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© 2002 American Society for Clinical Oncology
Chemoradiation for Locally Advanced Cervical Cancer: Does It Help?Case Western Reserve University, Cleveland, OH; Gynecologic Oncology Group Statistical Office, Roswell Park Cancer Institute, Buffalo, NY THE NATIONAL CANCER Center released a clinical alert to practicing oncologists on February 23, 1999, based on significant improvement in both progression-free survival and overall survival when cisplatin-based chemotherapy was administered during radiation for various stages of cervical cancer.1-6 This clinical alert outlined the findings of the five clinical trials that had been completed and recommended ". . . strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer." These five randomized trials, involving approximately 1,800 women, demonstrated a 30% to 50% improvement in survival when cisplatin-based chemotherapy was administered concurrently with radiation therapy. Historically, chemotherapy given before or after radiation therapy for cervical cancer did not show improvement. In this issue, Pearcey et al7 report a National Cancer Institute of Canada (NCIC)–sponsored trial comparing cisplatin-based chemotherapy given concurrently with radiation versus radiation alone for patients with locally advanced cervical cancer. This represents the sixth randomized trial that uses cisplatin-based chemotherapy administered concurrently during radiation therapy for cervical cancer. In this trial, 253 patients treated at multiple institutions with stage IB (tumor size > 5 cm) to IVA squamous cervical cancer received radiation with weekly cisplatin at a dose of 40 mg/m2/wk or radiation therapy alone.7 Survival was not significantly different at 3 years (69% v 66%) or 5 years (62% v 58%) for chemotherapy and radiation or radiation alone, respectively. The strengths of the Canadian study were that it was a multicenter prospective randomized trial, it used appropriate doses of chemotherapy (cisplatin 40 mg/m2 delivered weekly), and the distribution of radiation therapy dose and schedule was similar between the two regimens. Are the results of this trial irreconcilable with the more positive results of the five previous trials? We gathered the evidence from all six trials for reduction in the risk of death with concurrent cisplatin-based chemotherapy and radiation therapy compared with their respective control groups. Figure 1 displays the reductions in risk and the 95% confidence intervals for the cisplatin-based chemoradiation treatment groups. Compared with the control group, the NCIC trial observed a 12% lower death rate for the chemoradiation group. Note the widest 95% confidence limit (-0.3,0.40) among the six trials, which does not exclude clinically important risk reductions of up to 39%. It is important to recognize that when pooling the results from these trials, including NCIC, the reduction in the risk estimate is 36%, which is within the NCIC 95% confidence limit. Consequently, the NCIC trial results may simply be a product of statistical variation. It may be instructive to realize that if one conducted six clinical trials that were identical in terms of patient eligibility, treatment regimens, and sample size goals (eg, 80% statistical power), there is a 74% chance that at least one of the trials will be negative when the experimental arm is better than the control by the designed difference.
We disagree with Pearcey et al,7 who suggest ". . . the addition of [cisplatin] to [radiotherapy] may only be effective when [radiotherapy] is protracted." The importance of total treatment time was identified as an important prognostic factor in radiation therapy for cervical cancer in the early 1990s.8,9 A total dose of 85 Gy to point A delivered in less than 8 weeks has been accepted as the optimal schedule.9 Two of the cisplatin-based chemoradiation trials delivered 81 Gy to point A, allowing up to 70 days for treatment.1,4 Both of these trials had median treatment times of 63 days. The total treatment times for each arm of these trials were nearly identical, suggesting the survival benefit seen was the result of the intervention, cisplatin-based chemoradiation, and not a difference in treatment time. We tested the relative risk estimates within the partitioned groups of those patients that received "optimal" versus "protracted" radiation therapy. Optimal radiation therapy was defined as having more than 85% of the prescribed dose without any substantial delay (median treatment time was 57 days; range, 39 to 65 days). In Gynecologic Oncology Group (GOG) Trial 120, patients given optimal radiation had a relative risk of death of 0.66 and 0.56 for the weekly cisplatin and three-drug cisplatin-containing combination, respectively. Similarly, in GOG 85, the relative risk of death for the cisplatin-containing regimen was 0.69 for the optimal radiation therapy subgroup. All three results demonstrate an important reduction in risk with the use of cisplatin-based chemotherapy. In both studies, the tests for differential benefit between optimal and protracted radiation subgroups were not even close to being significant (GOG 120, P = .77; GOG 85, P = .74). This suggests that although optimal radiation therapy is desirable, both optimal and protracted radiation have similar risk reductions with the addition of cisplatin-based chemotherapy. Lastly, a significant benefit to chemotherapy and radiation was seen in Radiation Therapy Oncology Group (RTOG) Trial 9001, which used a more optimal radiation schedule of 89 Gy in 58 days.2 The Canadian trial did not use surgical staging to identify and exclude patients with para-aortic nodal metastasis. In contrast, four of the five previously reported randomized studies used or required surgical staging, and patients with para-aortic nodal metastasis were not eligible.1-4 The only trial that did not use surgical staging studied patients with stage IB2 disease, in whom the likelihood of para-aortic nodal metastasis is only 6%.5,10 In contrast, para-aortic nodal metastasis occurs in 19% of stage IIB patients and 29% of stage IIIB patients.10 Computed tomography has demonstrated a sensitivity of only 34% for para-aortic nodal metastasis from cervical cancer.11 The potential for undiagnosed metastatic disease in the para-aortic nodes in the patient population reported by Pearcey et al7 is estimated to be 13%. Inclusion of these patients could have diluted the effect of chemoradiation. A major difference between the treatment arms in the Canadian trial was anemia, which was more common among the cisplatin-treated patients. The failure to correct this anemia in the chemoradiation therapy arm may have accounted for an up to 8% to 10% decrement in survival.12 In contrast, an analysis of the hemoglobin levels just before each chemotherapy administration in GOG 120 yielded very similar average hemoglobin levels at week 5 of therapy (weekly cisplatin regimen, 107 g/L; hydroxyurea regimen, 106 g/L). Figure 4 from the article by Pearcey et al7 indicates that approximately 53% of patients on the cisplatin plus radiotherapy regimen had decreases in their hemoglobin levels of 9 g/L or more. These results are greater than those of GOG 120, in which 43% of patients had a decrease of this magnitude. However, information regarding transfusion was not prospectively collected in these trials. Could the myelosuppressive effect of hydroxyurea, principally anemia, have resulted in a poorer outcome for the control arm of GOG 85 and GOG 120, thereby falsely increasing the effect of cisplatin-based chemoradiation? This adverse effect of hydroxyurea is unlikely, because a previous randomized trial of hydroxyurea versus misonidazole (which is not myelosuppressive) demonstrated improved long-term survival with hydroxyurea.13 In contrast, in a separate trial in which misonidazole with radiation was compared with radiation alone, no difference in outcome was noted.14 RTOG 9001 used extended-field radiation in their control arm, which is more myelosuppressive than pelvic radiation. However, this control regimen was based on a previous randomized trial that compared pelvic radiation versus pelvic and para-aortic radiation and demonstrated a 22% relative survival benefit to pelvic and para-aortic radiation.15 To evaluate the significance of anemia and the potential anemia protective effect of erythropoietin, the GOG plans to study radiation with weekly cisplatin with or without erythropoietin. Another possible explanation for the positive results of RTOG 9001 is the potential additive or synergistic effect of cisplatin and fluorouracil, which has not been specifically addressed in a randomized trial. Recently, the GOG compared radiation with concurrent weekly cisplatin versus radiation with continuous-infusion fluorouracil. This trial was closed based on the results of interim analysis, which showed no reasonable possibility of a superior outcome in the fluorouracil treatment group if it were to continue accrual. Prior studies have demonstrated an apparent improvement in local pelvic disease control.1-5 In the NCIC trial, a 6% difference in pelvic control (27% v 33%) was noted.7 This included one patient, randomized to chemotherapy and radiation, who refused all treatment. Despite including this patient, there is a 22% relative reduction in local recurrence with concurrent cisplatin chemotherapy and radiation. However, across all six studies, a decrease in pelvic recurrence is noted (Table 1). Collectively, this represents a 12.4% decrease of the pelvis being the site of first failure (odds ratio, 0.51; 95% confidence interval, 0.42 to 0.63). However, only the site of first failure was recorded in all six randomized studies, which does not exclude subsequent pelvic failure.
Collectively, the six trials continue to support improvement in local control, progression-free survival, and survival with concurrent cisplatin-based chemotherapy and radiation.1-5,7 Although the NCIC study alone fails to demonstrate significant differences in progression-free and overall survival, all outcomes slightly favored cisplatin chemoradiation.7 Despite the findings of this sixth trial, we agree with the authors, who conclude that ". . . the balance of evidence favors the use of combined-modality treatment for the types of patients studied in this trial." REFERENCES
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.
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
4.
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
5.
Keys HM, Bundy BM, Stehman FB, et al: A comparison of weekly 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. National Cancer Institute: NCI Clinical Announcement. Bethesda, MD, United States Department of Health and Human Services, Public Health Service, National Institutes of Health, February 1999
7.
Pearcey R, Brundage M, Drouin P, et al: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20: 966-972, 2002 8. Fyles A, Keane TJ, Barton M, et al: The effect of treatment duration in the local control of cervix cancer. Radiother Oncol 25: 273-279, 1992[CrossRef][Medline] 9. Lanciano RM, Pajak TF, Martz K, et al: The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: A patterns-of-care study. Int J Radiat Oncol Biol Phys 25: 391-397, 1993[Medline] 10. Perez CA, Kurman RJ, Stehman FB, et al: Uterine cervix, in Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology ( ed 1 ). Philadelphia, PA, Lippincott, 1992, p 594 11. Heller PB, Malfetano JH, Bundy BN, et al: Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix: Extended diagnostic evaluation for paraaortic node metastasis—A Gynecologic Oncology Group study. Gynecol Oncol 38: 425-430, 1990[CrossRef][Medline] 12. Grogan M, Thomas GM, Melamed I, et al: The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 86: 1528-1536, 1999[CrossRef][Medline]
13.
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 14. Grisby PW, Winter K, Wasserman TH, et al: Irradiation with or without misonidazole for patients with stage IIIB and IVA carcinoma of the cervix: Final results of RTOG 80-05 Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 44: 513-517, 1999[CrossRef][Medline] 15. Rotman M, Pajak TF, Choi K, et al: Prophylactic extended-field irradiation of para-aortic lymph node in stages IIB and bulky IB and IIA cervical carcinomas: Ten-year treatment results of RTOG 79-20. JAMA 274: 387-393, 1995[Abstract] This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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, Risk reduction; —, 95% confidence interval. Abbreviations: Cis, cisplatin; 5FU, fluorouracil; SWOG, Southwest Oncology Group; H, hydroxyurea.
