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A differential responsiveness of patients to ionizing radiation is observed after preoperative radiotherapy for rectal adenocarcinoma that might be related, in part, to an apoptosis defect. To establish if proteins of the apoptotic cascades [pro-apoptotic: active caspase 3, 8, and 9 and DIABLO (direct inhibitor of apoptosis-binding protein with low pI); anti-apoptotic: XIAP (X-linked inhibitor of apoptosis)] are involved, we analyzed their profile in radioresistant (SW480) and radiosensitive (SW48) human colorectal cell lines. We demonstrated that, after irradiation, the SW48 cells increased the expression of the pro-apoptotic proteins, whereas the SW480 cells increased the expression of the anti-apoptotic protein XIAP. Moreover, XIAP knockdown in SW480 cells enhanced the basal and radiation-induced apoptotic index; the propensity of the SW480 cells to undergo apoptosis after radiation was higher compared with SW48 cells. In a translational study of 38 patients with rectal carcinoma, we analyzed the apoptotic profile for tumor and noncancerous tissue for each biopsy specimen using IHC. According to their response to preoperative radiotherapy, patients were classified into two groups: responsive and nonresponsive. Although no difference in expression of caspase 3, 8, or 9 was observed in the tumor/normal tissue ratio between responsive and nonresponsive patients, the ratio decreased for DIABLO and increased for XIAP. In conclusion, inhibition of XIAP rescues cellular radiosensitivity and both DIABLO and XIAP might be potential predictive markers of radiation responsiveness in rectal adenocarcinoma.

Infiltrating MBC represents less than 1% of all male cancers. Our study details clinico-pathological features, treatments and prognostic factors in a large French cohort.Four hundred and eighty-nine patients were collected from 1990 to 2005. Median age was 66 years (34% over 70 years) and median follow-up 58 months.According to TN classification, we found T(1): 39%, T(2): 41%, T(3)T(4): 9%, T(x): 11% and N(1)N(2): 27%. Lumpectomy (L) and mastectomy (M) were performed in 8.6% and 91.4% of the cases. Axillary dissection (AD), sentinel node biopsy or both were performed in 90%, 2% and 5% of the cases, respectively. Ninety-five percent of tumours were ductal carcinomas; 47% were pT(1), 20% pT(2) and 33% pT(3)-T(4). Axillary nodal involvement was present in 52.8% cases. ER and PgR were positive in 92% and 89% cases. Radiotherapy (RT) was performed in 85% of the patients. Hormonal treatment (HT) was delivered in 72% of the cases. Tamoxifen and aromatase inhibitors were used in 85% and 12% of the cases; 34% of the patients received chemotherapy (CT). Local recurrence (LR), nodal recurrences (NR) and metastases occurred in 2%, 5% and 22% of the cases; 2% and 10% developed contralateral BC and second cancer. The 5- and 10-year overall survival (OS) rates were 81% and 59%; disease-specific survivals (DSS) were 89% and 72%. Death causes were BC 56%, second cancer 8%, complications 3%, intercurrent disease 15% and unknown 18%. In a univariate analysis, metastatic risk factors were T stage (T1: 19%, T(2): 26%, T(3)T(4): 40%; p=0.013), pN status (pN(0): 12% pN(1-3): 26% pN(3): 44%; p0.0001) and presence of locoregional recurrence (62% versus 18% p0.0001). In a multivariate analysis, axillary nodal involvement and high SBR remain prognostic factors.Earlier diagnosis and wide use of adjuvant treatments (RT/HT/CT) widely decreased LR and increased survival rates in MBC, reaching female ones. Prognostic factors were also very similar to female ones.

International audience; The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated ( = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; = 0.14) and in 126 patients treated ≥3 months before study termination (12.2 vs. 9.8 months; = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.

X-ray repair cross-complementing 1 (XRCC1) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5'-untranslated region (5'-UTR) variant -77T-->C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders, and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The -77T-->C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wild-type allele other positions) was associated with increased BC risk [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.12-3.23] and the H3 haplotype (wild-type allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, -77C, wild-type allele codons 194, 280, 399) (OR, 0.39; 95% CI, 0.16-0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival (P=0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 h following IR exposure. These results suggest that the -77T-->C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.

To report our patient experience with squamous cell carcinoma of the anal margin and to evaluate the prognostic factors influencing outcome. Between 1980 and 2001, 26 patients with anal margin squamous cell carcinoma were treated in Lyon-Sud: 7 T1, 14 T2, 4 T3, and 1 T4 with 20 N0, 3 N1, and 3 N2. The anal canal was invaded in five patients. Treatment consisted of definitive external irradiation in 14 patients and adjuvant irradiation (after a local excision) in 12 patients. External irradiation was combined with chemotherapy in seven patients, brachytherapy in four patients, and both brachytherapy and chemotherapy in one patient. The local control rate was initially 61.4%, and it was 80.8% after salvage treatment. The 5-year overall and specific survival rates were 71 and 88.3%, respectively. Three factors correlated with specific survival: cell differentiation (P=0.038) and T (P=0.001) and N category (P=0.0005). A salvage abdominoperineal resection was successfully employed in five of seven local recurrences. Four grade 3 and two grade 4 toxicities were observed. Sphincter preservation was possible in 66% of alive patients. Our results confirm the dominating place of definitive irradiation and radiochemotherapy in the treatment of anal margin squamous cell carcinoma. The indications for abdominoperineal resection must be limited to local relapse. The prognosis of squamous cell carcinoma is correlated to T and N staging and cell differentiation.

The aim of the study was to evaluate and compare incidence and risk factors of left ventricular dysfunction (LVD) in early breast cancer patients receiving (E+) or not (E-) epirubicin-based adjuvant chemotherapy.Among eight FASG trials, 3577 assessable patients were analyzed retrospectively: 2553 received epirubicin, 662 received hormonotherapy alone and 362 had no systemic treatment. Chemotherapy was FEC regimen in 86% of cases (fluorouracil, epirubicin, cyclophosphamide). Epirubicin cumulative dose was300 mg/m2 in 1040 patients, 300-600 in 1155,or = 600 in 279, followed by radiotherapy in 96% of cases.Twenty delayed LVD occurred: two in E- patients and 18 in E+ patients. In E+ patients, 14 patients normalized their cardiac function or did not require further investigations, one patient was stabilized with specific treatment, two patients worsened their functions and one died of congestive heart failure. The 7-year risk of LVD was 1.36% (95% CI 0.85-1.87) in E+ patients and 0.21% (95%CI: 0.00-0.52) in E- patients (P = 0.004). Two significant risk factors were identified: ageor = 65 years and body mass index27 kg/m2.After a long-term follow-up, epirubicin-related LVD risk was acceptable (1.36%) with one toxic death (0.04%). In 78% of cases, LVD were transient or well controlled.

Over the past 20 years there have been many advances in the management of rectal cancer. The medico-surgical school in Lyon, France, has a long tradition in managing this malignancy. The progression of ideas and practices requires a better knowledge of the patterns of tumor spread and local recurrence. Technical advances have greatly helped to facilitate sphincter preservation. Advances in radiotherapy have led to its routine use in the preoperative period. This approach has now emerged as the best therapeutic sequence. Our experience concerns 46 patients with low rectal carcinoma treated with this strategy. There were no post-operative deaths and no leakage. One patient (2%) had a pelvic abscess. Median follow-up was 50 months (1-151). At five years, the local recurrence rate was 8.5% and the actuarial survival rate was 72%, with a local control rate of 91%. Functional outcome, evaluated with a scoring system, was good in 60% of cases at one year and 78% at 5 years. Quality of life, evaluated with the American Society of Colon and Rectal Surgeons scale (A.S.C.R.S.), was 107 +/- 21 (range 33-140). The absence of defunctioning stoma (initial or late), good sexual and urinary well-being, and psychologic assessment are essential factors, requiring rigorous evaluation before the operation and specialized management after the operation. The proposed strategy based on this safe procedure and "French-type" neoadjuvant radiotherapy, permits sphincter preservation in patients with T2 and T3 tumors located near the dentate line, with good late oncological outcome. It is often amenable to the laparoscopic approach.

The identification of an interaction between BRCA1 and acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in lipid synthesis, led us to investigate the role of ACCalpha in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACCalpha alleles may be high-risk breast cancer susceptibility alleles, 37 extended breast and breast/ovarian cancer families negative for BRCA1 and BRCA2 mutations were exhaustively screened for sequence variations in the entire coding sequence, intron-exon junctions, 5'UTR, 3'UTR (untranslated regions) and the promoter regions of the ACCalpha gene. Two possibly disease-associated ACCalpha variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including 12 single nucleotide polymorphisms where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACCalpha coding region along with the presence of extended areas of linkage disequilibrium and low haplotype diversity indicates an overall high preservation of this gene. The prevalence of the ACCalpha haplotypes composed of common polymorphisms was determined in 453 breast cancer cases and 469 female controls. One haplotype was found to be associated with a substantial and highly significant increase in breast cancer risk (odds ratio = 3.10, 95% confidence interval 1.87-5.14, P < 0.0001), whereas three other haplotypes were found to have a protective effect. Our results indicate that mutations in the ACCalpha gene are unlikely to be a major cause of high-risk breast cancer susceptibility; however, certain common ACCalpha alleles may influence breast cancer risk. This study provides the first insight into the involvement of the ACCalpha gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACCalpha in tumour susceptibility and development.

To the Editor, In most institutions, standard treatment of T2-T3 rectal adenocarcinoma is radical surgery using total mesorectal excision (TME) with or without neo-adjuvant treatment [radiotherapy ...

BACKGROUND The authors performed a specific analysis of the clinical significance of inguinal lymph nodes metastases in patients with anal canal carcinoma (ACC). METHODS A retrospective analysis was conducted of 270 patients who were treated in Lyon between 1980 and 1996 with radiotherapy with curative intent for ACC: No elective irradiation of clinically normal inguinal areas was performed. Patients with metastatic inguinal lymph nodes were treated with inguinal dissection and postoperative irradiation with a dose of 50 grays over 5 weeks. Concomitant chemoradiation, usually with a regimen of fluorouracil and cisplatinum, was given to 159 patients. RESULTS The median follow-up for the whole series was 72 months. Synchronous inguinal metastases were observed in 10% of patients (n = 27; the rate was 16% for patients with T3–T4 lesions), and the 5-year overall survival rate was 54.4%. Metachronous inguinal metastases were seen in 19 patients (7.8%), and the 5-year overall survival rate of these patients was 41.4%. An original finding was that, when the primary tumor clearly was located on a single lateral side of the anal canal, the inguinal lymphatic metastases was always homolateral to it (36 of 36 synchronous plus metachronous tumors). CONCLUSIONS The data from this series of patients and a review of the literature are in favor of a selective approach in the management of inguinal lymph node involvement for patients with ACC, depending on the disease stage and the location of the primary tumors. Cancer 2001;92:77–84. © 2001 American Cancer Society.

Learning Objectives After completing this course, the reader will be able to: Evaluate the therapeutic impact of hysterectomy after chemoradiation therapy in locally advanced cervical cancer.Evaluate the rate of histologic residual disease in patients with complete clinical and radiologic response after chemoradiation therapy. This article is available for continuing medical education credit at CME.TheOncologist.com Background. Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery. Methods. A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6–8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003–2006) and are reported on here. Results. Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively. Conclusions. Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).

Background: The purpose was to compare disease-free survival (DFS) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive (N1–3), estrogen-receptor-positive (ER+), postmenopausal early breast cancer (EBC) patients. Patients and methods: We analyzed, retrospectively, 457 patients randomized in FASG 02 and 07 trials who received: tamoxifen alone (30 mg/day, 3 years); or FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) plus tamoxifen started concurrently. Radiotherapy was delivered after the third cycle in FASG 02 trial, and after the sixth in FASG 07 trial. Results: The 9-year DFS rates were 72% with tamoxifen and 84% with FEC50-tamoxifen (P = 0.008). The multivariate analysis showed that pathological tumor size >2 cm was an independent prognostic factor (P = 0.002), and treatment effects remained significantly in favor of chemoendocrine therapy (P = 0.0008). The 9-year overall survival rates were 78% and 86%, respectively (P = 0.11). In the multivariate model, there was a trend in favor of chemoendocrine therapy (P = 0.07). Conclusion: The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1–3, ER+ and postmenopausal women. Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival.

Over the past 20 years there have been many advances in the management of rectal cancer. The medico-surgical school in Lyon, France, has a long tradition in managing this malignancy. The progression of ideas and practices requires a better knowledge of the patterns of tumor spread and local recurrence. Technical advances have greatly helped to facilitate sphincter preservation. Advances in radiotherapy have led to its routine use in the preoperative period. This approach has now emerged as the best therapeutic sequence. Our experience concerns 46 patients with low rectal carcinoma treated with this strategy. There were no post-operative deaths and no leakage. One patient (2%) had a pelvic abscess. Median follow-up was 50 months (1-151). At five years, the local recurrence rate was 8.5% and the actuarial survival rate was 72%, with a local control rate of 91%. Functional outcome, evaluated with a scoring system, was good in 60% of cases at one year and 78% at 5 years. Quality of life, evaluated with the American Society of Colon and Rectal Surgeons scale (A.S.C.R.S.), was 107 +/- 21 (range 33-140). The absence of defunctioning stoma (initial or late), good sexual and urinary well-being, and psychologic assessment are essential factors, requiring rigorous evaluation before the operation and specialized management after the operation. The proposed strategy based on this safe procedure and "French-type" neoadjuvant radiotherapy, permits sphincter preservation in patients with T2 and T3 tumors located near the dentate line, with good late oncological outcome. It is often amenable to the laparoscopic approach.

Background: The purpose of this study was to evaluate incidence and risk factors of secondary leukemia after adjuvant epirubicin-based chemotherapy in breast cancer patients. Patients and methods: Among eight French Adjuvant Study Group trials, 3653 patients were assessable: 2603 received epirubicin; 682 received hormonotherapy; and 368 had no systemic treatment. Chemotherapy was FEC regimen in 85% of cases (fluorouracil 500 mg/m 2 , epirubicin 50, 75 or 100 mg/m 2 , cyclophosphamide 500 mg/m 2 , three or six cycles). Epirubicin cumulative dose was 600 mg/m 2 in 286, followed by radiotherapy in 96% of cases. The median follow-up was 104 months. Results: Eight cases of leukemia occurred in epirubicin-exposed patients and one in non-exposed patients. After 9 years, the risk of developing a leukemia was 0.34% (95% confidence interval 0.11 –0.57) in epirubicin-exposed patients. In patients receiving chemotherapy, leukemia subtypes were: AML2 (two), AML3 (one), AML4 (three) and ALL (two). None of the classically recognized risk factors was significantly correlated with the occurrence of a leukemia. Conclusion: Irrespective of the dose, the incidence of secondary leukemia after adjuvant epirubicinbased chemotherapy was low. After a long follow-up, the benefit/risk ratio for early breast cancer patients remained in favor of epirubicin-based adjuvant chemotherapy: eight cases (0.31%) occurred, and in some of them, treatment causality could be debatable.

The ATM gene, mutated in the cancer-prone and radiation-sensitive syndrome ataxia-telangiectasia (AT), could predispose to breast cancer (BC) development and adverse radiotherapy responses. Sixteen ATM variants were genotyped in 254 BC cases, 70 of whom were adverse radiotherapy responders (RS-BC), and 312 control subjects and the ATM haplotypes were constructed. Constitutive ATM protein, cell survival, and the p53 response after exposure to ionizing radiation were compared in lymphoblastoid cell lines (LCLs) established from the BC cases, AT, and normal individuals. The tightly linked intronic ATM polymorphisms IVS22-77 TC and IVS48 + 238 CG, in the homozygote state were associated with increased BC risk [IVS22-77 CC versus TT odds ratio (OR), 1.67; 95% confidence interval (CI), 1.00-2.81], and in the heterozygote state with clinical radioprotection (IVS22-77 CT versus TT OR, 0.45; 95% CI, 0.24-0.85). Homozygote carriers of the G5557A variant were over-represented in RS-BC cases compared with non-RS-BC cases (OR, 6.76; 95% CI, 1.19-38.43). These three single nucleotide polymorphisms were associated with the three major ATM haplotypes present in80% of the study population. BC LCLs treated with ionizing radiation exhibited an intermediate cell survival and p53 response between that of normal and AT LCLs, with the response in the RS-BC LCLs being more compromised than in the non-RS-BC LCLs. Our study suggests a general pattern of increased BC risk associated with carrying any one of the ATM variants studied, with a significant association being observed in individuals carrying variants on both ATM alleles (OR, 1.75; 95% CI, 1.09-2.81) and that ATM variants may impact on radiation sensitivity.

The study goal was to examine the association of three polymorphisms in the XRCC1 gene (Arg194Trp, Arg280His, and Arg399Gln) involved in repairing DNA damage produced by ionizing radiation, a known breast cancer (BC) risk factor, with BC incidence and the possibility of developing an adverse radiotherapy response. Genomic DNA from 254 BC cases, 70 of whom were adverse radiotherapy responders [radiation-sensitive breast cancer (RS-BC) patients], and 312 female blood donors were genotyped using either TaqMan technology or variant specific restriction enzyme digestion. Neither the exon 6 codon 194Trp allele [BC versus controls: odds ratio (OR), 1.03; 95% confidence interval (CI) 0.62-1.67] nor the exon 10 codon 399Gln allele (BC versus controls: OR, 0.95; 95% CI, 0.74-1.23) alone was associated with an increased BC risk. The exon 9 codon 280His allele was associated with an increased risk (OR, 1.8; 95% CI, 1.07-3.05) in both the radiation-sensitive and non-radiation-sensitive cases and, in combination with the 399Gln allele, was found more frequently in cases than in controls (OR, 2.54; 95% CI, 1.04-6.22). The exon 6 194Trp allele was associated with the risk of developing an adverse response to radiotherapy (RS-BC versus non-radiation-sensitive BC: OR, 1.98; 95% CI, 0.92-4.17). This allele, in combination with the 399Gln allele, was found more frequently in RS-BC cases than in the non-radiation-sensitive BC cases (OR, 4.33; 95% CI, 1.24-15.12). Distinct combinations of XRCC1 polymorphisms appear to be associated with either an increased BC risk or the possibility of developing an adverse radiotherapy response seen in some BC patients.

Background/aims—Radiotherapy has been proposed as an alternative treatment for patients with subfoveal choroidal neovascularisation (CNV) that is untreatable according to macular photocoagulation study guidelines. This prospective study was designed to evaluate whether radiotherapy may aVect the functional and anatomical outcome in a large cohort of patients aVected by subfoveal CNV, with a follow up period up to 24 months. Methods—212 patients (231 eyes) with newly diagnosed subfoveal CNV not amenable to laser therapy were included in this study. Two radiotherapy methods, the lateral beam technique (6 MV, 20 Gy in five fractions) and lateral arc therapy (25 MV, 16 to 20 Gy, in four or five fractions), were used. Comparisons of best corrected visual acuity (VA), fluorescein (FA) and indocyanine green (ICG) angiography, at inclusion and 6, 12, 18, and 24 months after radiotherapy were performed using univariate analysis. Results—A VA improvement of two or more lines was observed in 34% at 12 months, 31% at 18 months, and 32% of the eyes at 24 months. Paired comparisons of CNV areas in FA and ICG showed no significant change between baseline and each visit. However, 12 and 18 months after treatment, 47% of the eyes showed a decrease of 10% or more in CNV size both in ICG and FA. Radiation side eVects included radiation retinopathy (eight eyes), optic neuropathy (four eyes), choroidal vasculopathy (five eyes), and branch retinal vein occlusion (three eyes). Conclusion—Compared with the natural course of subfoveal CNV, the results of this prospective study suggest that radiotherapy could stabilise visual and anatomical outcome in selected cases. (Br J Ophthalmol 1999;83:923‐928)

The role of irradiation in the management of anal and rectal cancer has changed during the past ten years. In small epidermoid carcinomas of the anal canal (T1 T2) irradiation is in most departments considered the primary treatment, giving a 5-year survival rate of between 60 and 80% with good sphincter preservation. Even in larger tumors, irradiation can still offer some chance of cure without colostomy. Surgery remains the basic treatment of rectal cancer but irradiation is used in association with surgery in many cases. Radiotherapy is of value in the conservative management of cancer of the rectum in three situations; In small polypoid cancers contact x-ray therapy can give local control in about 90%. In cancers of the middle rectum, preoperative external irradiation may increase the chances of restorative surgery and reduce the risk of local relapse. In inoperable patients, external radiotherapy and/or intracavitary irradiation may cure some patients with infiltrating tumors (T2 T3) without colostomy.