Philippe Rouanet

Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma In Situ: 15-Year Recurrence Rates and Outcome After a Recurrence, From the EORTC 10853 Randomized Phase III Trial

PURPOSE Adjuvant radiotherapy (RT) after a local excision (LE) for ductal carcinoma in situ (DCIS) aims at reduction of the incidence of a local recurrence (LR). We analyzed the long-term risk on developing LR and its impact on survival after local treatment for DCIS. PATIENTS AND METHODS Between 1986 and 1996, 1,010 women with complete LE of DCIS less than 5 cm were randomly assigned to no further treatment (LE group, n = 503) or RT (LE+RT group, n = 507). The median follow-up time was 15.8 years. RESULTS Radiotherapy reduced the risk of any LR by 48% (hazard ratio [HR], 0.52; 95% CI, 0.40 to 0.68; P < .001). The 15-year LR-free rate was 69% in the LE group, which was increased to 82% in the LE+RT group. The 15-year invasive LR-free rate was 84% in the LE group and 90% in the LE+RT group (HR, 0.61; 95% CI, 0.42 to 0.87). The differences in LR in both arms did not lead to differences in breast cancer-specific survival (BCSS; HR, 1.07; 95% CI, 0.60 to 1.91) or overall survival (OS; HR, 1.02; 95% CI, 0.71 to 1.44). Patients with invasive LR had a significantly worse BCSS (HR, 17.66; 95% CI, 8.86 to 35.18) and OS (HR, 5.17; 95% CI, 3.09 to 8.66) compared with those who did not experience recurrence. A lower overall salvage mastectomy rate after LR was observed in the LE+RT group than in the LE group (13% v 19%, respectively). CONCLUSION At 15 years, almost one in three nonirradiated women developed an LR after LE for DCIS. RT reduced this risk by a factor of 2. Although women who developed an invasive recurrence had worse survival, the long-term prognosis was good and independent of the given treatment.

Safety and efficacy of dynamic muscle plasty for anal incontinence: Lessons from a prospective, multicenter trial

BACKGROUND & AIMS Dynamic muscle plasty has been advocated as therapy for refractory fecal incontinence and for anorectal reconstruction to avoid colostomy after abdominoperineal resection. This study evaluates the results of a multicenter experience with dynamic muscle plasty in the treatment of fecal incontinence and total anal reconstruction. METHODS One hundred thirty-nine patients were enrolled at 12 centers between June 1992 and November 1994 and followed up through June 1996. Intramuscular leads and neurostimulators were implanted to stimulate transposed gracilis or gluteus muscle. Success was defined as 70% reduction in solid stool incontinence for patients with baseline incontinence and zero incontinence to solid stool for patients with baseline stomas and for patients undergoing total anal reconstruction. RESULTS Overall, 85 of 128 graciloplasty patients (66%) achieved and maintained a successful outcome over the follow-up period. By etiology, these proportions were 71%, 50%, and 66% for patients with acquired fecal incontinence, congenital incontinence, and total anal reconstruction, respectively. One third of graciloplasty patients experienced a major wound complication, with therapy failing in 41%. Experienced centers had better outcomes and lower complication rates than inexperienced centers. Of the 11 gluteoplasty patients, 5 (45%) achieved and maintained a successful outcome. CONCLUSIONS Dynamic graciloplasty may be an effective procedure for patients with refractory, end-stage fecal incontinence as well as for patients who require anorectal excision for low-lying malignancy. However, the procedure has significant morbidity that can lead to functional failure. Outcome after dynamic graciloplasty appears to correlate with surgical experience. In contrast to graciloplasty, the use of dynamic gluteoplasty should be limited to investigational purposes.

Rectal cancer surgery with or without bowel preparation: The French GRECCAR III multicenter single-blinded randomized trial.

Objective:To assess with a single-blinded, multicenter, randomized trial, the postoperative results in patients undergoing sphincter-saving rectal resection for cancer without preoperative mechanical bowel preparation (MBP). Background:The collective evidence from literature strongly suggests that MBP, before elective colonic surgery, is of no benefit in terms of postoperative morbidity. Very few data and no randomized study are available for rectal surgery and preliminary results conclude toward the safety of rectal resection without MBP. Methods:From October 2007 to January 2009, patients scheduled for elective rectal cancer sphincter-saving resection were randomized to receive preoperative MBP (ie, retrograde enema and oral laxatives) or not. Primary endpoint was the overall 30-day morbidity rate. Secondary endpoints included mortality rate, anastomotic leakage rate, major morbidity rate (Dindo III or more), degree of discomfort for the patient, and hospital stay. Results:A total of 178 patients (103 men), including 89 in both groups (no-MBP and MBP groups), were included in the study. The overall and infectious morbidity rates were significantly higher in no-MBP versus MBP group, 44% versus 27%, P = 0.018, and 34% versus 16%, P = 0.005, respectively. Regarding both anastomotic leakage and major morbidity rates, there was no significant difference between no-MBP and MBP group: 19% versus 10% (P = 0.09) and 18% versus 11% (P = 0.69), respectively. Moderate or severe discomfort was reported by 40% of prepared patients. Mortality rate (1.1% vs 3.4%) and mean hospital stay (16 vs 14 days) did not differ significantly between both groups. Conclusions:This first randomized trial demonstrated that rectal cancer surgery without MBP was associated with higher risk of overall and infectious morbidity rates without any significant increase of anastomotic leakage rate. Thus, it suggests continuing to perform MBP before elective rectal resection for cancer. This study is registered with clinicaltrials.gov, number NCT00554892.

Transanal endoscopic proctectomy: an innovative procedure for difficult resection of rectal tumors in men with narrow pelvis.

BACKGROUND: In rectal surgery, some situations can be critical, such as anterior topography of locally advanced low tumors with a positive predictive radial margin, especially in a narrow pelvis of men who are obese. Transanal proctectomy is a new laparoscopic technique that uses the transanal endoscopic microsurgery device. OBJECTIVE: The aim of this study is to evaluate the technical feasibility of laparoscopic transanal proctectomy in patients with unfavorable features. DESIGN AND PATIENTS: This is a single-center, prospective analysis of selected patients with rectal cancer operated on from January 2009 to June 2011. MAIN OUTCOME MEASURES: Intraoperative details and short-term postoperative outcome were described. RESULTS: Thirty men with advanced or recurrent low rectal tumors associated with unfavorable anatomical and/or tumor characteristics underwent a sphincter-sparing transanal endoscopic proctectomy. Twenty-nine patients had received preoperative treatment. We report a 6% conversion rate, no postoperative mortality, and a 30% morbidity rate. At the beginning of our experience, a urethral injury was diagnosed in 2 patients and easily sutured intraoperatively, without postoperative after-effect. The mesorectal resection was graded as “good” in all patients. R0 resection was achieved in 26 patients (87%). The short-term stoma closure rate was 85%. After a median follow-up of 21 months, 4 patients experienced locoregional recurrence alone. Overall survival rates at 12 and 24 months were 96.6% (95% CI, 78.0–99.5) and 80.5% (95% CI, 53.0–92.9). Relapse-free survival rates at 12 and 24 months were 93.3% (95% CI, 75.9–98.3) and 88.9% (95% CI, 69.0–96.3). LIMITATIONS: Although the transanal endoscopic proctectomy was performed by trained surgeons, we report a slight increase in early postoperative morbidity and relatively poor early outcome. There was a clear selection bias related to the study cohort exclusively composed of high-risk patients, but we need to be cautious before generalizing this technique. CONCLUSION: The transanal endoscopic proctectomy is a feasible alternative surgical option to conventional laparoscopy for radical rectal resection in selected cases with unfavorable characteristics. Further investigations with larger cohorts are required to validate its safety and to clarify its best indication.

Micrometastases in Sentinel Lymph Node in a Multicentric Study: Predictive Factors of Nonsentinel Lymph Node Involvement—Groupe Des Chirurgiens De La Federation Des Centres De Lutte Contre Le Cancer

PURPOSE To determine the rate of nonsentinel lymph node (NSN) involvement at axillary lymph node dissection (ALND) and predictive factors of this involvement following detection of micrometastasis in sentinel nodes (SN). METHODS We analyzed 700 observations of SN micrometastases with additional ALND with the characteristics of the patients, tumors, and SN. RESULTS Involvement of SN was diagnosed 388 times by serial sections (55.4%) with standard hemoxylin and eosin staining (HES) and 312 times solely on immunohistochemical analysis (IHC; 44.6%). The accurate size of the micrometastases was indicated in 488 cases: 301 larger than 0.2 mm (61.7%) and 187 < or = 0.2 mm (38.3%). Ninety-four patients (13.4%) presented an NSN involvement with only one NSN involved in 62 cases (66%). Predictive factors of NSN involvement were in univariate analysis (pT stage [P < .000], menopausal status [P = .048], T stage [P = .006], grade [P = .013], lymphovascular invasion [LVI; P = .013], histologic tumor type [P = .017], and method of micrometastasis detection, by HES or IHC [P = .015]) and in multivariate analysis (pT stage < or = or > 20 mm [odds ratio, 2.54], micrometastases detected by HES or IHC [odds ratio,1.734], presence or absence of LVI [odds ratio, 1.706]). Micrometastasis size < or = or greater than 0.2 mm was not predictive. CONCLUSION This study confirms the value of serial sections and the vital role played by IHC in screening for small micrometastases. Omission of additional ALND may be envisaged with minimal risk for pT1a and pT1b tumors, and pT1a-b-c tumors corresponding to tubular, colloidal, or medullar cancers.

A nomogram predictive of non-sentinel lymph node involvement in breast cancer patients with a sentinel lymph node micrometastasis

PURPOSE Predictive factors of non-sentinel lymph node (NSN) involvement at axillary lymph node dissection (ALND) have been studied in the case of sentinel node (SN) involvement, with validation of a nomogram. This nomogram is not accurate for SN micrometastasis. The purpose of our study was to determine a nomogram for predicting the likelihood of NSN involvement in breast cancer patients with a SN micrometastasis. METHODS We collated 909 observations of SN micrometastases with additional ALND. Characteristics of the patients, tumours and SN were analysed. RESULTS Involvement of SN was diagnosed 490 times (53.9%) with standard staining (HES) and 419 times solely on immunohistochemical analysis (IHC) (46.1%). NSN invasion was observed in 114 patients (12.5%), whereas 62.3% (71) had only one NSN involved and 37.7% (43) two or more NSN involved. In multivariate analysis, significant predictive factors were: tumour size (pT stage < or = 10 mm or >11 and < or = 20 or >20 mm [odds ratio (OR) 2.1 and 3.43], micrometastases detected by HES or IHC [OR 1.64], presence or absence of lymphovascular invasion (LVI) [OR 1.76], tumour histological type mixed or not [OR 2.64]. The rate and probability of NSN involvement with the model are given for 24 groups, with a representation by a nomogram. CONCLUSION One group, corresponding to 10.1% of the patients, was associated with a risk of NSN involvement of less than 5%, and five groups, corresponding to 29.8% of the patients, were associated with a risk < or = 10%. Omission of ALND could be proposed with minimal risk for a low probability of NSN involvement.

Restorative and nonrestorative surgery for low rectal cancer after high-dose radiation: long-term oncologic and functional results.

AbstractPURPOSE: This prospective, nonrandomized study evaluates, with a seven-year median follow-up, the morbidity and the functional and oncologic results of conservative surgery after high-dose radiation for cancer of the lower third of the rectum of patients who would otherwise have undergone abdominoperineal resection. METHODS: Between June 1990 and June 1996, 43 patients with distal rectal adenocarcinoma were treated by preoperative radiotherapy (40 + 20 Gy delivered with three fields) and curative surgery. The mean distance from the anal verge was 50 (range, 25–60) mm, and none of the tumors was fixed (15 percent T2N0, 53 percent T3N0, 32 percent T3N1). RESULTS: Postoperative mortality (2 percent) and morbidity (35 percent) were not increased by high-dose preoperative radiation. Conservative surgery was done in 30 patients (70 percent: 26 coloanal anastomoses and 4 low stapled anastomoses). After conservative surgery, long-term functional results showed 30 percent complete continence and 20 percent serious incontinence. Four patients had local recurrence as first development (13 percent). The seven-year overall survival rate was 53 percent, 62 percent after conservative surgery and 31 percent after abdominoperineal resection. The univariate analysis underscores the tumor response impact on long-term survival (pT<3 = 81 percent; pT3 = 35 percent; P = 0.0008). CONCLUSIONS: These long-term results confirm the feasibility of conservative surgery for low rectal carcinoma after high-dose radiation. A prospective multicentric trial began in France in June 1996 to evaluate the reproducibility of these results.

Identification of a new panel of serum autoantibodies associated with the presence of in situ carcinoma of the breast in younger women.

Purpose: We examined the feasibility of using a panel of autoantibodies to multiple tumor-associated proteins as a method for early detection of breast cancer and, more particularly, carcinoma in situ (CIS). Experimental Design: PPIA, PRDX2, and FKBP52 were identified as early-stage breast cancer autoantigens by proteomic approaches. The seroreactivity of a panel of antibodies consisting of these three antigens and two previously described autoantigens, HSP60 and MUC1, was tested on 235 samples (60 from primary breast cancer patients, 82 from CIS patients, and 93 from healthy controls) with the use of specific ELISAs. FKBP52, PPIA, and PRDX2 mRNA and protein expression levels were evaluated by reverse transcription-PCR and immunohistochemistry in early-stage breast tumors. Results: Three of five autoantibodies, FKBP52, PPIA, and PRDX2, showed significantly increased reactivity in primary breast cancer and CIS compared with healthy controls. When combined, the five markers significantly discriminated primary breast cancer [receiver operating characteristic area under the curve, 0.73; 95% confidence interval (95% CI), 0.60-0.79] and CIS (receiver operating characteristic area under the curve, 0.80; 95% CI, 0.71-0.85) from healthy individuals. Importantly, the receiver operating characteristic–area under the curve value of the autoantibody panel was able to distinguish CIS, including high grades, from healthy controls in women under the age of 50 years (receiver operating characteristic area under the curve, 0.85; 95% CI, 0.61-0.92). Finally, only FKBP52 mRNA and protein levels were found to be increased in CIS and primary breast cancer compared with healthy breast tissue. Conclusions: This autoantibody assay against a panel of five antigens allows for an accurate discrimination between early-stage breast cancer, especially CIS, and healthy individuals. These results could be of interest in detecting early breast cancer as an aid to mammography, especially in women under the age of 50 years with aggressive cancers.

Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)

Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes [8.5%]). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum [I] 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.

MR Volumetric Measurement of Low Rectal Cancer Helps Predict Tumor Response and Outcome after Combined Chemotherapy and Radiation Therapy

PURPOSE To retrospectively determine whether magnetic resonance (MR) volumetry of rectal cancer is a reproducible method for predicting disease-free survival (DFS) in patients with locally advanced low or midrectal tumors who undergo combined chemotherapy and radiation therapy (CRT) before total mesorectal excision. MATERIALS AND METHODS The institutional review board does not require approval for the use of patient data obtained for an observational retrospective study. Fifty-eight patients were included in the study; 42 patients had low-lying tumors. Two radiologists independently measured tumor volumes before and after CRT with use of semiautomated software. The radiologists were blinded to the clinical information for each patient. The tumor volume reduction ratio, circumferential resection margin, T stage, and occurrence of downstaging were compared with the histopathologic response and DFS. The threshold of tumor volume reduction for predicting DFS was assessed with receiver operating characteristic curve analysis. DFS was estimated with the Kaplan-Meier method and compared between groups with the log-rank test. RESULTS The interobserver correlation coefficient between the two radiologists was 0.87 (95% confidence interval [CI]: 0.76, 0.93) for pre-CRT volumetry and 0.81 (95% CI: 0.74, 0.90) for post-CRT volumetry. A tumor volume reduction of at least 70% was significantly associated with good histologic regression (tumor regression grade [TRG], 3 or 4) (P <.0001) compared with a volume reduction rate of less than 70%. DFS was studied in 51 patients. The mean follow-up of survivors at the time of analysis was 52 months ± 20 (standard deviation). Patients with a volume reduction ratio of at least 70% had a higher DFS (P <.0001). Tumor volume reduction was an independent prognostic parameter in multivariate analysis for DFS (P = .003; 95% CI: 0.01, 0.4). CONCLUSION The results demonstrate that volumetric measurements are reliable markers of rectal cancer prognosis, enabling the prediction of DFS and TRG. The cutoff of 70% is an easy parameter to use as a surrogate for clinical response to predict both TRG and outcome.