Correspondence
Treatment of High-Risk Cervical Cancer
N Engl J Med 1999; 341:695-697August 26, 1999
- Article
To the Editor:
In the April 15 issue, Morris et al.1 and Rose et al.2 reported the results of randomized clinical trials comparing radiotherapy and concurrent cisplatin-containing chemotherapy with radiotherapy alone or radiotherapy combined with hydroxyurea for the treatment of cervical cancer. The median durations of radiotherapy in these trials were 58 days and 63 days, respectively. The duration of treatment appeared to be independent of variations in or the absence of chemotherapy from the treatment regimen. In both trials, the intended dose of radiotherapy would optimally have been delivered within 50 days.
For cervical cancer, the rates of local control in the pelvis and survival at 5 to 10 years decline at a rate of about 1 percent per day of extended treatment time when the duration of radiotherapy is protracted beyond the ideal.3-6 Using data in the report by Rose et al., we approximated the distribution of the durations of treatment. On the basis of the duration of treatment for the patients in the 10th, 50th, and 90th percentiles (50, 63, and 80 days, respectively), we made conservative, liberal, and balanced estimates of treatment duration and estimated the loss in the rate of pelvic control after protraction of treatment for more than 50 days (Table 1Table 1
Estimated Loss in Pelvic Control Due to Treatment Protraction in the Trial Conducted by Rose et Al.).Protraction of treatment probably magnifies the apparent benefit of concurrent cisplatin therapy. The estimated potential loss in pelvic control due to protracted radiotherapy in these studies is similar to the apparent benefit of adding cisplatin-containing chemotherapy. Although concurrent cisplatin therapy conferred a substantial benefit in terms of local control and survival when radiotherapy was protracted, the magnitude of these benefits when radiotherapy is delivered within an optimal overall treatment period remains unclear.
6 ReferencesRobert G. Pearcey, M.B., B.S.
Islam G. Mohamed, M.D.
John Hanson, M.S.
Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada1
Morris M ,Eifel PJ ,Lu J , et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-1143
Full Text | Web of Science | Medline2
Rose PG ,Bundy BN ,Watkins EB , et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144-1153
Full Text | Web of Science | Medline3
Fyles A ,Keane TJ ,Barton M ,Simm J . The effect of treatment dura-tion in the local control of cervix cancer. Radiother Oncol 1992;25:273-279
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Girinsky T ,Rey A ,Roche B , et al. Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome. Int J Radiat Oncol Biol Phys 1993;27:1051-1056
CrossRef | Web of Science | Medline5
Perez CA ,Grigsby PW ,Castro-Vita H ,Lockett MA . Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275-1288
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Petereit DG ,Sarkaria JN ,Chappell R , et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301-1307
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To the Editor:
Rose and coauthors report that survival for patients who received radiation plus cisplatin or radiation plus cisplatin, fluorouracil, and hydroxyurea was significantly better than that for those who received hydroxyurea plus radiation. Such a finding may have been a self-fulfilling prophecy, since the study called for the patients to receive hydroxyurea only during the time they received radiation therapy.
In a prospective, double-blind, randomized study of hydroxyurea as compared with placebo, each given during radiation and for four weeks after radiation in patients with stage IIB (negative paraortic lymph nodes) cervical cancer, we reported a significant improvement in survival among patients who received hydroxyurea plus pelvic radiation as compared with those who received placebo plus pelvic radiation.1 Although any improvement in survival among patients with cervical cancer is welcome, the method of administration of hydroxyurea in the trial conducted by Rose et al. may not have settled the issue of whether cisplatin-based chemotherapy is significantly better than hydroxyurea. However, because of the current reports on cisplatin, this answer will probably never be known.
1 ReferencesM. Steven Piver, M.D.
Roswell Park Cancer Institute, Buffalo, NY 142631
Piver MS ,Barlow JJ ,Vongtama V ,Blumenson L . Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. Am J Obstet Gynecol 1983;147:803-808
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Pearcey and colleagues have raised a valid concern regarding total treatment time for women undergoing radiation therapy for advanced cervical cancer. We acknowledge that shorter total treatment time is associated with a more favorable outcome. Also critical to the outcome is the total dose of radiation delivered. In our study, the median duration of therapy was 58 days.1 The mean dose of radiation delivered was 89 Gy to point A (a reference location 2 cm lateral and 2 cm superior to the cervical os). No differences in total treatment time or total dose to point A were noted between the treatment groups.
A recent study of patterns of care in radiation therapy in the United States indicates that the median total dose to point A was 82.5 Gy and the median total duration of treatment was 63 days.2 For women with advanced lesions, additional therapy in the form of a pelvic boost is often necessary. This additional therapy increases the total treatment time. Our study was designed to provide more intensive therapy over a shorter period. With the regimen we used, we observed a 50 percent improvement in overall survival in the group that received chemotherapy with radiation, as compared with the radiation-therapy group. It is not likely that this difference would be overcome by further shortening the treatment time by another five or six days, if such a reduction were possible in this cohort of patients.
Delays in treatment are often preventable, and radiation oncologists should take steps to avoid unnecessary protraction of treatment and to improve patient compliance. The evidence in the literature strongly supports the use of chemotherapy in conjunction with radiation therapy in the treatment of advanced cervical cancer.
2 ReferencesMitchell Morris, M.D.
Patricia J. Eifel, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 770301
Morris M ,Eifel PJ ,Lu J , et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-1143
Full Text | Web of Science | Medline2
Eifel PJ ,Moughan J ,Owen J ,Katz A ,Mahon I ,Hanks GE . Patterns of radiotherapy practice for patients with squamous carcinoma of the uterine cervix: patterns of care study. Int J Radiat Oncol Biol Phys 1999;43:351-358
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Author/Editor Response
Dr. Piver suggests that continuation of hydroxyurea after the completion of radiation therapy may have been a more effective schedule than the one we used. However, there are no randomized trials comparing different schedules of hydroxyurea. The trial cited by Dr. Piver included only 40 patients.1 In a previous study by the Gynecologic Oncology Group comparing hydroxyurea given only during radiation therapy with radiation therapy alone, there was a significant improvement in the progression-free interval and in survival.2 This schedule of hydroxyurea has been studied for the past 28 years in trials conducted by the Gynecologic Oncology Group involving over 1300 patients.2-5 Two recent Gynecologic Oncology Group trials demonstrate that platinum-containing chemotherapy plus radiation is superior to radiation therapy plus hydroxyurea.4,5 The role of chemotherapy after radiation therapy has not been addressed in a randomized clinical trial. However, in a recently completed trial of concurrent chemotherapy and radiation in high-risk women after radical hysterectomy, there was no apparent difference in benefit with respect to survival among the women receiving radiation alone and those receiving an additional six weeks of chemotherapy after radiation therapy, although the costs were higher in the latter group.6 We agree with Dr. Piver that it is unlikely that hydroxyurea will again be compared with cisplatin-based regimens.
Dr. Pearcey suggests that a shorter treatment duration might explain the differences in survival with platinum-containing regimens. The importance of treatment duration to the efficacy of radiation therapy for cervical cancer has been demonstrated by retrospective studies but has not been confirmed by a prospective, randomized trial. Even if there is a benefit to shortening the treatment duration, this does not imply that the addition of cisplatin would be less effective. The assumption that there is an antagonistic interaction between radiation therapy and cisplatin is unreasonable. The median duration of treatment in our study was 9 weeks (63 days).5 The durations of treatment in the treatment groups were similar, suggesting that the survival benefit was due to the addition of cisplatin chemotherapy. In the study by Morris et al., a treatment time of less than 8 weeks was prescribed, and the actual median duration was 58 days.7 Again, the cisplatin chemotherapy plus radiation therapy was superior to radiation therapy alone.
7 ReferencesPeter G. Rose, M.D.
Case Western Reserve University, Cleveland, OH 44106Brian N. Bundy, Ph.D.
Gynecologic Oncology Group, Buffalo, NY 142631
Piver MS ,Barlow JJ ,Vongtama V ,Blumenson L . Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. Am J Obstet Gynecol 1983;147:803-808
Web of Science | Medline2
Hreshchyshyn MM ,Aron BS ,Boronow RC , et al. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys 1979;5:317-322
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Stehman F ,Bundy BM ,Keys H ,Currie JL ,Mortel R ,Creasman WT . A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix: a preliminary report of a Gynecologic Oncology Group study. Am J Obstet Gynecol 1988;159:87-94
Web of Science | Medline4
Whitney CW ,Sause W ,Bundy BN , et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339-1348
Web of Science | Medline5
Rose PG ,Bundy BN ,Watkins EB , et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144-1153
Full Text | Web of Science | Medline6
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. Gynecol Oncol 1999;72:443-443 abstract.
CrossRef | Medline7
Morris M ,Eifel PJ ,Lu J , et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-1143
Full Text | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Na Wang, Quan-Lin Guan, Kai Wang, Xin Zhou, Chen Gao, Han-Teng Yang, Tian-Gen Ni. (2011) Radiochemotherapy versus radiotherapy in locally advanced cervical cancer: a meta-analysis. Archives of Gynecology and Obstetrics 283:1, 103-108
CrossRef2
L. GOEDHALS, A.L. van WIYK, B.L. SMITH, S.J. FOURIE. (2006) Pemetrexed (AlimtaR, LY231514) demonstrates clinical activity in chemonaive patients with cervical cancer in a phase II single-agent trial. International Journal of Gynecological Cancer 16:3, 1172-1178
CrossRef3
H. Lukka, H. Hirte, A. Fyles, G. Thomas, L. Elit, M. Johnston, M. Fung Kee Fung, G. Browman. (2002) Concurrent Cisplatin-based Chemotherapy plus Radiotherapy for Cervical Cancer–a Meta-analysis. Clinical Oncology 14:3, 203-212
CrossRef
