to their completion history for the previous three assessments. The time course, or trajectory, of QOL was described by the mean scores among completers and drop-outs at each assessment point by treatment arm. Detailed QOL results beyond the scope of this article will be reported elsewhere.
Statistical Considerations
A total of 280 patients were enrolled in the study; 16 patients (6%; eight assigned to each treatment arm) were later declared ineligible for the following reasons: wrong cell type (n = 7), inadequate pathology materials (n = 8), and wrong stage (n = 1). After randomization, 134 patients were to receive cisplatin alone, and 130 patients were to receive C+P. Both groups were well matched with respect to age, ethnicity, performance status, tumor grade, site of disease, and median number of treatment cycles received on the current study (Table 1). Among the 264 eligible patients, five patients never received protocol chemotherapy but were included in the intent-to-treat analysis.
Overall, 71 women received chemotherapy plus radiation as primary treatment for cervical carcinoma, including 40 (30%) of 134 patients randomly assigned to receive cisplatin and 31 (24%) of 130 patients randomly assigned to receive C+P. It is interesting to note that cisplatin represents only one of four chemotherapeutic agents (cisplatin, fluorouracil, hydroxyurea, and navelbine) used alone or in combination as a radiation sensitizer. There was also no difference in median time from diagnosis to study entry, with 434 days for the cisplatin-alone arm and 436 days for the C+P arm. Objective responses were documented in 19% (6% complete responses plus 13% partial responses) of patients receiving cisplatin alone versus 36% (15% complete responses plus 21% partial responses) of patients receiving C+P (P = .002; Table 2). Apparent differences between the two arms in the prior use of chemoradiotherapy are not significant. Comparing patients who had received versus those who had not received prior chemoradiotherapy, response rates were two (5%) of 40 patients versus 24 (26%) of 94 patients, respectively, in the cisplatin arm, and 10 (32%) of 31 patients versus 37 (37%) of 99 patients, respectively, in the C+P arm.
A subgroup analysis of PFS and survival in patients who did not receive prior chemoradiotherapy indicates that median PFS was 3.0 months for the cisplatin arm versus 4.9 months for the C+P arm (P < .02). No survival difference was noted; median survival for the cisplatin arm was 8.9 months versus 9.9 months for the C+P arm. There were 118 patients who had recurrent or persistent cervical cancer limited to the pelvis and 146 patients with distant disease. Among the 118 patients with pelvic disease, 66 received cisplatin only and 52 received C+P. Objective responses occurred in 14 (21%) of 66 patients treated with cisplatin alone and in 17 (33%) of 52 patients treated with C+P. Among the 146 patients with distant disease, 68 received cisplatin alone and 78 received C+P. Objective responses occurred in 12 (18%) of 68 patients treated with cisplatin and in 30 (38%) of 78 patients treated with C+P. The median PFS for patients receiving cisplatin alone versus C+P was 2.8 and 4.8 months, respectively (P < .001; Fig 1). There was no difference in median survival for patients receiving cisplatin alone versus C+P (8.8 months and 9.7 months, respectively; Fig 2). The most common toxicity in both groups was myelosuppression, with grade 3 to 4 anemia and neutropenia more common among patients receiving combination therapy (Table 3). Considerable nausea and vomiting occurred in 28 patients, with no difference between the groups.
The submission of QOL information progressively declined during the treatment period (Table 4). Overall, 60% of patients were completers of the QOL part of the study; namely, patients who were alive and who completed questionnaires at the fourth time point. Comparing scores for drop-outs with those for completers, the former had worsening QOL scores (Fig 3). Regardless of assigned treatment, Treatment Outcome Index and BPI were stable among completers and worsened among drop-outs.
Notably, among those who dropped out of the QOL portion of the study after completing at least one questionnaire, there was a disproportionate number of drop-outs among patients randomly allocated to receive cisplatin alone (50 of 133 patients) versus C+P (33 of 128 patients; P < .05). However, among completers or drop-outs, there were no significant differences between treatment arms for any QOL subscale or summary scores. Data were not missing at random. Patients who completed the fourth QOL assessment were almost exclusively those who achieved a better clinical response, and on average, they reported stable or slightly improving QOL over time. By contrast, a large proportion (> 30%) of patients who failed to complete the final assessment were nonresponders to chemotherapy and reported a worsening QOL over time. Although the C+P arm included a higher proportion of responders than the cisplatin-only arm, application of the Pattern Mixture Model17 did not result in a statistically significant difference in overall QOL between the two. We found no evidence that patients receiving the combination arm experienced worse QOL, and they did have a higher response rate. QOL was measured relatively early in the treatment course. Thus the results suggest a modest but nonsignificant overall QOL benefit, as carried by a better objective rate of response to therapy with the C+P arm. Conversely, we found no evidence that the higher response rate was achieved at the expense of a detriment to QOL with the combination arm.
Median survival for patients with advanced or recurrent cervical carcinoma who cannot be treated with surgery or radiation therapy is poor, and fewer than 20% of these patients survive 1 year. Despite numerous clinical trials, there exists no widely acclaimed chemotherapeutic standard. Many factors complicate the administration of conventional chemotherapeutic agents in this patient population, including the following. First, the majority of patients who experience relapse will have received prior radiation therapy, limiting bone marrow function. Second, adequate drug distribution may be limited for recurrences in previously irradiated tissues. Third, some patients will have ureteral obstruction leading to renal dysfunction, restricting or precluding the use of drugs such as cisplatin. Fourth, approximately 80% of patients will have squamous cell carcinomas for whom chemotherapy responses are usually few and brief.18,19 Cisplatin is the most active and widely used drug in the treatment of squamous cell carcinoma of the cervix. Dose-intensity has not been associated with improvements in the complete response rate, PFS, or survival.20 There seems to be lower toxicity with prolonged infusion.21 The impact of single-agent cisplatin chemotherapy on overall survival is negligible. Other drugs shown to have considerable activity for squamous cell carcinoma of the cervix are the camptothecin derivatives irinotecan and topotecan. In a phase II study, 24% of patients with advanced or recurrent cervical cancer responded to irinotecan. Approximately two thirds of the patients in this trial had previously received chemotherapy, and 78% had previously received radiation therapy.22 A phase II trial of topotecan in a similar patient population resulted in an 18% response rate.23 Other drugs with promising activity include vinorelbine, which produced an 18% response rate as a single agent and a 43% objective response rate in combination with cisplatin.24,25 Results from phase II trials cannot be used to ascertain the efficacy of systemic chemotherapy in the treatment of cervical carcinoma. Most reported studies involve small numbers of selected patients, lack control groups, and, in the case of combination regimens, often incorporate agents with previously recognized activity. In GOG Protocol 110, a prospective study, 454 women with advanced or metastatic squamous cell carcinoma of the cervix were randomly assigned to receive one of three treatments: cisplatin alone (50 mg/m2), cisplatin (50 mg/m2) plus mitolactol (180 mg/m2 orally four times daily for 5 days), or cisplatin (50 mg/m2) plus ifosfamide (5.0 g/m2 over 24 hours) with mesna. Although the response rate for cisplatin/ifosfamide (31%) was greater than that of cisplatin alone (18%) and median duration of response was also greater (10 months v 5.5 months), there was no difference in overall survival between combination therapy and cisplatin alone (8.3 months and 8 months, respectively), and peripheral and central neurotoxicities were increased for patients receiving combination therapy. This is the first randomized controlled trial of palliative chemotherapy in cervical carcinoma to obtain QOL measurements in addition to traditional clinical outcomes measures (response rate, PFS, survival). Because median survival in this patient population is poor, it is imperative that palliative chemotherapy does not severely compromise short-term QOL. The overall objective response rates (36% and 19%) and complete response rates (15% and 6%) were significantly better for patients receiving C+P versus cisplatin alone, respectively. Although it is disappointing that no significant improvement in QOL scores were seen on the C+P arm, the converse is that the combination therapy did not compromise QOL through greater toxicity. Furthermore, the higher clinical response rate was correlated with completion of the QOL component of the study, which in turn was correlated with stable rather than deteriorating QOL. There are several plausible theories to explain this observation. In the protocol design, QOL assessments were to be obtained at each of the first four chemotherapy cycles. Anticipating that the majority of patients in both arms would not respond to palliative treatment and that survival for all patients would be brief, QOL questionnaires were viewed as important patient-reported data to complement the collection of standard toxicity data by health care providers. Assessments were limited to time points when most patients would still be receiving active treatment and thus be experiencing treatment-related toxicity. This strategy may have minimized the potential to detect any immediate treatment-related benefits because of the overriding presence of reversible acute adverse effects from combination chemotherapy. Although the objective response rate was almost doubled (and the complete response rate was more than doubled) by the addition of paclitaxel to cisplatin, it is interesting that there was no difference between the two arms in the median number of chemotherapy cycles administered. Both arms prescribed, in the absence of increasing disease or severe toxicity, the administration of six treatment cycles. Few patients failed to complete the prescribed six cycles of chemotherapy because of severe adverse effects. In a study of non–small-cell lung cancer, although baseline QOL data were completed by 94% of patients, this rate of compliance decreased to 60% by the 12-week follow-up period.26 Investigators should develop strategies to locate these patients and obtain QOL data, although to some extent, lack of QOL data is an inevitable but informative reflection of worsening clinical or functional condition. It seems the combination of C+P is superior to cisplatin alone with respect to objective response rate, PFS, and sustained QOL, with no improvement in overall survival, in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. This combination should be compared with alternative chemotherapy regimens in future phase III trials of palliative chemotherapy in cervical carcinoma. Furthermore, the comparative assessment of health-related QOL should be integral to all prospective trials in this patient population.
The appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adober Acrobat Readerr) version. Member institutions participating in this study are as follows: University of Alabama at Birmingham, Duke University Medical Center, The Milton S. Hershey School of Medicine of the Pennsylvania State University, Rush-Presbyterian–St Lukes Medical Center, Indiana University School of Medicine, University of Iowa Hospitals and Clinics, University of California Irvine Medical Center, University of Kentucky, University of Massachusetts Medical Center, University of Texas M.D. Anderson Cancer Center, University of Minnesota Medical School, University of Mississippi Medical Center, University of North Carolina School of Medicine, University of Oklahoma Health Sciences Center, Eastern Pennsylvania Hospital, Hospital of the University of Pennsylvania, Medical University of South Carolina, State University of New York at Stony Brook, Tacoma General Hospital, Abington Memorial Hospital, University of Texas Southwestern Medical Center, Wake Forest University School of Medicine, Tufts New England Medical Center, University of California Medical Center at Los Angeles, University of Virginia Health Science Center, Walter Reed Army Medical Center, Wayne State University School of Medicine, University of Washington Medical Center, Washington University School of Medicine, Cooper Hospital/University of Medicine and Dentistry of New Jersey, Columbus Cancer Council, Women's Cancer Center, University of Chicago, Thomas Jefferson University Hospital, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, and Carolina Gynecologic Oncology.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: David H. Moore, Aventis, Lilly Oncology.
Supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (grant No. CA 27469) and the Gynecologic Oncology Group Statistical and Data Cancer (grant No. CA 37517). Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Omura GA: Current status of chemotherapy for cancer of the cervix. Oncology 6:27-32, 1992 2. Thigpen JT, Shingleton H, Homesley H, et al: Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: A phase II trial of the Gynecologic Oncology Group. Cancer 48:899-903, 1981[CrossRef][Medline] 3. McGuire WP, Arseneau JC, Blessing JA, et al: A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: A Gynecologic Oncology Group study. J Clin Oncol 7:1462-1468, 1989[Abstract] 4. Stehman FB, Blessing JA, McGehee R, et al: A phase II evaluation of mitolactol in carcinoma of the cervix. J Clin Oncol 7:1892-1895, 1989[Abstract] 5. Coleman RE, Harper PG, Gallagher C, et al: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 18:280-283, 1986[Medline] 6. Meanwell CA, Mould JJ, Blackledge G, et al: Phase II study of ifosfamide in cervical cancer. Cancer Treat Rep 70:727-730, 1986[Medline] 7. Sutton GP, Blessing JA, McGuire WP, et al: Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: A Gynecologic Oncology Group study. Am J Obstet Gynecol 168:805-807, 1993[Medline]
8. Omura GA, Blessing JA, Vaccarello L, et al: A randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 15:165-171, 1997
9. McGuire WP, Blessing JA, Moore DH, et al: Paclitaxel has moderate activity in squamous cervix cancer: A Gynecologic Oncology Group study. J Clin Oncol 14:792-795, 1996
10. Papadimitriou CA, Sarris K, Moulopoulos LA, et al: Phase II trial of paclitaxel and cisplatin in metastatic and recurrent carcinoma of the uterine cervix. J Clin Oncol 17:761-766, 1999
11. Rose PG, Blessing JA, Gershenson DM, et al: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 17:2676-2680, 1999 12. Cella DF: Manual for the Functional Assessment of Cancer Therapy (FACT) Measurement System (Version 3). Chicago, IL, Rush Cancer Center, 1994
13. Cella DF, Tulsky DS, Gray G, et al: The functional assessment of cancer therapy scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993 14. Cleeland CS: Pain assessment in cancer, in Osoba D (ed): Effect of Cancer on Quality of Life. Boston, MA, CRC Press, 1991 15. Casagrande JT, Pike MC, Smith PG: An improved approximate formula for calculating sample size for comparing two binomial distributions. Biometrics 34:483-486, 1978[CrossRef][Medline] 16. Rubinstein LV, Gail MH, Santner TJ: Planning the duration of a comparative clinical trial with loss to follow-up and a period of continued observation. J Chron Dis 34:469-479, 1981[CrossRef][Medline] 17. Hedeker D, Gibbons RD: Application of random-effects pattern-mixture models for missing data in longitudinal studies. Psychol Methods 2:64-78, 1997 18. Thigpen T, Vance R, Khansur T, et al: The role of ifosfamide and systemic therapy in the management of carcinoma of the cervix. Semin Oncol 23:56-64, 1996 (suppl) 19. Brader KR, Morris M, Levenback C, et al: Chemotherapy for cervical carcinoma: Factors determining response and implications for clinical trial design. J Clin Oncol 16:1879-1884, 1998[Abstract]
20. Bonomi P, Blessing J, Stehman FB, et al: Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 3:1079-1085, 1985 21. Thigpen JT, Blessing JA, DiSaia PJ, et al: A randomized comparison of rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: A Gynecologic Oncology Group study. Gynecol Oncol 32:198-202, 1989[CrossRef][Medline] 22. Kavanagh JJ, Kudelka AP, Edwards CE, et al: CPT-11 (Irinotecan): Phase II study in refractory squamous cell carcinoma of the cervix. Proc Am Assoc Cancer Res 35:234, 1994 (abstr 1397) 23. Noda K, Sasaki H, Yamamoto K, et al: Phase II trial of topotecan for cervical cancer of the uterus. Proc Am Soc Clin Oncol 15:280, 1996 (abstr 754) 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 Oncol 16:1094-1098, 1998[Abstract]
25. Pignata S, Silvestro G, Ferrari E, et al: Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix. J Clin Oncol 17:756-760, 1999
26. Bonomi P, Kim KM, Fairclough D, et al: Comparison of survival and quality of life in advanced non–small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18:623-631, 2000 Submitted April 24, 2003; accepted April 29, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
100,000/mL, adequate renal (serum creatinine 
2.0 mg/dL) and liver function (bilirubin 
), completers receiving CisPt plus paclitaxel (CisPt + Taxol); (
), drop-outs receiving CisPt alone; (
), drop-outs receiving CisPt + Taxol; (——), completers; (- - -), drop-outs; CTx, chemotherapy.
