Cumulative Incidence Of Local Relapse Research Articles

Very APBI in 1 or 2 Days: Late Toxicity and Early Oncological Outcomes of the GEC-ESTRO Cohort

To analyze late toxicity after very accelerated partial breast irradiation (VAPBI) for low-risk breast cancer. In this retrospective observational international multicenter study (HDH F20220713143949) from 7 European centers, patients with low-risk breast cancer underwent lumpectomy + adjuvant VAPBI based on high-dose rate (HDR) multicatheter interstitial brachytherapy (MIB). VAPBI was performed with 4 (4 × 6.2 Gy/2 d), 3 (3 × 7.45 Gy/2 d) or 1 fraction (1 × 16 Gy or 1 × 18 Gy/1 d). Primary endpoint was late toxicity. Secondary endpoints were oncological outcome based on cumulative incidence of breast cancer local relapse (LR) and distant metastasis disease (DMD) and cause-specific (CSS) and overall (OS) survival. Prognostic factors for late toxicity were analyzed. From 01/2012 to 06/2022, the GEC-ESTRO VAPBI cohort included 516 pts with an early breast cancer. Median follow-up was 42 months [95% CI = 39 - 44]. Median age was 71 years [40 - 100]. Median tumor size was 12 mm [1 - 46]. Tumor was mainly invasive ductal carcinoma (78%), pN0 (88.5%), with positive hormonal receptors (98.5%) and negative HER2 overexpression (96%). Patients underwent hormonal and chemo-therapy in 93.8% and 2.3% respectively. Catheter placement was performed peri or post-operatively in 50.2% and 49.8% respectively. Median time interval between surgery and VABPI was 10 days [6 - 65]. VAPBI delivered 1, 3 and 4 fractions for 205 pts (39.7%), 167 pts (32.4%) and 144 pts (28%) respectively. Median CTV was 40.7 cc [95% CI = 26.6 - 72], median V100%, V150%, D90% and Dose non-uniformity ratio (DNR) were 90.2% [95% CI = 84.1 - 97.2], 24.2% [95% CI = 18.9 - 31.6], 103.8% [95% CI = 100.1 - 107.4] and 0.28 [95% CI = 0.23 - 0.33] respectively, 211 late toxicity events were observed in 168 pts (32.6%). Fibrosis, dyschromia, pain and telangiectasia were observed in 26.7%, 7.9%, 7.2% and 0.4 respectively. Grade 2 and 3 late toxicities were observed in 7.2 and 0.6% respectively (no G4). Grade ≥2 late toxicity was observed in 8.1%, 16.7% and 3.7% after 1, 3 and 4 fractions, respectively (p = 0.004). CTV > 50 cc (p = 0.007) and V150 > 40% (p = 0.027) were prognostic factors for G≥2 late toxicity. Regarding oncological outcome, 4-year cumulative incidence of LR, RR and DMD were 2% [95% CI = 0 - 3], 1% [95% CI = 0 - 2] and 1% [95% CI = 0 - 2] respectively. CSS and OS were 98% [95% CI = 96 - 100] and 93% [95% CI = 90 - 96] respectively. No significant difference was observed in terms of oncological outcome between the 3-fractionation groups. VAPBI based on 1 or 2 days of HDR MIB represents an attractive de-escalation irradiation approach for low-risk breast cancer. Late toxicity profile appears acceptable while early oncological outcome shows excellent local control. Brachytherapy technique remains a key component of clinical outcome. Longer follow-up is warranted in order to confirm these encouraging preliminary results.

Pathological and radiological response following neoadjuvant treatments in primary localized resectable myxofibrosarcoma and undifferentiated pleomorphic sarcoma of the extremities and trunk wall.

To explore the correlation between pathological and radiological response to preoperative treatments and outcome in surgically treated patients with myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). All consecutive patients with primary localized MFS and UPS of the extremities and trunk wall surgically treated with curative intent at our center (2005-2021) were included. Clinical data including residual visible tumor (VT%) on surgical specimen and Response Evaluation Criteria in Solid Tumor (RECIST) were retrieved. Kaplan-Meier curves for overall survival and disease-free survival, and cumulative incidence of local relapse and distant metastasis were estimated in a competing risk framework according to RECIST and VT%, overall and by treatment group. Cox and Fine and Gray multivariable models were performed. Of 693 patients affected by primary MFS and UPS, 233 (66 MFS and 167 UPS) were treated by neoadjuvant chemotherapy (naChT), radiotherapy (naRT), or both (naChT-RT). VT% was ≤5% in 13/46 (28.2%), 24/99 (24.2%), and 40/88 (45.4%) patients, respectively. There were 11/46 (29.7%), 22/99 (22.7%), and 23/88 (26.1%) RECIST partial responses and 18/46 (48.6%), 59/99 (60.8%), and 60/88 (68.2%) RECIST stable disease, respectively. In naChT, a trend for a better survival was observed when VT% ≤5% (p=.09), whereas RECIST partial responses and stable disease had the same outcome. VT% was not associated with outcome in naRT or naChT-RT, whereas RECIST response was. In primary localized MFS and UPS treated with neoadjuvant therapies, VT% seems more relevant than size reduction after naChT, whereas the opposite is true when naRT is administered alone or concurrent to ChT.

Patterns of Failure After Stereotactic Body Radiotherapy to Sacral Metastases

AimsStereotactic body radiotherapy (SBRT) is increasingly used to treat sacral metastases. We analysed our centre's local relapse rates and patterns of failure after sacral SBRT and assessed whether using the consensus contouring recommendation (CCR) may have prevented local relapse. Materials and methodsWe conducted a single-centre retrospective review of patients treated with sacral SBRT between February 2012 and December 2021. The cumulative incidence of local relapse, patterns of failure and overall survival were determined. Two investigators reviewed planning computed tomography scans and imaging at relapse to determine if local relapse was potentially preventable with a larger CCR-derived radiotherapy field. ResultsIn total, 34 patients received sacral SBRT, with doses ranging from 24 to 40 Gy over three to five fractions. The most frequently used schedule was 30 Gy in three fractions. Common primaries treated included prostate (n = 16), breast (n = 6), lung (n = 3) and renal (n = 3) cancers. The median follow-up was 20 months (interquartile range 13–55 months). The cumulative incidence of local relapse (4/34) was 2.9% (95% confidence interval 0.2–13.2), 6.3% (95% confidence interval 1.1–18.5) and 16.8% (95% confidence interval 4.7–35.4) at 6 months, 1 year and 2 years, respectively. The patterns of failure were local-only (1/34), local and distant (3/34) and distant relapse (10/34). The overall survival was 96.7% (95% confidence interval 90.5–100) and 90.6% (95% confidence interval 78.6–100) at 1 and 2 years, respectively. For prostate/breast primaries, the cumulative incidence of local relapse was 4.5% (95% confidence interval 0.3–19.4), 4.5% (95% confidence interval 0.3–19.4) and 12.5% (95% confidence interval 1.7–34.8) at 6 months, 1 and 2 years, respectively. Twenty-nine cases (85.3%) deviated from the CCR. Sacral relapse was potentially preventable if the CCR was used in one patient (2.9% of the whole cohort and 25% of the relapsed cohort). DiscussionWe have shown excellent local control rates with sacral SBRT, which was largely planned with a margin expansion approach.

Prognostic impact of germline BRCA1/2 pathogenic variants in breast cancer.

This study investigates the impact of different subtypes of pathogenic BRCA variants on the prognosis and on the survival of breast cancer (BC) patients. Associations between BRCA1/2 pathogenic variants (PVs) mutations, clinicopathological features, locoregional tumor reappearance, and survival data were analyzed. The Gray's test was used to test difference of the cumulative incidence of local relapse between missense/splicing and other mutations, taking into of competing events. The multivariate proportional hazard model was used to assess the independent association between type of mutation and local relapse, after adjustment for other prognostic factors and clinicopathological characteristics. Out of 482 patients, 285 presented 98 differentBRCA1 PVs and 201 harbored 103 different BRCA2 PVs. Missense mutations were found in 46 BC patients (9.5%), splicing mutations in 42 (8.6%), deletions in 206 (42.4%), insertions in 73 (15%), indel mutations in 6 (1.2%), nonsense mutations in 86 (17.7%), and large rearrangements in 27 (5.6%). Kalbfleisch and Prentice cumulative incidence curves analysis showed a significantly lower locoregional recurrence incidence in the missense/splicing group (Gray-test P-value = 0.011). We found that the risk of local relapse was 58% less likely in women carrying missense/splicing variants than in those with other PV subtypes (HR 95% CI 0.42 [0.21-0.82]; P-value = 0.0108). No significant differences were observed in overall survival (OS) in all groups. Having been found to be associated with a lower risk of BC reappearance, germline BRCA1/2 PVs of the missense/splicing subtypes can be used as prognostic predictors and are likely to improve BC patients' management.

Unplanned Excision of Extremity and Trunk Wall Soft Tissue Sarcoma: To Re-resect or Not to Re-resect?

The need for systematic reexcision in patients who underwent unplanned excision (UE) for extremity and superficial trunk soft tissue sarcoma (ESTSTS) has been questioned. We investigated the outcome of patients who underwent reexcision for ESTSTS compared with primarily resected at our institution and the prognostic impact of microscopic residual disease (MR) in the reexcision specimen. Primary ESTSTS patients surgically treated at our institution between 1997 and 2017 were divided in three groups: primarily resected (A), reexcised after macroscopically complete UE (B), and incomplete UE (C). Weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR), and distant metastasis (CCI-DM) were calculated and compared. In group B, multivariable models were performed to assess factors associated with the outcomes. A total of 1962 patients were identified: 1076,697 and 189 in groups A, B, and C, respectively. Overall median follow-up was 85 months. Seven-year weighted-OS was 73.8%, 84.1%, and 80.7% (p < 0.001) for groups A, B, and C respectively. Seven-year CCI-LR and DM were 5.0% and 25.3%, 12.1% and 15.8%, and 13.6% and 29.4% (both p < 0.001) for groups A, B, and C, respectively. At multivariable analysis, the presence MR was associated with LR (p < 0.001) but not with OS nor CCI-DM. UE and the presence of MR at pathology in reexcision specimen are associated to a higher risk of LR but not to a higher risk of DM or lower OS. After macroscopic complete UE, postponing reexcision until a LR occurs may be considered on an individualized basis.

Pilot study of loss of the p53/p63 target gene PERP at the surgical margin as a potential predictor of local relapse in head and neck squamous cell carcinoma.

PERP (p53 apoptosis effector related to PMP22) localizes to desmosomes and suppresses squamous cell carcinoma development. Loss of PERP leads to worse local control in head and neck squamous cell carcinoma (HNSCC), likely by destabilizing desmosomes. We evaluated PERP loss at HNSCC surgical margins as a predictor of local relapse. Combining discovery (n = 17) and validation (n = 31) cohorts, we examined membranous PERP protein expression by immunohistochemistry in surgical mucosal margins with competing risk analysis of the relationship between local relapse and PERP expression. Of the 44 analyzable patients, the 2-year cumulative incidence of local relapse was 44.4% for the PERP-negative group and 16.4% for the PERP-positive group (P = .01). A trend toward worse progression-free survival (P = .09) and overall survival (P = .06) was observed with loss of PERP. PERP loss at surgical margins is associated with higher risk of local recurrence in HNSCC, warranting further evaluation in a larger prospective study.

The prognostic impact of unplanned excision in primary STS of the extremities and trunk wall: Is re-excision always mandatory?

e23557 Background: To investigate the outcome of patients affected by soft tissue sarcomas (STS) of the extremities and trunk wall who underwent unplanned excision (UE) and the prognostic impact of microscopic residual tumor at re-excision. Methods: All consecutive patients affected by primary STS of the extremity and trunk wall operated at Fondazione IRCCS Istituto Nazionale dei Tumori from Jan 1997 to Dec 2017 were included and divided in 3 groups: patients primarily resected at our institution (group A), patients undergoing re-excision after macroscopically complete UE (group B) and patients undergoing completion resection after macroscopically incomplete UE (group C). Inverse probability treatment weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR) and of distant metastasis (CCI-DM) were calculated and compared. Histological subgroup curves were drawn and multivariable models were performed in group B. Results: 1965 patients were identified; 1079, 679 and 189 in group A, B and C respectively. Median follow-up was 84.41 months. 7-yrs OS was 0.74, 0.84 and 0.81 (p &lt; .001) for group A, B and C respectively; 7-yrs CCI-LR and DM were 0.05 and 0.25, 0.12 and 0.16, 0.14 and 0.29 (p &lt; .001 for both) for group A, B and C respectively. In group B, microscopic residual tumor was present in 26.9% of the surgical specimens, but this figure varied broadly among the histologic subtypes (being the lowest in Solitary Fibrous Tumor, 7.7%, and the highest in Myxofibrosarcoma [MFS], 46.5%). At multivariable analysis, age (for OS only), grade, size and histology were associated to OS and CCI-DM; while age, presence of residual tumor (p &lt; .001) and grade to CCI-LR. Of note, Myxoid liposarcoma (MLPS) and MFS showed the highest CCI-LR in presence of residual disease (18.6% vs 1.3% and 24.7% vs 7.2% respectively). Conclusions: Patients who underwent UE had a risk of LR twice as high as those primarily resected at a referral institution. However, this higher risk was not associated to a higher risk of DM or worse OS. In patients undergoing re-excision after macroscopic complete UE the presence of residual tumor was associated to a higher LR risk, again with no association with DM or OS. Despite the probable presence of a residual selection bias, it is possible that postponing re-excision after macroscopic complete UE doesn’t impact on the outcome. However, higher caution should be exerted for MLPS and MFS, given the higher probability of local relapse when microscopic residual tumor is found in the surgical specimen.

Image Guided Adaptive Endorectal Brachytherapy in the Nonoperative Management of Patients With Rectal Cancer

Organ preservation or nonoperative management of rectal cancer is of growing interest. Image guided adaptive endorectal brachytherapy is a radiation dose escalation modality: we explored its role in elderly patients unfit for surgery and patients refusing surgery. In this registry study, patients with rectal cancer who were ineligible for surgery received 40 Gy in 16 fractions of pelvic external beam radiation therapy. They subsequently received 3 weekly image guided adaptive brachytherapy boosts of 10 Gy to the residual tumor, for a total of 30 Gy in 3 fractions. Complete clinical response (cCR) and local control were the primary endpoints. 94 patients were included; the median age was 81.1 years. With a median follow-up of 1.9 years, the proportion of cCR was 86.2%, the tumor regrowth proportion was 13.6%, and the cumulative incidence of local relapse was 2.7% at 1 year and 16.8% at 2 years. When considering responders and nonresponders, the 2-year local control was 71.5%. The overall survival at 2 years was 63.6%. Acute rectal grade 1 to 2 toxicity included all patients: 12.8% of patients had late bleeding requiring iron replacement, blood transfusions, or argon plasma therapy. Results of this registry study, evaluating radiation dose escalation for elderly medically unfit patients with unselected tumors, reveal that a high proportion of patients achieved cCR with a manageable toxicity profile. This technology will likely contribute to the challenging nonoperative management paradigm of rectal cancer.

Local Control of Breast Conservation Therapy versus Mastectomy in Multifocal or Multicentric Breast Cancer: A Systematic Review and Meta-Analysis

Objective: Breast conservation therapy (BCT) for female patients with multifocal or multicentric (MF/MC) breast cancer remains controversial. The purpose of the present meta-analysis was to explore whether BCT was feasible for female patients with MF/MC breast cancer and to compare the results of treatment with those of female patients with unifocal breast cancer who underwent BCT and female patients with MF/MC breast cancer who underwent mastectomy. Methods: Online databases, including PubMed and Embase, were independently searched from inception to January 2018 and reviewed by two authors. The present meta-analysis compared local relapse (LR) of BCT versus mastectomy for patients with MF/MC breast cancer and LR of patients with unifocal breast cancer versus patients with MF/MC breast cancer who underwent BCT. Ten studies comprising 19,272 patients were included. Results: The cumulative incidence of LR was 5.6% (65/1,163) for MF/MC disease treated with BCT, 4.2% (750/17,656) for unifocal disease treated with BCT, and 2.0% (9/453) for MF/MC disease treated with mastectomy. Thus, the cumulative incidence of LR for MF/MC patients treated with BCT was significantly higher than for mastectomy (p < 0.001). However, the forest plot analysis showed no significant differences in LR between BCT and mastectomy procedures (OR = 1.22, 95% CI = 0.49–3.00, p = 0.67, I² = 0%). Compared with the unifocal group treated with BCT, BCT for MF/MC breast cancer showed a significant difference in LR (OR = 2.25, 95% CI = 1.48–3.42, p = 0.0001, I² = 0%). Conclusion: The LR of BCT for patients with MF/MC breast cancer was higher than that of BCT for patients with unifocal breast cancer. However, no significant difference was found in the incidence of LR between the BCT group and the mastectomy group in patients with MF/MC breast cancer.

Local Relapse After Breast-Conserving Therapy Versus Mastectomy for Extensive Pure Ductal Carcinoma In Situ ≥4 cm

The optimal treatment for patients with extensive pure ductal carcinoma in situ (DCIS) ≥4cm is controversial. This study evaluates local relapse according to type of local therapy: mastectomy, breast-conserving surgery (BCS) alone, and BCS+radiation therapy (RT). Subjects were female patients who received diagnoses of pure DCIS ≥4cm between 1989 and 2010 and were referred to British Columbia Cancer. Clinicopathologic and treatment characteristics were compared between treatment cohorts. Local relapse (LR) was estimated using competing risk analysis. Multivariable analysis was performed using Cox regression analysis. Patients had the following treatments: 490 mastectomy, 38 BCS alone, and 192 BCS+RT. The 10-year cumulative incidence of LR was 16% after BCS (95% confidence interval [CI], 6-29%), 8% after BCS+RT (95% CI, 4-12%), and 2% after mastectomy (95% CI, 1-4%). On multivariable analysis, estrogen receptor-negative disease (hazard ratio [HR], 3.32; 95% CI, 1.08-10.18; P=.04) and positive margins (HR, 3.55; 95% CI, 1.56-8.05; P=.002) were associated with increased LR. BCS alone (HR, 7.87; 95% CI, 2.82-21.92; P<.0001), BCS+RT+no boost (HR, 3.80; 95% CI, 1.56-9.28; P=.003), and BCS+RT+boost (HR, 5.76; 95% CI, 2.59-12.83; P<.0001) were all associated with a higher risk of relapse relative to mastectomy. Mastectomy remains a standard local treatment option for extensive DCIS, but BCS+RT may also be reasonably considered in selected patients with a careful discussion of the benefits, side effects, and patient preferences.

Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013

The objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma. Between 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy. Median follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival. We confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival.

Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study

EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

Preoperative Versus Postoperative Chemoradiotherapy for Locally Advanced Rectal Cancer: Results of the German CAO/ARO/AIO-94 Randomized Phase III Trial After a Median Follow-Up of 11 Years

Preoperative chemoradiotherapy (CRT) has been established as standard treatment for locally advanced rectal cancer after first results of the CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] trial, published in 2004, showed an improved local control rate. However, after a median follow-up of 46 months, no survival benefit could be shown. Here, we report long-term results with a median follow-up of 134 months. A total of 823 patients with stage II to III rectal cancer were randomly assigned to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or the same schedule of CRT used postoperatively. The study was designed to have 80% power to detect a difference of 10% in 5-year overall survival as the primary end point. Secondary end points included the cumulative incidence of local and distant relapses and disease-free survival. Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT. According to intention-to-treat analysis, overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P = .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P = .048). No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P = .9) and disease-free survival. There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. Integrating more effective systemic treatment into the multimodal therapy has been adopted in the CAO/ARO/AIO-04 trial to possibly reduce distant metastases and improve survival.

Postoperative versus preoperative chemoradiotherapy in locally advanced rectal cancer patients.

e14156 Background: Postoperative chemo-radiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative with postoperative chemo-radiotherapy for locally advanced rectal cancer patients. Methods: 84 patients with locally advanced resectable rectal cancer (clinical stage T3 or T4 or node-positive disease), 44 from them received neo- adjuvant radio-chemotherapy (Group I) before surgical resection versus 40 locally advanced rectal cancer patients received adjuvant radio-chemotherapy then chemotherapy after surgical resection (Group II). Statistical analysis of treatment response, duration of disease free, time to progression, survival rates, treatment tolerability and toxicity. Results: There is no statistically significant difference between rectal cancer patients as regard either survival function or disease recurrence. The overall three-year survival rates OS were 95.5 % (Group I) and 95 % (Group II), respectively (P=0.638). The disease free three-year survival rates DFS were 75% (Group I) and 70 % (Group II), respectively (P=0.908). The three-year cumulative incidence of local relapse was 25 percent for patients assigned to preoperative chemo-radiotherapy and 30 percent in the postoperative-treatment group (P=0.63). After preoperative chemo-radiotherapy, there is a significant shift toward earlier TNM stages (P=0.002) tumour with down staging. Conclusions: Preoperative as compared with post operative chemo-radiotherapy has a significant down staging given that it is associated with a superior overall compliance rate, an improved rate of local control, reduced toxicity, and an increased rate (66 %) of sphincter preservation in patients with low-lying tumours but did not improve survival rate.

Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years.

3516 Background: CAO/ARO/AIO-94 was published in 2004 with a median follow-up of 46 months (Sauer et al., N Engl J Med 2004). This trial established preoperative CRT as standard treatment for rectal cancer based on an improved local control rate at 5 years, however, no survival benefit could be shown. We here report results with a median follow-up of 134 months. Methods: We randomly assigned 823 patients with stage II or III rectal cancer to preoperative CRT (50.4 Gy) with 5-FU (1 g/msq/days 1-5, 29-33), surgery, and adjuvant 5-FU (500 mg/msq/days 1-5, 4 cycles), or the same schedule applied postoperatively. The study was designed to have 80% power to detect a difference of 10% in the 5-year overall survival as primary endpoint. Secondary endpoints included the cumulative incidence of local and distant relapses and disease-free survival. Results: Of 823 patients, 404 and 395 were randomized to preoperative and postoperative CRT, respectively; 24 were ineligible, and 38 requested a change in treatment group. Thus, 406 patients received preoperative CRT, 393 were treated in the postoperative arm. As of 12/2010, updated data for life and tumor status were available for 791 and 783 of 799 eligible patients, respectively. Overall survival at 10 years was 59.9 years (95% CI, 55.0-64.8%) in the preoperative arm, and 59.5% (95% CI, 54.6-64.4%) in the postoperative arm (p=0.86, log-rank test, according to intention to treat). The 10-year cumulative incidence of local relapse after macroscopically complete resection was 5.7% (95% CI, 3.2-8.2%) and 10.4% (95% CI, 7.1-13.4%) in the pre- and postoperative arms, respectively (p=0.009, log-rank test, according to actual treatment). No significant differences were detected for 10-year cumulative incidence of distant metastases (25.5% both, p=0.88) and DFS. Conclusions: There is a persisting significant improvement of pre- vs. postoperative CRT on local control, however, no effect on overall survival. Integrating more effective systemic treatment into the combined modality treatment has been adopted in trial CAO/ARO/AIO-04 to possibly reduce distant metastases and improve survival.

The Impact of Hypofractionated Whole Breast Radiotherapy on Local Relapse in Patients With Grade 3 Early Breast Cancer: A Population-Based Cohort Study

To determine whether patients with Grade 3 early breast cancer have an inferior rate of local disease control at 10 years with hypofractionated radiotherapy compared with more conventionally fractionated schedules. Local relapse rates were compared between patients receiving hypofractionated radiotherapy or conventionally fractionated radiotherapy to the whole breast in a population-based cohort of women with early-stage (T1-T2, N0, M0) Grade 3 breast cancers diagnosed between 1990 and 2000 and referred to the British Columbia Cancer Agency. Cumulative rates of local relapse were estimated using a competing risk method, and factors significant on univariate analysis were included with fractionation group in a multivariate model. The primary end point was local control at 10 years. A total of 1,335 patients with Grade 3 tumors were treated with adjuvant radiotherapy, 252 with conventional fractionation, and 1,083 with a hypofractionated schedule. The 10-year cumulative incidence of local relapse was 6.9% in the hypofractionated group and 6.2% in the conventionally fractionated group (p= 0.99). There is no evidence that hypofractionation is inferior to conventional fractionation for breast conserving therapy in patients with Grade 3 breast cancer in this large population-based series after 10 years of follow-up.

Conservative surgery in patients with multifocal/multicentric breast cancer

Many physicians recommend mastectomy in case of multifocal (MF) or multicentric (MC) breast cancer due to a theoretical risk of poor local control with less extensive surgery. We retrospectively evaluate outcome of patients with MF/MC cancers who had breast conservation with specific attention on local control and predictive factors of recurrence. Four hundred and seventy six patients with either MF (n = 421) or MC (n = 55) breast cancer, underwent breast-conserving surgery between 1997 and 2002 in a single institution. Median follow up was 73 months (range 11-118). Median age was 53 years (range 23-86). Invasive lobular carcinoma was found in 88 patients (18.5%) and mixed ductal-lobular cancer in 27 (5.7%) patients. Two hundred and sixty-seven patients (76.7%) had two identified tumor foci, 55 patients (15.3%) had three and 29 patients (8.0%) had four or more. Two hundred and sixty-one patients (55.3%) had nodal involvement. The 5-year cumulative incidence of local relapse was 5.1%. At the multivariate analysis, over-expression of HER2/neu and lack of both estrogen and progesterone receptors (HR: 3.2, 95% C.I. 1.01-10.0, and HR: 2.7, 95% C.I. 1.06-7.7, respectively) were associated with a higher ipsilateral breast cancer reappearance rate. Involvement of four or more lymph nodes and lack of estrogen and progesterone receptors (HR: 2.7, 95% C.I. 1.06-6.7, and HR: 4.7, 95% C.I. 2.1-10.4, respectively) were associated with poorer overall survival. In selected patients with MF/MC breast cancer, wide conservative surgery is not associated with poor local disease control and can be considered whenever acceptable cosmetic results can be achieved.

When can a second conservative approach be considered for ipsilateral breast tumour recurrence?

Mastectomy is considered the treatment of choice in patients with ipsilateral breast tumour recurrence (IBTR) after breast-conserving surgery (BCS). One hundred and sixty-one patients with invasive IBTR who underwent a second conservative approach were retrospectively evaluated in order to describe prognosis, determine predictive factors of outcome and select the subset of patients with the best local control. Fifty-seven patients (35.4%) relapsed after IBTR. Thirty-four patients (21.1%) had further in-breast recurrences and four patients (2.5%) had skin relapses. Five years cumulative incidence of local relapse was 31.4%. Twenty-four patients (17.8%, 5 years cumulative incidence) died during the follow-up. At the multivariate analysis, recurrent tumour size >2 cm was found to affect local-disease-free survival [hazard ratio (HR): 2.8, 95% confidence interval (CI) 1.2-6.2], whereas Ki-67 >or=20% and time to relapse <or=48 months were associated with disease-free survival (HR: 1.7, 95% CI 1.0-3.1, and HR: 2.1, 95% CI 1.2-3.6, respectively). Absence of oestrogen receptors affected overall survival (HR: 2.5, 95% CI 1.1-6.0). Among 64 patients with recurrent tumour <or=2 cm and time to IBTR >48 months, eight (12.8%, 5 years cumulative incidence) had further local relapses. Some patients with IBTR might receive a second BCS, especially when a good local control can be estimated (small recurrent tumour, late relapse), also taking into account patients' preference.

Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer

Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer. We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival. Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01). Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.

Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group☆

Objective To evaluate, in a randomized clinical trial, the role of adjuvant hysterectomy after standardized radiation in improving progression-free survival and survival for patients with “bulky” stage IB cervical cancer. Methods A total of 256 eligible patients with exophytic or “barrel” shaped tumors measuring ≥4 cm were randomized to either external and intracavitary irradiation (RT, N = 124) or attenuated irradiation followed by extrafascial hysterectomy (RT + HYST, N = 132). Twenty-five percent of patients had tumors with a maximum diameter of ≥7 cm. Results Tumor size was the most pronounced prognostic factor followed by performance status 2 and age at diagnosis. Hysterectomy did not increase the frequency of reported grade 3 and 4 adverse effects (both groups, 10%). The majority of these adverse effects were from the gastrointestinal or genitourinary tracts exclusively. There was a lower cumulative incidence of local relapse in the RT + HYST group (at 5 years, 27% vs. 14%). There were no statistical differences in outcomes between regimens except for the adjusted comparison of progression-free survival, although all indicated a lower risk in the adjuvant hysterectomy regimen (unadjusted relative risk [URR] of progression, 0.77, P = 0.07; URR of death, P = 0.26, both one tail). Conclusion Overall, there was no clinically important benefit with the use of extrafascial hysterectomy. However, there is good evidence to suggest that patients with 4-, 5-, and 6-cm tumors may have benefitted from extrafascial hysterectomy (URR of progression; 0.58; URR of death, 0.60).