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Background: This trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications.Patients and methods: Patients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 Â 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin).Results: Patients (N ¼ 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70-1.15; P ¼ 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75-1.19; P ¼ 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR ¼ 1.08, 95% CI 0.70-1.23, P ¼ 0.60, 35% versus 32% and HR ¼ 1.10, 95% CI 0.68-1.23, P ¼ 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P ¼ 0.66), grade 3þ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively. Conclusion:The superiority of preoperative short-course/CCT over chemoradiation was not demonstrated.

It has been suggested based on familial data that Nijmegen breakage syndrome (NBS) heterozygotes have an increased risk of malignant tumors. We found 15 carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of the NBS1 gene among 1,289 consecutive patients from Central Poland with various cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from this region. Most of the 657del5 mutation carriers were found among patients with melanoma (4/105), non-Hodgkin lymphoma (2/ 42) and breast cancer (4/224) and of the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3 others the R215W molecular variant. The frequencies of 657del5 mutation carriers among patients with melanoma and non-Hodgkin lymphoma and of R215W carriers in patients with colorectal cancer were significantly higher than in controls (p < 0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and R215W mutations in all cancer patients were also significantly higher than in controls (p < 0.05). Two carriers of the 657del5 mutation had second primary tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers (14/77) were twice more frequent than in population controls. Three carriers of this mutation (2 probands with melanoma) reported melanoma in relatives. These results suggest strongly that NBS1 heterozygosity may be associated with elevated risk of some cancers. Larger studies are needed to evaluate the impact of the high frequency of germline NBS1 mutations on the cancer burden in the Slav populations. © 2004 Wiley-Liss, Inc. Key words: NBS1 gene; heterozygous mutation carriers; 657del5 mutation; R215W molecular variant; cancer riskThe chromosomal instability disorder, Nijmegen breakage syndrome (NBS), is characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to X-irradiation and increased predisposition to lymphoid malignancy. 1 The gene mutated in NBS was identified in 1998. [2][3][4] Nibrin, the product of the NBS1 gene, is part of the MRE11/RAD50 complex, which is involved in the repair of DNA double strand breaks (DSBs). Double strand breaks are not only induced by mutagens but are also intermediates of DNA processing in immune gene rearrangements, the maintenance of telomeres, and in meiotic recombination. Nibrin is involved in the processing of all these types of DSBs. 2 This explains the complex NBS phenotype, including the very high incidence of lymphomas and other malignant tumors, which are the major cause of deaths among NBS patients already during childhood and adolescence. 5 The majority of NBS patients are of Central and Eastern European origin and share the common founder mutation in the NBS1 gene, 657del5. 6 NBS shares many clinical and cellular features with ataxiatelangiectasia (AT), and it was shown that they are also pathogenetically related. 7-10 Interestingly, the cancer risk in NBS1 homozygotes is higher than that of AT patients. 5 Heterozygous relatives of AT probands have an approximately 2...

The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.

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