The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer
Introduction
There are potential advantages in giving chemotherapy before radiotherapy in the treatment of locally advanced cervical cancer [1]. Both clinical studies and animal experiments have shown that radiation doses which will consistently eradicate small tumours will be effective in only a minority of larger lesions. However the maximum radiation dose that can be given to patients with carcinoma of the cervix is limited by the tolerance of surrounding organs such as the bladder or bowel. Even employing what we currently regarded as optimal external beam fractionation policies in combination with intracavity treatment, local control is seen in only approximately half of patients with advanced tumours. Attempts to increase pelvic radiation dosage have resulted in increased morbidity outweighing any increase in local control [2]. However, local control using conventional radiotherapy schedules could be increased if the tumour size were to be reduced by chemotherapy given before radiotherapy.
In a pilot study [1] the response rate following two pulses of cisplatin, vincristine and bleomycin combination chemotherapy was 53%. Patients then received full dose radical radiotherapy. The survival of chemotherapy responders was markedly superior to non-responders.
The actuarial survival at 24 months of responders to chemotherapy was 71% against 37% for non-responders. The responding patients had an estimated reduction in mortality of 36% (P=0.014, 95% confidence interval (CI) 15–81%).
These results demonstrated the feasibility of this approach and a multicentre randomised trial was designed. A 2-weekly schedule of methotrexate and cisplatin was chosen. Both agents are active against cervical cancer and are relatively non-myelosuppressive allowing chemotherapy to be given every 2 weeks [3]. Three cycles of chemotherapy were given over 28 days and radiotherapy was only delayed by 6 weeks. This short period of chemotherapy may have two advantages. The first is pragmatic, as the delay in beginning potentially curative radiotherapy is short. The second is more theoretical and speculative as the scheduling and dose intensity of cisplatin may be important in obtaining tumour shrinkage.
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Patients and methods
Patients in the trial had bulky stage IIb (tumour size >5 cm), stage III or stage IVa squamous or adenosquamous carcinoma of cervix. Performance status was normal or near normal (WHO performance status 0–2) and all were aged up to and including 70 years. Patients had to be fit for both chemotherapy and radiotherapy with adequate marrow reserves (white blood cell count (WBC)>3×109/l and platelets>100×109/l) and good renal function (glomerular filtration rates (GFR)>50 ml/min). The trial was
Results
215 patients were randomised into the study. 11 patients were judged to be ineligible when patient details were checked prior to analysis. The reasons for exclusion are listed in Table 1. Only entered eligible patients were considered for subsequent analysis. Although all but one of the excluded patients were in the radiotherapy only arm there was no suggestion of problems with the randomisation or that their exclusion led to a bias in the comparisons. The clinical and pathological
Discussion
Trials of neo-adjuvant chemotherapy have so far produced conflicting results. Survival was better in the radiotherapy control arm in two studies but the majority showed no significant differences between each arm. In contrast, three cycles of vincristine, bleomycin and cisplatin given at 10-day intervals has improved survival in patients with bulky stage Ib and stage IIIb tumours (see Table 8).
The most striking negative finding was seen in patients treated in the countries of the Pacific rim
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Cited by (27)
Systemic therapy in cervical cancer: 30 years in review
2019, Critical Reviews in Oncology/HematologyCitation Excerpt :Under this perspective, several studies were conducted during 80 s and 90 s examining the effect on NACT prior to radiotherapy that was considered that period the standard of care for locally advanced disease. In these studies cisplatin (Chiara et al., 1994), platinum based regimens (Leborgne et al., 1997; Souhami et al., 1991; Sundf et al., 1996; Symonds et al., 2000; Tattersall et al., 1995; Herod et al., 2000) or vinorelbine (Lacava et al., 1997) were used for NACT, but no survival benefit was demonstrated versus radiotherapy alone. Randomized studies, examining the role of NACT prior to definitive RT in cervical cancer are presented in Table 2.
Efficacy and Safety Evaluation of the Various Therapeutic Options in Locally Advanced Cervix Cancer: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials
2019, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :Thus, with 13 different interventions in the control and study groups, a maximum of 21 pairwise comparisons between the competing modalities was feasible. These included RT versus CTRT(wkly Pt) (n = 5),11-15 RT versus CTRT(3 wkly Pt) (n = 3),32-34 RT versus CTRT(non-Pt) (n = 2),16,38 RT versus CTRT(Pt+) (n = 4),19-22 RT versus RT + ACT (n = 1),38 RT versus CTRT + ACT (n = 1),38 CTRT(non-Pt) versus CTRT + ACT (n = 1),38 RT + ACT versus CTRT(non-Pt) (n = 1),38 RT versus NACT + RT (n = 10),1-10 RT versus NACT + RT + ACT (n = 1),40 RT versus RT + HypCS (n = 8),41-48 RT versus RT + Imm (n = 4),49-53 RT versus HTRT (n = 4),55-59 CTRT(wkly Pt) versus CTRT(non-Pt) (n = 2),17,18 CTRT(wkly Pt) versus CTRT(Pt+) (n = 8),23-30 CTRT(wkly Pt) versus CTRT + ACT (n = 1),31 RT + ACT versus CTRT + ACT (n = 2),38,39 CTRT(wkly Pt) versus HTRT (n = 1),60 CTRT(wkly Pt) versus HTCTRT (n = 1),61 CTRT(wkly Pt) versus RT + Imm (n = 1),54 and CTRT(wkly Pt) versus CTRT(3wkly Pt) (n = 3).35-37 A conventional pairwise meta-analysis was undertaken for these direct comparisons for LRC, OS, AM, and LM (Fig. E1; available online at https://doi.org/10.1016/j.ijrobp.2018.09.037).
Clinical Outcome for Chemoradiotherapy in Carcinoma of the Cervix
2009, Clinical OncologyCitation Excerpt :There are no data on the use of neoadjuvant chemotherapy before chemoradiation. The only data available are on the use of neoadjuvant chemotherapy before surgery or radiation alone [20]. A possible explanation for this may be the importance of overall treatment time in the treatment of cervical cancer.
Concomitant and Neoadjuvant Chemotherapy for Cervical Cancer
2008, Clinical OncologyEffects of different chemotherapy regimens on survival for advanced cervical cancer: Systematic review and meta-analysis
2007, Cancer Treatment ReviewsCitation Excerpt :A total of 3364 items were retrieved electronically and 90 articles were screened in full text for eligibility. After exclusions (Fig. 1), 64 articles7,8,19–80 on different randomized trials were eligible for the systematic review and one of them included two different estimates of survival from different trials (Table 1). Forty of the trials had been published in 1991 or later and 17 of them had been published in 2001–2005.
Invasive cervical cancer in Spain (1995). Survey of the Spanish Society of Obstetrics and Gynecology
2005, Progresos de Obstetricia y Ginecologia