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Originally published as JCO Early Release 10.1200/JCO.2006.09.4532 on May 14 2007 © 2007 American Society of Clinical Oncology.
Long-Term Follow-Up of a Randomized Trial Comparing Concurrent Single Agent Cisplatin, Cisplatin-Based Combination Chemotherapy, or Hydroxyurea During Pelvic Irradiation for Locally Advanced Cervical Cancer: A Gynecologic Oncology Group Study
From Case Western Reserve University and Cleveland Clinic Foundation, Cleveland, OH; Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY; Columbus Regional Hospital, Columbus, IN; University of Mississippi Medical Center, Jackson, MS; Wayne State University/Karmanos Cancer Institute, Detroit, MI; University of North Carolina, Chapel Hill, NC; and the Tacoma General Hospital, Tacoma, WA Address reprint requests to Peter G. Rose, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, A81, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: rosep{at}ccf.org
Purpose: We report the long-term survival and toxicity of a randomized phase III study comparing cisplatin alone with cisplatin, flurouracil, and hydroxyurea versus hydroxyurea concurrent with pelvic irradiation for patients with locally advanced cervical cancer with pathologically negative para-aortic nodes.
Patients and Methods: Comparisons of progression-free (PFS) and overall survival (OS) between treatment arms utilized Kaplan-Meier and log-rank statistics. Relative risk estimates adjusting for prognostic factors were determined using the Cox proportional hazards regression model. Pearson's Results: The analysis included 526 patients. The median follow-up among surviving patients was 106 months. Consistent with the original report, improvement in PFS and OS was evident for both cisplatin-containing arms compared with hydroxyurea (P < .001). Analogous results were seen for stage IIB and for stage III disease (each P < .025). The relative risk of progression of disease or death was 0.57 (95% CI, 0.43 to 0.75) with cisplatin and 0.51 (95% CI, 0.38 to 0.67) with cisplatin-based combination chemotherapy compared with hydroxyurea. Among 518 patients who received radiation, acute (grade 3 or 4) gastrointestinal or urologic toxicities occurred in 66 with cisplatin (19.1%) and 29 with hydroxyurea (16.8%). Delayed radiation toxicity occurred in six patients who received cisplatin (1.7%) and two who received hydroxyurea (1.2%; P = .680). Conclusion: Cisplatin-based chemotherapy during pelvic radiation therapy improves long-term PFS and OS among locally advanced cervical cancer patients collectively and for stage IIB and III disease, individually. There was no observed increase in late toxicity with cisplatin-based chemoradiotherapy.
Based on the consistent results of five randomized trials of concurrent cisplatin-based chemotherapy and pelvic radiation therapy for a variety of stages of cervical cancer, the National Cancer Institute convened a meeting to discuss these findings in October 1998.1-5 A clinical alert drafted at that time was subsequently released in February 1999 with the simultaneous expedited publication of three of these studies.2,3,5 Only one of the five studies (Gynecologic Oncology Group [GOG] protocol 85) had longer than 5-year follow-up,1 while the median follow-up of the other studies ranged from 35 (GOG 120) to 43 months (Radiation Therapy Oncology Group [RTOG] 9001).2-5 Although cisplatin chemotherapy was utilized in all of these studies, the drug regimens differed in cisplatin dose and schedule and in the use of additional agents including fluorouracil and hydroxyurea. In the three subsequent GOG trials that have been developed since the clinical alert was issued, once per week cisplatin has been utilized as the control regimen. The median follow-up with the weekly cisplatin regimen was the shortest among the five trials, with a median follow-up of 35 months in GOG 1203 and 36 months in GOG 123.5 The initial report of GOG 120 reported the outcome of all patients by treatment arm. However, the original report of the RTOG study 9001 reported a subset analysis for stage IB-II versus III-IV2 RTOG 9001 demonstrated statistical significance only for the stage IB-II subset, leading some to suggest that chemoradiotherapy therapy was not effective in more advanced disease stage.6 To address this concern, an update of RTOG 9001 was performed and recently published.7 This update of RTOG 9001 again demonstrated that due to the early stage of disease of most of the patients accrued to RTOG 9001, only a strong trend without statistical significance was observed in the patients with more advanced stage disease (stage III-IV). In addition, in the updated results of RTOG 9001, the late toxicity of concurrent chemotherapy and pelvic radiation was similar to the toxicity of extended-field radiation. These findings led us to evaluate the long-term results of GOG 120 in which a greater percentage of patients enrolled had III-IV disease. In addition, it allowed us to compare the long-term (delayed) toxicity of concurrent cisplatin-based chemotherapy and pelvic irradiation with hydroxyurea and pelvic irradiation. Previous randomized trials comparing hydroxyurea with misonidazole with pelvic irradiation therapy or misonidazole with pelvic irradiation versus irradiation alone have not demonstrated increased late toxicity with hydroxyurea and irradiation.8,9
The detailed methodology of the trial has been published previously.3 Briefly, patients with untreated, invasive squamous, adenosquamous, or adenocarcinoma of the cervix (confirmed by central pathologic review), stages IIB, III, and IVA, were entered into this study. A complete physical examination, pelvic examination performed under anesthesia, and chest radiograph were required to determine the clinical stage of the cervical cancer. In addition, patients were required to have undergone a specified extraperitoneal para-aortic lymphadenectomy.10 Patients with disease outside the pelvis, or those with para-aortic node metastasis or intraperitoneal disease were not eligible. Patients were required to have a GOG performance status of 0, 1, 2, or 3 normal hematologic, hepatic, and renal function (creatinine  2.0 mg/dL) and no history of other malignancy. All patients provided written informed consent consistent with institutional, state, and federal regulations before entry onto study.
Chemotherapy
Radiation Therapy The radiation therapy techniques and doses were strictly defined and identical for all regimens. Whole pelvic irradiation was delivered by anterior-posterior and posterior-anterior parallel ports or a four-field box technique utilizing x-ray energies of 4 MV or greater. Pelvic radiation therapy was administered in 1.7 Gy fractions with a total dose of 40.8 Gy or 51.0 Gy for patients with stage IIB or IIIB/IVA, respectively. The pelvic field extended from the upper margin of L5 to the midportion of the obturator foramen or the lowest level of disease with a 3-cm margin and laterally 1.5 to 2 cm beyond the lateral margins of the bony pelvic wall (at least 7 cm from the midline). For lateral fields, the anterior border was the pubic symphysis and the posterior border was the space between S2 and S3. The fields could be modified to include areas of known tumor. Modifications as necessary to include areas of known tumor were allowed. Intracavitary low-dose rate brachytherapy was to follow external radiation after a 1- to 3-week rest. If two intracavitary applications were to be used, the second was to be given within 2 weeks of the first implant. The brachytherapy dose was 40 Gy or 30 Gy for patients with stage IIB or IIIB/IVA, respectively. The planned dose to point A was 80.8 Gy for stage IIB patients and 81.0 Gy for III and IV patients. If intracavitary brachytherapy could not be delivered, the tumor was treated with additional external radiation therapy to a total pelvic dose of 61.2 Gy. Interstitial and high-dose rate brachytherapy was not utilized in this protocol. The total elapsed time for completion of external and intracavitary therapy was to be fewer than 10 weeks. Radiotherapy was withheld in the event of grade 3 or 4 leukopenia and up to a 1-week delay was also allowed for gastrointestinal or genitourinary radiation-related toxicity. A central review of dosimetry and external-beam verification films was performed by the Radiologic Physics Center (Houston, TX).
Statistical Methods
From April 1992 to April 1997, 575 patients were enrolled with a distribution of 192, 191, and 192 in the once per week cisplatin regimen (regimen I), the three-drug regimen (regimen II), and the hydroxyurea-only regimen (regimen III), respectively (Fig 1). Forty-nine patients (8.5%) were ineligible; 44 were ineligible because of deficiencies associated with the para-aortic nodal evaluation. Other exclusions included wrong stage (n = 2), positive para-aortic nodes (n = 1), wrong primary (n = 1), and incomplete pretreatment testing (n = 1), leaving 526 patients eligible for evaluation. Variations in baseline patient and disease characteristics among treatment regimens were not statistically significant. The median follow-up for surviving patients was 106 months with a maximum follow-up of 153.2 months.
PFS rates for the treatment arms of cisplatin, cisplatin, fluorouracil infusion and hydroxyurea, and hydroxyurea alone were 63%, 62%, and 42% at 30 months, 58%, 57%, and 35% at 60 months (5 year), and 46%, 43%, and 26% at 120 months (10 year), respectively. OS rates for the treatment arms of cisplatin, cisplatin, fluorouracil infusion and hydroxyurea, and hydroxyurea alone were 70%, 70%, and 53% at 30 months, 60%, 61%, and 40% at 60 months (5 year), and 53%, 53%, and 34% at 120 months (10 year), respectively. The relative risk of progression of disease or death was 0.57 (95% CI, 0.43 to 0.75) for cisplatin and 0.51 for cisplatin-based combination (95% CI, 0.38 to 0.67) chemotherapy as compared with hydroxyurea. OS by treatment arm is shown in Figure 2. There were 22 patients in whom PFS time was equivalent to survival time because they died without a documented recurrence. PFS and OS by stage were analyzed to evaluate the impact of concurrent cisplatin-based chemotherapy on stage IIB versus III disease (Figs 3 and 4). sFor both of these stages a significant benefit of cisplatin-based chemotherapy was seen in both PFS and OS (stage IIB P < .001 and P < .001, respectively, stage III P < .005 and P < .025, respectively). Table 3 presents relative risk (hazard ratio), 95% CIs, and P values for each stage-specific comparison.
Site of Recurrence Local progression was significantly less among patients in the group given radiotherapy combined with cisplatin therapy (22%; P = .014) and in the group given radiotherapy combined with cisplatin, fluorouracil, and hydroxyurea (21%; P = .009) than those in the group given radiotherapy combined with hydroxyurea (34%). Patients in the two cisplatin treated groups also had lower frequency of lung metastases (4% and 5% respectively, P < .025 for both comparisons) than patients treated with hydroxyurea alone (11%). Univariate and multivariate analyses were conducted adjusting for cervical cancer prognostic factors identified from prior GOG studies: disease stage, performance status, pelvic nodal status, age, and tumor size. In univariate analysis, concurrent cisplatin containing chemotherapy (P < .0001), disease stage (P < .0001), performance status (P = .0069), pelvic nodal status (P = .0724), and tumor size (P = .0618), were identified as the most important prognostic factors for PFS and OS. In a multivariate analysis only stage and treatment remain significant (P = .0113 and P = .0003), respectively, while tumor size approached statistical significance (P = .0532). Delayed or late toxicities are defined as occurring more than 60 days after the completion of therapy and are presented in Table 4. Adverse events as recorded reflect the maximum grade observed while on study. In all there were 77 gastrointestinal and 18 urologic events of maximum grade 3 or 4 occurring in 89 of 518 patients who received radiation. A comparison of these events (95 in total) between patients who received radiation plus cisplatin-based therapy versus those who received radiation and hydroxyurea alone, revealed no significant difference (P = .680). Eight of the events were assessed as late gastrointestinal/urologic toxicity attributed to radiation occurring in five patients (2.8%) treated with once per week cisplatin, one patient (0.6%) treated with cisplatin, fluorouracil infusion, and hydroxyurea, and two patients (1.1) treated with hydroxyurea alone. Correcting for the surviving population at risk, the percentage of late grade 3 or 4 gastrointestinal/urologic events were not significantly different across therapeutic regimens with frequencies of 4.7%, 0.9%, and 2.6%, respectively. The percentage of patients developing late grade 3 or 4 gastrointestinal/urologic adverse effects, was not statistically different for those receiving radiation with a cisplatin-based regimen (six of 215; 2.8%), and was compared with the noncisplatin regimen (two of 75; 2.6%).
Previous studies of locally advanced cancer have demonstrated that the 70% of patients with stage III and 83% of patients with stage II disease who recur will do so in 24 months after completion of radiation therapy.14 This fact, and the significant improvement in PFS and OS seen in all of the chemoradiotherapy trials, is the reason the National Cancer Institute elected to issue the clinical alert. However, as noted earlier, the lack of long-term follow-up has led some to question the validity of the data. Since the National Cancer Institute clinical alert in March 1999, a rapid acceptance of concurrent cisplatin-based chemoradiotherapy has been reported. In a patterns of care study, 63% of patients receiving radiation therapy for cervical cancer in 1999 were treated with concurrent cisplatin-based chemotherapy compared with 19%, 28%, and 26% in 1996, 1997, and 1998, respectively.15 However, despite this acceptance, concerns regarding the efficacy of therapy especially for advanced stage disease and the potential for increased acute and late toxicity persist. Therefore, the long-term follow-up of the patients in these trials is important to confirm the efficacy and evaluate late toxicity of concurrent cisplatin-based chemoradiotherapy. In the current update of GOG 120, a significant improvement in PFS and OS is seen for all patients who received cisplatin-based chemoradiotherapy compared with radiation with hydroxyurea. In addition, patients who received cisplatin-based chemoradiotherapy had an improvement in both local disease control and OS, suggesting local disease control decreases the risk of distant disease. Decrease in both local recurrence and distant recurrence was also reported in the RTOG 9001 trial. Furthermore, on subgroup analysis improvement in both PFS and OS was seen for stage IIB and III patient subgroups who received cisplatin-based chemoradation. While stage IIB and III subgroups have different survival rates, their hazard ratios are very similar. In comparison, the long-term follow-up of the RTOG 9001 trial demonstrated highly significant improvements in locoregional disease control, PFS, and OS for stage IB-IIB patients. However, for patients with more advanced stage disease IIIB-IVA, only PFS was improved (P = .05), while no statistical improvement in locoregional disease control or OS were noted. Because only 26.7% of the patients in the RTOG trial had advanced stage disease (IIIB-IVA), this lack of improvement may be the result of the small sample size of advanced stage patients. Similarly, utilizing fluorouracil as a radiation sensitizer, Thomas et al16 demonstrated improvements with chemoradiotherapy therapy only in a subset of patients with less extensive disease (IB and IIB with only unilateral parametrial involvement but not those with more advanced disease). The findings of the current GOG 120 update support the routine use of cisplatin-based chemoradiotherapy therapy in patients with advanced stage disease. Among stage III cervical cancer patients, 28% present with ureteral obstruction.17 In this patient population, efforts to maximize renal function by relieving ureteral obstruction is warranted as it allows the use of concurrent cisplatin-based chemoradiotherapy. In patients with persistently altered renal function concurrent chemoradiotherapy with non-nephrotoxic platinum analogs could be considered. The long-term analysis of this study demonstrates that there is a continued decrease in PFS and OS until 8 years of follow-up. As suggested by RTOG 9001 for these more advanced stage tumors, this may be due to better tumor responses locally that do not achieve a complete response or long-term locoregional control. While it was reported by all five chemoradiotherapy studies that the acute adverse effects, particularly hematologic and gastrointestinal toxicity, were increased with concurrent chemoradiotherapy, the relatively short follow-up prevented analysis of late complications. In this current analysis of GOG 120, the median time for late gastrointestinal and urologic complications occurred at 1.7 years (range, 0.2 to 7.9 years). While the absolute number of late toxic events appears to be increased with cisplatin-based chemoradiotherapy, when corrected for the number of long-term survivors, the overall incidence of late complications is similar, occurring in 2.8% of cisplatin-treated patients compared with 2.6% of patients treated with hydroxyurea. While the absolute number of events in the once per week cisplatin-treated patients appears higher in the three-drug cisplatin-based chemotherapy regimen, the absolute number of events is too few to implement a formal significance test. Furthermore, the more frequent delays in radiation therapy seen with the three-drug cisplatin-based arm may be responsible for this lower toxicity rate. In the updated results of RTOG 9001, late treatment-related complications were similar for patients who received concurrent chemotherapy and pelvic radiation or pelvic and extended-field radiation alone. Although this finding is encouraging, the difference in the volume of tissue irradiated in the two arms complicates this comparison. In addition, the authors stated that the overall cumulative incidence of major complications in patients who received concurrent chemotherapy and pelvic radiation was somewhat higher than has been reported in patients treated with pelvic radiation alone in the earlier RTOG trial 79-20. In conclusion, both acute and late complications of cisplatin-based chemotherapy concurrent with radiation therapy are likely increased. The increase in the absolute number of late complications is likely related to their increased survival. Collectively, this follow-up analysis continues to support the use of cisplatin-based concurrent chemotherapy with pelvic radiation therapy for locally advanced stage cervical cancer. The results reported further suggests no difference in delayed urologic toxicity attributed to radiation when cisplatin-based regimens were compared with the noncisplatin regimen.
The author(s) indicated no potential conflicts of interest.
Conception and design: Peter G. Rose, J. Tate Thigpen, Daniel Clarke-Pearson Provision of study materials or patients: Peter G. Rose, J. Tate Thigpen, Gunter Deppe Collection and assembly of data: Peter G. Rose, Edwin Watkins, Daniel Clarke-Pearson Data analysis and interpretation: Peter G. Rose, Shamshad Ali, Edwin Watkins, Daniel Clarke-Pearson Manuscript writing: Peter G. Rose, Shamshad Ali, Daniel Clarke-Pearson Final approval of manuscript: Peter G. Rose, Shamshad Ali, Edwin Watkins, J. Tate Thigpen, Gunter Deppe, Daniel Clarke-Pearson Other: Samuel Insalaco [pathology review]
The following Gynecologic Oncology Group member institutions participated in this study: University of Alabama at Birmingham, Oregon Health Sciences University, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, Emory University Clinic, University of Southern California at Los Angeles, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, University of Miami School of Medicine, Milton S. Hershey Medical Center, Georgetown University Hospital, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University School of Medicine, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke's Medical Center, SUNY Downstate Medical Center, University of Kentucky, Eastern Virginia Medical School, The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, State University of New York at Stony Brook, Eastern Pennsylvania GYN/ONC Center, P.C., Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Fox Chase Cancer Center, Medical University of South Carolina, Women's Cancer Center, University of Oklahoma, University of Virginia Health Sciences Center, University of Chicago, University of Arizona Health Science Center, Tacoma General Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, and The New York Hospital/Cornell Medical Center.
published online ahead of print at www.jco.org on May 14, 2007. Supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and to the Gynecologic Oncology Group Statistical and Data Center (CA 37517) and by Amgen. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Whitney CW, Sause W, Bundy BN, et al: A randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17:1339-1348, 1999 2. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high risk cervical cancer: A randomized Radiation Therapy Oncology Group clinical trial. N Engl J Med 340:1137-1143, 1999 3. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based chemoradiation improves progression free and overall survival in advanced cervical cancer: Results of a randomized Gynecologic Oncology Group study. N Engl J Med 340:1144-1153, 1999 4. Peters WA III, Liu PY, Barrett RJ, et al: Cisplatin and 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive in high-risk early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a phase III intergroup study. J Clin Oncol 18:1606-1613, 2000 5. Keys HM, Bundy BM, Stehman FB, et al: A comparison of once per week cisplatin during radiation therapy versus irradiation alone each followed by adjuvant hysterectomy in bulky stage IB cervical carcinoma: A randomized trial of the Gynecologic Oncology Group. N Engl J Med 340:1154-1161, 1999 6. Thomas GM: Concurrent chemotherapy and radiation for locally advanced cervical cancer: The new standard of care. Semin Radiat Oncol 10:44-50, 2000[CrossRef][Medline] 7. Eifel PJ, Winter K, Morris M, et al: Pelvic irradiation therapy with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer. J Clin Oncol 22:872-880, 2004 8. Leibel S, Bauer M, Wasserman T, et al: Radiotherapy with or without misonidazole for patients with stage IIIB or stage IVA squamous cell carcinoma of the uterine cervix: Preliminary report of a Radiation Therapy Oncology Group randomized trial. Int J Radiat Oncol Biol Phys 13:541-549, 1987[Medline] 9. Stehman FB, Bundy BN, Thomas G, et al: Hydroxyurea versus misonidazole with radiation in cervical carcinoma: Long-term follow-up of a Gynecologic Oncology Group trial. J Clin Oncol 11:1523-1528, 1993 10. Wiser EB, Bundy BN, Hoskins WJ, et al: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical cancer (a Gynecologic Oncology Group study). Gynecol Oncol 33:283-289, 1989[CrossRef][Medline] 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 12. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-220, 1972 13. Stehman FB, Bundy BN, DiSaia PJ, et al: Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67:2776-2785, 1991[CrossRef][Medline] 14. Perez CA, Camel HM, Walz BJ, et al: Radiation therapy alone in the treatment of carcinoma of the uterine cervix: A 20 year experience. Gynecol Oncol 27:127-140, 1987[CrossRef] 15. Eifel PJ, Moughan J, Erickson B, et al: Patterns of radiotherapy practice for patients with carcinoma of the uterine cervix: A patterns of care study. Int J Radiat Oncol Biol Phys 60:1144-1153, 2004[CrossRef][Medline] 16. Thomas G, Dembo A, Ackerman I, et al: A randomized trial of standard versus partially hyperfractionated radiation with or without concurrent 5-fluorouracil in locally advanced cervical cancer. Gynecol Oncol 69:137-145, 1988[CrossRef] 17. Chao KS, Leung WM, Grigsby PW, et al: The clinical implications of hydronephrosis and the level of ureteral obstruction in stage IIIB cervical cancer. Int J Radia Oncol Biol Phys 40:1095-1100, 1998[CrossRef][Medline] Submitted November 21, 2006; accepted April 4, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to assess differences in adverse events. 
