Journal of Clinical Oncology, Vol 15, 2040-2049, Copyright © 1997 by American Society of Clinical Oncology
Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups
H Bartelink, F Roelofsen, F Eschwege, P Rougier, JF Bosset, DG Gonzalez, D Peiffert, M van Glabbeke and M Pierart
Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Amsterdam, The Netherlands. hbart@nki.nl
PURPOSE: To investigate the potential gain of the concomitant use of
radiotherapy and chemotherapy in improving local control and reducing the
need for colostomy, a randomized phase III trial was performed in patients
with locally advanced anal cancer. MATERIALS AND METHODS: From 1987 to
1994, 110 patients were randomized between radiotherapy alone and a
combination of radiotherapy and chemotherapy. The patients had T3- 4NO-3 or
T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks,
with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20
or 15 Gy was given in case of partial or complete response, respectively.
Surgical resection as part of the primary treatment was performed if
possible in patients who had not responded 6 weeks after 45 Gy or with
residual palpable disease after the completion of treatment. Chemotherapy
was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous
infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15
mg/m2 administered on day 1. RESULTS: The addition of chemotherapy to
radiotherapy resulted in a significant increase in the complete remission
rate from 54% for radiotherapy alone to 80% for radiotherapy and
chemotherapy, and from 85% to 96%, respectively, if results are considered
after surgical resections. This led to a significant improvement of
locoregional control and colostomy- free interval (P = .02 and P = .002,
respectively), both in favor of the combined modality treatment. The
locoregional control rate improved by 18% at 5 years, while the
colostomy-free rate at that time increased by 32% by the addition of
chemotherapy to radiotherapy. No significant difference was found when
severe side effects were considered, although anal ulcers were more
frequently observed in the combined-treatment arm. The survival rate
remained similar in both treatment arms. Skin ulceration, nodal
involvement, and sex were the most important prognostic factors for both
local control and survival. These remained significant after multivariate
analysis. The improvement seen in local control by adding chemotherapy to
radiotherapy also remained significant after adjusting for prognostic
factors in the multivariate analysis. Event-free survival, defined as free
of locoregional progression, no colostomy, and no severe side effects or
death, showed significant improvement (P = .03) in favor of the
combined-treatment modality. The 5-year survival rate was 56% for the whole
patient group. CONCLUSION: The concomitant use of radiotherapy and
chemotherapy resulted in a significantly improved locoregional control rate
and a reduction of the need for colostomy in patients with locally advanced
anal cancer without a significant increase in late side effects.
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