- Email: [email protected]
Concurrent Cisplatin-based Chemotherapy plus Radiotherapy for Cervical Cancer: A Meta-analysis
82
CLINICAL ONCOLOGY
References 1 Hadden PW, Barry CJ. Herpetic encephalitis and acute retinal necrosis. N Engl J Med 2002;347:1932. 2 Picard FJ, Dekaban GA, Silva J, et al. Mollaret’s meningitis associated with herpes simplex type 2 infection. Neurology 1993; 43:1722–1777. 3 Skoldenberg B. Herpes simplex encephalitis. Scand J Infect Dis 1996;100(suppl):8–13. 4 Ganatra JB, Chandler D, Santos C, et al. Viral causes of acute retinal necrosis syndrome. Am J Ophthalmol 2000;129:166–172. 5 Perry JD, Girkin CA, Miller NR, et al. Herpes simplex encephalitis and bilateral retinal necrosis after craniotomy. Am J Ophthalmol 1998;126:456–460. doi:10.1016/j.clon.2003.08.004
Concurrent Cisplatin-based Chemotherapy plus Radiotherapy for Cervical Cancer: A Meta-analysis Sir – The review by Lukka et al. [1] was restricted to randomised studies of cisplatin-based chemoradiation, of which they identified eight studies based on the databases searched, as described in the accompanying editorial [2]. The Cochrane Group had carried out an earlier review, which identified 19 trials, of which 12 were cisplatinbased and examined survival, overall disease-free survival, recurrence and toxicity [3]. By restricting their literature searches to published randomised controlled trials in English language journals, and only searching ASCO 2000 proceedings, Lukka et al. have missed two published studies (Lira Puerto, 1990 and Chen, 1997), one abstract (Leborgne, 2000), and one unpublished study (Pras), quoted in the Cochrane review, which may have led to bias in their assessment of the evidence base for concurrent chemoradiation for cervix cancer. The main analysis of survival is largely based on the overall number of deaths ‘by the end of the study’. As many patients are still likely to be in follow-up, the studies are certainly not at an end. Also, using the overall number of deaths in each trial to calculate an odds ratio can be problematic. Not all trial publications report the overall number of deaths, and the length of follow-up varies considerably among those that do. Therefore, the calculated odds ratio for each trial is based on a different point in time. This may be appropriate if death ratios remain constant over time (the hazards are proportional) as the authors have assumed, but it is not possible to test this with the published data. Furthermore, no account is taken of censoring. The hazard ratio is the more appropriate summary statistic to use for time-to-event outcomes, such as survival, because it takes account of the whole survival experience and methods are available to estimate it from published data. The interpretation of their meta-analysis is flawed in a number of ways: two of their main conclusions relating to early stage, stated in the abstract to the paper, are drawn from subgroup analysis. The data in stage 1B tumours before surgery come solely from GOG 123, whereas the conclusion on the value of chemoradiation in high-risk patients after surgery comes from SWOG 8797 as reported by Peters et al. [4]. These are two different sets of circumstances and, as stated by the authors, the planned combined modalities of surgery and chemoradiation would not normally be recommended because of toxicity,
whereas adequate staging should minimise the proportion of patients at primary radical surgery found to have residual disease. The post-hoc analysis in the Cochrane review suggested a greater beneficial effect in Stage I and II patients, and this was supported in an earlier review by Thomas [5]. Rose [6] has reported a sub-group analysis based on unpublished data, which claims statistical benefit for both Stage II and III patients in one GOG trial. Clinicians will intuitively feel more comfortable with the increased risk of toxicity associated with chemoradiation in the earlier stage group, compared with the stage III or IV groups where co-morbidity may be important, and the incidence of para-aortic lymph-node involvement (an exclusion criterion in most of the published studies) is correspondingly higher. An alternative strategy subjected to meta-analysis only in preliminary form [7] based on five trials would be to give chemotherapy before surgery, and this is being compared with chemoradiation in the EORTC trial 55994 in stages IB2–IIB. The question raised by Symonds [2] of randomised trials addressing the role of erythropoeitin in combination with chemoradiation is under investigation in two co-operative group studies in Germany [8] and the U.S.A. (GOG 191). The rationale is sound: anaemia may contribute to resistance to chemoradiation, the biological hypothesis being that there is associated tumour hypoxia in anaemic patients; however, the control arms will be subject to incremental drift because of more aggressive transfusion policies. However, the most recent interim analysis of the German study [8] has shown a relapse-free benefit at 2 years approaching statistical significance 81% vs 70% (P=0.058). J. A. GREEN
Clatterbridge Center for Oncology Bebington, Wirral, U.K.
References 1 Lukka H, Hirte H, Fyles A, et al. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer: a meta-analysis. Clin Oncol 2002;14:203–212. 2 Symonds P. Chemoradiation: the new gold standard for nonsurgical treatment of cervical cancer. Clin Oncol 2002;14:201–202. 3 Green JA, Kirwan JM, Tierney JE, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001; 358:781–786. 4 Peters WA, Lin PY, Barrett RJ. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–1613. 5 Thomas G. Concurrent chemotherapy and radiation for locally advanced cervical cancer: the new standard of care. Semin Radiat Oncol 2000;10:44–50. 6 Rose PG. Chemoradiotherapy for cervical cancer. Eur J Cancer 2002;38:270–278. 7 Stewart L, Tierney J. Neoadjuvant chemotherapy followed by surgery for locally advanced cervical cancer: a meta-analysis using individual patient data from randomised controlled trials (RCTs). Proc ASCO 2002;21:207a. 8 Blohmer JU, Wurschmidt F, Petry G, et al. Sixth interim analysis of a prospective, randomised open and controlled AGO- and NOGGO-Intergroup study: sequential adjuvant chemoradiotherapy with vs without epoetin alfa for patients with high risk cervical cancer. Proc ASCO 2003;22:447a.
CLINICAL ONCOLOGY
References 1 Hadden PW, Barry CJ. Herpetic encephalitis and acute retinal necrosis. N Engl J Med 2002;347:1932. 2 Picard FJ, Dekaban GA, Silva J, et al. Mollaret’s meningitis associated with herpes simplex type 2 infection. Neurology 1993; 43:1722–1777. 3 Skoldenberg B. Herpes simplex encephalitis. Scand J Infect Dis 1996;100(suppl):8–13. 4 Ganatra JB, Chandler D, Santos C, et al. Viral causes of acute retinal necrosis syndrome. Am J Ophthalmol 2000;129:166–172. 5 Perry JD, Girkin CA, Miller NR, et al. Herpes simplex encephalitis and bilateral retinal necrosis after craniotomy. Am J Ophthalmol 1998;126:456–460. doi:10.1016/j.clon.2003.08.004
Concurrent Cisplatin-based Chemotherapy plus Radiotherapy for Cervical Cancer: A Meta-analysis Sir – The review by Lukka et al. [1] was restricted to randomised studies of cisplatin-based chemoradiation, of which they identified eight studies based on the databases searched, as described in the accompanying editorial [2]. The Cochrane Group had carried out an earlier review, which identified 19 trials, of which 12 were cisplatinbased and examined survival, overall disease-free survival, recurrence and toxicity [3]. By restricting their literature searches to published randomised controlled trials in English language journals, and only searching ASCO 2000 proceedings, Lukka et al. have missed two published studies (Lira Puerto, 1990 and Chen, 1997), one abstract (Leborgne, 2000), and one unpublished study (Pras), quoted in the Cochrane review, which may have led to bias in their assessment of the evidence base for concurrent chemoradiation for cervix cancer. The main analysis of survival is largely based on the overall number of deaths ‘by the end of the study’. As many patients are still likely to be in follow-up, the studies are certainly not at an end. Also, using the overall number of deaths in each trial to calculate an odds ratio can be problematic. Not all trial publications report the overall number of deaths, and the length of follow-up varies considerably among those that do. Therefore, the calculated odds ratio for each trial is based on a different point in time. This may be appropriate if death ratios remain constant over time (the hazards are proportional) as the authors have assumed, but it is not possible to test this with the published data. Furthermore, no account is taken of censoring. The hazard ratio is the more appropriate summary statistic to use for time-to-event outcomes, such as survival, because it takes account of the whole survival experience and methods are available to estimate it from published data. The interpretation of their meta-analysis is flawed in a number of ways: two of their main conclusions relating to early stage, stated in the abstract to the paper, are drawn from subgroup analysis. The data in stage 1B tumours before surgery come solely from GOG 123, whereas the conclusion on the value of chemoradiation in high-risk patients after surgery comes from SWOG 8797 as reported by Peters et al. [4]. These are two different sets of circumstances and, as stated by the authors, the planned combined modalities of surgery and chemoradiation would not normally be recommended because of toxicity,
whereas adequate staging should minimise the proportion of patients at primary radical surgery found to have residual disease. The post-hoc analysis in the Cochrane review suggested a greater beneficial effect in Stage I and II patients, and this was supported in an earlier review by Thomas [5]. Rose [6] has reported a sub-group analysis based on unpublished data, which claims statistical benefit for both Stage II and III patients in one GOG trial. Clinicians will intuitively feel more comfortable with the increased risk of toxicity associated with chemoradiation in the earlier stage group, compared with the stage III or IV groups where co-morbidity may be important, and the incidence of para-aortic lymph-node involvement (an exclusion criterion in most of the published studies) is correspondingly higher. An alternative strategy subjected to meta-analysis only in preliminary form [7] based on five trials would be to give chemotherapy before surgery, and this is being compared with chemoradiation in the EORTC trial 55994 in stages IB2–IIB. The question raised by Symonds [2] of randomised trials addressing the role of erythropoeitin in combination with chemoradiation is under investigation in two co-operative group studies in Germany [8] and the U.S.A. (GOG 191). The rationale is sound: anaemia may contribute to resistance to chemoradiation, the biological hypothesis being that there is associated tumour hypoxia in anaemic patients; however, the control arms will be subject to incremental drift because of more aggressive transfusion policies. However, the most recent interim analysis of the German study [8] has shown a relapse-free benefit at 2 years approaching statistical significance 81% vs 70% (P=0.058). J. A. GREEN
Clatterbridge Center for Oncology Bebington, Wirral, U.K.
References 1 Lukka H, Hirte H, Fyles A, et al. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer: a meta-analysis. Clin Oncol 2002;14:203–212. 2 Symonds P. Chemoradiation: the new gold standard for nonsurgical treatment of cervical cancer. Clin Oncol 2002;14:201–202. 3 Green JA, Kirwan JM, Tierney JE, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001; 358:781–786. 4 Peters WA, Lin PY, Barrett RJ. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–1613. 5 Thomas G. Concurrent chemotherapy and radiation for locally advanced cervical cancer: the new standard of care. Semin Radiat Oncol 2000;10:44–50. 6 Rose PG. Chemoradiotherapy for cervical cancer. Eur J Cancer 2002;38:270–278. 7 Stewart L, Tierney J. Neoadjuvant chemotherapy followed by surgery for locally advanced cervical cancer: a meta-analysis using individual patient data from randomised controlled trials (RCTs). Proc ASCO 2002;21:207a. 8 Blohmer JU, Wurschmidt F, Petry G, et al. Sixth interim analysis of a prospective, randomised open and controlled AGO- and NOGGO-Intergroup study: sequential adjuvant chemoradiotherapy with vs without epoetin alfa for patients with high risk cervical cancer. Proc ASCO 2003;22:447a.