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LARC is managed by multimodal treatments whose intensity can be highly modulated. In this context, we need surrogate endpoints to help predict long-term outcomes and better personalize treatments. A previous study identified 2yDFS as a stronger predictor of OS than pCR in LARC patients undergoing neoadjuvant RT. The aim of this pooled analysis was to assess the role of pCR and 2yDFS as surrogate endpoints for OS in a larger cohort. The pooled and subgroup analyses were performed on large rectal cancer randomized trial cohorts who received long-course RT. Our analysis focused on the evaluation of OS in relation to the pCR and 2-year disease status. A total of 4600 patients were analyzed. Four groups were identified according to intermediate outcomes: 12% had both pCR and 2yDFS (the better); 67% achieved 2yDFS but not pCR (the good); 1% had pCR but not 2yDFS; and 20% had neither pCR nor 2yDFS (the bad). The pCR and 2yDFS were favorably associated with OS in the univariate analysis, and 2yDFS maintained a statistically significant association in the multivariate analysis independently of the pCR status. The combination of the pCR and 2yDFS results in a strong predictor of OS, whereas failure to achieve 2yDFS carries a poor prognosis regardless of the pCR status. This new stratification of LARC patients could help design predictive models where the combination of 2yDFS and pCR should be employed as the primary outcome.

Background Frequency and predictive factors for a clinical complete response (cCR) in unselected patients are unclear. Material and methods Two prospective observational studies were designed and pooled to explore predictive factors for cCR. Both studies evaluated the watch-and-wait strategy in consecutive patients; the first single-institutional study in elderly with a small tumour, the second multi-institutional study in all the patients receiving standard of care preoperative radiotherapy. Results Four hundred and ninety patients were analysed. Short-course radiotherapy alone, or with consolidation chemotherapy or chemoradiation was given to 40.6%, 40.2% and 19.2% of the patients, respectively. The median interval from the radiation start to the first tumour response assessment was 10.2 weeks for short-course radiation and 13.2 weeks for chemoradiation. Seventy-three patients had cCR and 71 underwent w&w with the median follow-up of 24 months. The regrowth rate was 26.8%. cCR rate was 39.0% for low-risk cancer (cT1-2N0), 16.8% for intermediate-risk (cT3 with unthreatened mesorectal fascia [MRF−] or cT2N+) and 5.4% for high-risk (cT4 or MRF+). In the multivariable analysis, tumour volume (or tumour length and circumferential extent) and cN status were significant predictors for cCR. In circular cancers or with a length ≥7 cm (n = 184), cCR rate was only 2.7%, sustained cCR 1.6% and the sensitivity of cCR diagnosis 23.1%. None of 27 patients with a tumour larger than 120 cm3 achieved cCR. Conclusions Considering watch-and-wait strategy is questionable in patients with circular tumours or with tumour length ≥7 cm.

Summary Background Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. Methods We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. Findings We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0–75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8–90·9), for 3 years was 97·3% (95·2–98·6), and for 5 years was 98·6% (97·6–100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3–95·9), for 3 years was 97·8% (96·6–99·3), and for 5 years was 96·6% (94·0–98·9). Interpretation These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. Funding European Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d’HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.

Aim To evaluate the role of oxaliplatin in neoadjuvant chemotherapy delivered after short-course irradiation. Background Using oxaliplatin in the above setting is uncertain. Patients and methods A subgroup of 136 patients managed by short-course radiotherapy and 3 cycles of consolidation chemotherapy within the framework of a randomised study was included in this post-hoc analysis. Sixty-seven patients received FOLFOX4 (oxaliplatin group) while oxaliplatin was omitted in the second period of accrual in 69 patients because of protocol amendment (fluorouracil-only group). Results Grade 3+ acute toxicity from neoadjuvant treatment was observed in 30% of patients in the oxaliplatin group vs. 16% in the fluorouracil-only group (p = 0.053). The corresponding proportions of patients having radical surgery or achieving complete pathological response were 72% vs. 77% (odds ratio [OR] = 0.88; 95% confidence interval [CI]: 0.39–1.98; p = 0.75) and 15% vs. 7% (OR = 2.25; 95% CI: 0.83–6.94; p = 0.16), respectively. The long-term outcomes were similar in the two groups. Overall and disease-free survival rates at 5 years were 63% vs. 56% (p = 0.78) and 49% vs. 44% (p = 0.59), respectively. The corresponding numbers for cumulative incidence of local failure or distant metastases were 33% vs. 38% (hazard ratio [HR] = 0.89; 95% CI: 0.52–1.52; p = 0.68) and 33% vs. 33% (HR = 0.78; 95% CI: 0.43–1.40; p = 0.41), respectively. Conclusion Our findings do not support adding oxaliplatin to three cycles of chemotherapy delivered after short-course irradiation.

Objective: In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread - MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT. Methods and materials: A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed. Results: Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p

Background The watch-and-wait (w&w) strategy is associated with frequent local regrowth (LR). Distant metastases (DM) occur more often in the patients with LR than in those without. However, it is unknown whether omitting immediate surgery results in the additional risk of DM. Materials/methods A systematic review and meta-analysis were performed to determine the maximum risk of additional DM. To estimate this, we used data showing the proportions of DM in patients with and without LR, assuming that the excess DM in patients with LR may develop in two ways: from subclinical DM already present at baseline and due to seeding from the uncontrolled primary tumor, and that the incidence of subclinical DM at baseline in the LR subgroup is at least not lower than in the non-LR subgroup. Based on the calculated rate of excess DM in the LR subgroup we have obtained the rate for the whole group of patients undergoing w&w. Results The maximum estimated risk of additional DM was 3.0% (95% CI: 1.2–4.9%) in the total group. After correction for short follow-up, the maximum risk at 5 years was 6.5%. Thus, the risk of excess DM is between 0% and 6.5%. Other evidence from a systematic review and the conservative assumptions taken for the calculation of the correction suggest that this maximum risk may be overestimated. Conclusions The additional risk of DM seems to be low. However, the high probability of bias, heterogeneity of the patients’ population and low quality of evidence make our estimation uncertain.

The impact of the tumour volume or size on achieving clinical complete response (cCR) after radio(chemo)therapy is poorly understood. A literature search was performed to gather data on the predictive value of baseline tumour volume or size in achieving cCR. In total, nine reports were identified. In two of three studies evaluating the baseline tumour volumetry, the tumour volume was the most powerful predictor for cCR. In four of six studies evaluating baseline tumour size without volumetry, tumour dimension was significantly associated with cCR, in one study reached borderline significance and in one report was insignificant. In three of four studies where a multivariable analysis was performed, the cT category did not show an independent predictive value for cCR. Because the tumour shape is often (semi)annular, its circumferential rectal extent along with the tumour length probably impact the tumour volume most, and thus, could be considered an acceptable alternative for time-consuming volumetry. Our review suggests that baseline tumour volume (or alternatively, tumour length along with its circumferential rectal extent) is the most relevant clinical predictor of cCR. Therefore, we postulate assessing and reporting these parameters in studies on the watch-and-wait strategy.

Background: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. Methods: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. Results: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. Conclusion: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM.

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 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin). Results Patients (N = 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 = 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 = 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 = 1.08, 95% CI 0.70–1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68–1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ 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. Clinical trial number The trial is registered as ClinicalTrials.gov number NCT00833131.

Background There are no guidelines on clinical target volume (CTV) delineation for cT2 rectal cancer treated with organ preservation. Materials and methods A systematic review and meta-analysis were performed to determine the extent of distal mesorectal (DMS) and distal intramural spread (DIS), the risk of lateral lymph node (LLN) metastases in pT2 tumours, and regional recurrence pattern after organ preservation. Results The rate of DMS > 1 cm was 1.9% (95% CI: 0.4–5.4%), maximum extent: 1.3 cm. The rate of DIS > 0.5 cm was 4.7% (95% CI: 1.3–11.5%), maximum extent: 0.8 cm. The rate of LLN metastases was 8.2% (95% CI: 6.7–9.9%) for tumours below or at peritoneal reflexion and 0% for higher tumours. Regional nodal recurrences alone were recorded in 1.0% (95% CI: 0.5–1.7%) of patients after watch-and-wait and in 2.1% (95% CI: 1.2–3.4%) after preoperative radiotherapy and local excision. Thus, the following rules for CTV delineation are proposed: caudal border 1.5 cm from the tumour to account for DMS or 1 cm to account for DIS, whichever is more caudal; cranial border at S2/S3 interspace; inclusion of LLN for tumours at or below peritoneal reflexion. A planning study was performed in eight patients to compare dose–volume parameters obtained using these rules to that obtained using current guidelines for advanced cancers. The proposed rules led to a mean 18% relative reduction of planning target volume, which resulted in better sparing of organs-at-risk. Conclusion This meta-analysis suggests a smaller CTV for cT2 tumours than the current guidelines designed for advanced cancers.

Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or local excision. Organ preservation strategies can enable patients with a complete response or near-complete clinical responses after radiotherapy with or without concomitant chemotherapy to safely avoid the morbidities associated with radical surgery, and thus to maintain anorectal function and quality of life. However, standardization of the key outcome measures of organ preservation strategies is currently lacking; this includes a lack of consensus of the optimal definitions and selection of primary end points according to the trial phase and design; the optimal time points for response assessment; response-based decision-making; follow-up schedules; use of specific anorectal function tests; and quality of life and patient-reported outcomes. Thus, a consensus statement on outcome measures is necessary to ensure consistency and facilitate more accurate comparisons of data from ongoing and future trials. Here, we have convened an international group of experts with extensive experience in the management of patients with rectal cancer, including organ preservation approaches, and used a Delphi process to establish the first international consensus recommendations for key outcome measures of organ preservation, in an attempt to standardize the reporting of data from both trials and routine practice in this emerging area. Patients with early-stage rectal cancer might potentially benefit from treatment with an organ-sparing approach, which preserves quality of life owing to avoidance of the need for permanent colostomy. Trials conducted to investigate this have so far been hampered by considerable inter-trial heterogeneity in several key features. In this Consensus Statement, the authors provide guidance on the optimal end points, response assessment time points, follow-up procedures and quality of life measures in an attempt to improve the comparability of clinical research in this area. Yorkshire Cancer Research Academic Fellowship fund [L389AA]; Yorkshire Cancer Research; Cancer Research UKCancer Research UK [CRUK/28301]

ispartof: RADIOTHERAPY AND ONCOLOGY vol:148 pages:213-215 ispartof: location:Ireland status: published

BACKGROUND AND PURPOSES: To describe current practice in the management of rectal cancer, to identify uncertainties that usually arise in the multidisciplinary team (MDT)'s discussions ('grey zones') and propose next generation studies which may provide answers to them. MATERIALS AND METHODS: A questionnaire on the areas of controversy in managing T2, T3 and T4 rectal cancer was drawn up and distributed to the Rectal-Assisi Think Tank Meeting (ATTM) Expert European Board. Less than 70% agreement on a treatment option was indicated as uncertainty and selected as a 'grey zone'. Topics with large disagreement were selected by the task force group for discussion at the Rectal-ATTM. RESULTS: The controversial clinical issues that had been identified within cT2-cT3-cT4 needed further investigation. The discussions focused on the role of (1) neoadjuvant therapy and organ preservation on cT2-3a low-middle rectal cancer; (2) neoadjuvant therapy in cT3 low rectal cancer without high risk features; (3) total neoadjuvant therapy, radiotherapy boost and the best chemo-radiotherapy schedule in T4 tumors. A description of each area of investigation and trial proposals are reported. CONCLUSION: The meeting successfully identified 'grey zones' and, in the light of new evidence, proposed clinical trials for treatment of early, intermediate and advanced stage rectal cancer. ispartof: RADIOTHERAPY AND ONCOLOGY vol:142 pages:6-16 ispartof: location:ITALY, Assisi status: published

Recommendations for the application of post-operative adjuvant chemotherapy in patients who received preope­rative radio-chemotherapy are not consistent. Some of them advise post-operative chemotherapy, whilst others follow-up without any adjuvant treatment. The objective of this paper is to undertake an overview of the randomised studies evaluating whether the administration of adjuvant chemotherapy can be justified with clinical evidence. A systematic overview of the publications shows 5 randomised trials in which only the patients after pre-operative radio-chemotherapy were enrolled, whilst randomisation concerned adjuvant therapy vs follow-up without adjuvant therapy. None of the studies showed any improvement after post-operative chemotherapy with regards to both the overall survival and disease-free survival rate. Moreover, 3 randomised studies were found in which post-operative chemotherapy with fluoropyrimidine was compared with post-operative chemotherapy with fluoropyrimidine with the addition of oxaliplatin. One of these studies showed an improvement in the overall survival rate after the use of post-operative chemotherapy, whereas in two others the difference was statistically insignificant. Two studies showed a slight improvement after chemotherapy with regards to disease-free survival rates, whilst no such effect was observed in the third. A meta-analysis of the studies comparing the results after the administration of post-ope­rative chemotherapy with the results after the chemotherapy-free follow-up did not demonstrate any positive effect of the chemotherapy on the overall and disease-free survival rate. A meta-analysis of randomised studies in which post-operative chemotherapy with fluoropyrimidine was compared with post-operative chemotherapy with fluoro­pyrimidine with the addition of oxaliplatin did not show any improvement in disease-free survival rates in patients receiving oxaliplatin. The overall survival was not analysed because of the lack of appropriate data at the moment the meta-analysis was made. The above overview of the randomised trials points to a lack of any strong evidence justifying the administration of post-operative chemotherapy.

Purpose A previous randomized study conducted by our group showed that application of gentamicin-collagen implant (GCI) into the pelvic cavity after total mesorectal excision (TME) reduced the incidence of distant metastases. Therefore, we decided to conduct a confirmatory study. Methods Patients with rectal cancer were included in the study if they met the following criteria: adenocarcinoma of the rectum, preoperative short-term radiotherapy (5 × 5 Gy), and WHO performance score 0–1. Results One hundred seventy-six patients were randomly assigned either to an experimental group in which GCI was applied (n = 81) or to a control group without GCI (n = 81). Median follow-up was 80 months. Cumulative incidence of distant metastases at 5 years was higher in the control group compared to the experimental group: 23.5 vs 8.6% (HR 2.4 [95% CI 1.1–5.5], P = 0.005). Overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) did not differ between the experimental group and the control group: HR 0.95 [95% CI 0.55–1.70], P = 0.864; HR 0.85 [95% CI 0.50–1.45], P = 0.548, and HR 0.5 [95%CI 0.22–1.22], P = 0.093, respectively. The predefined by the protocol subgroup analysis for yp stage III disease showed better DFS in the experimental group compared to the control group; HR 0.47 [95%CI 0.23–0.97], P = 0.042). Conclusions The results confirmed our previous finding that GCI applied in the pelvis significantly reduced the rate of distant metastases in patients after radical rectal cancer resection. Electronic supplementary material The online version of this article (10.1007/s00384-018-3045-3) contains supplementary material, which is available to authorized users.

Introduction. The strategy of undertaking a watch-and-wait policy without surgical treatment is currently being debated in those patients where complete clinical response/regression (cCR) has been diagnosed after preoperative irradiation. Its proponents maintain that there is sufficient evidence of efficacy allowing routine use. This means that following preoperative chemoradiotherapy, each patient should be investigated for cCR. If so diagnosed, physicians are then obliged to give the patient the choice of two treatment options: surgical treatment or watch-and-wait without surgery. Radical surgical treatment is adopted as a rescue/salvage therapy if during the watch-and-wait period, local recurrence in patients occurs. In contrast, opponents of the strategy of watch-and-wait, purport that evidence for its efficacy is inadequate to justify routine use. Results. Literature data indicates that the rate of cCR depends on the tumour size, with incidence ranging between 5% and 78% of those patients irradiated prior to surgery. If the patients were kept under watch-and-wait without surgery, then the local recurrence rate was around 30%. Such high rates of local recurrences does not however disqualify this approach because the efficacy of rescue surgery was high. Distant metastases were rare, up 10% of patients, and survivals were even better compared to control patient groups who had been operated on due to not achieving cCR; this difference arising from the inherently less aggressive tumours that are sensitive to irradiation. Conclusions. The data hitherto indicate that a policy of watch-and-wait may be adopted in patients with CCR after chemoradiotherapy. Nevertheless, introducing this strategy requires acquiring experience for diagnosing CCR and an efficient organisation and supervision of treatment along with the rigorous follow-up.

Recent evidence shows that the majority of rectal cancers demonstrate occult tumor scatter after neoadjuvant chemoradiotherapy that can extend for several centimeters under adjacent normal-appearing mucosa beside the residual mucosal abnormality or scar.This systematic review aimed to determine all of the published selection criteria and technical descriptions for local excision to date with regard to this phenomenon.PubMed, MEDLINE, and Embase were searched using the following key words: rectal cancer, local excision, radiotherapy, and neoadjuvant.Studies that assessed local excision of rectal cancer after neoadjuvant chemoradiotherapy were included. Duplicate series were excluded from final analysis.All of the data points were tabulated and analyzed using Microsoft Excel.Criteria for patient selection, surgical technique, clinical restaging, pathologic assessment, and indications for completion surgery were analyzed.After exclusions, data from 25 studies that in total evaluated local excision in 1001 patients were included. Compared with the single accepted technique of total mesorectal excision, described techniques for local excision after neoadjuvant therapy demonstrate significant variability in many critical technical issues, such as marking/tattooing original tumor margins before neoadjuvant therapy, using pretreatment tumor size/stage as exclusion criteria, and specifically stating lateral excision margins. Where detailed, the majority of local recurrences occurred in patients with clear pathological margins, yet significant variation existed for pathological assessment and reporting, with few studies detailing R status and some not reporting margin status at all. Significant variability also existed for adverse tumor features that mandated completion surgery, and, importantly, many series describe patients refusing completion surgery where indicated.We were unable to perform meta-analysis because studies lacked sufficient methodologic homogeneity to synthesize.The observations from this study prompt additional study, standardization of technique, and cautious use of local excision of rectal cancer in the setting of neoadjuvant chemoradiotherapy.

Purpose To evaluate if neurological/cognitive function outcomes in patients with resected single brain metastasis (BM) after stereotactic radiotherapy of the tumor bed (SRT-TB) are not inferior compared to those achieved with whole-brain radiotherapy (WBRT). Methods Patients with total/subtotal resection of single BM were randomly assigned either to SRT-TB ( n =29) or WBRT ( n =30). SRT-TB arm consisted of 15Gy/1 fraction, or 5×5Gy. WBRT consisted of 30Gy/10 fractions. Neurological/cognitive failure was defined as a decrease of neurological score by one point or more, or a worsening of the MiniMental test by at least 3 points, or neurological death. Cumulative incidence of neurological/cognitive failure (CINCF), neurological death (CIND), and overall survival (OS) were compared. Results Median follow-up was 29months (range: 8–45) for 15 patients still alive. The difference in the probability of CINCF at 6months (primary endpoint) was −8% in favor of WBRT (95% confidence interval: +17% −35%; non-inferiority margin: −20%). In the intention-to-treat analysis, two-year CIND rates were 66% vs. 31%, for SRT-TB and WBRT arm, respectively, p =.015. The corresponding figures for OS were 10% vs. 37%, p =.046. Conclusions Non-inferiority of SRT-TB was not demonstrated in our underpowered study. More data from randomized studies are needed for confirmation of the value of this method.

Background During an ongoing phase II observational study on watch and wait policy in rectal cancer, a substantial number of patients presented residual lesion after radiotherapy with a clinical benign appearance. This article aims to discuss the clinical significance of such findings. Materials and methods Main entry criteria were age ≥70 years and small tumour (≤5 cm and ≤60% of circumferential involvement) located in the low rectum. Patients received chemoradiation (50 Gy, 2 Gy per fraction concomitantly with a 5-Fu bolus and leucovorin) or 5 × 5 Gy if considered unfit for chemotherapy. Patients with clinical complete response (cCR) were observed. Those with persistent tumours underwent transanal endoscopic microsurgery [TEM] if the baseline tumour was ≤3 cm and cN0 or total mesorectal excision. Results The watch and wait procedure was used in 11 out of the total 35 patients (31%) with a cCR; 17 patients (49%) with residual tumours that appeared clinically malignant were referred for TEM or abdominal surgery. In the remaining seven (20%), the residual tumour clinically appeared benign. Of these, there were two invasive cancers, four high-grade dysplasias and one low-grade dysplasia. The five patients with dysplasia, underwent local lesion resection without recurrence within a median of 11 months follow-up. Conclusions The majority of lesions that appeared clinically benign after radio(chemo)therapy were also benign on pathological examination. Thus, local excision of such lesions should be considered.

The Stockholm III randomized trial showed that short-course radiotherapy and delayed surgery can be used routinely for resectable tumours [1,2]. The interim analysis of this trial demonstrated path...

Background: Randomized trials have shown a lower efficacy of postoperative chemotherapy in rectal cancer patients having received preoperative radiotherapy than in nonirradiated colorectal cancer (CRC) patients. We hypothesized that preoperative radio(chemo)therapy impairs the relative dose intensity (RDI) of further chemotherapy because of long-term radiation damage. This retrospective study aimed to test this hypothesis. Methods: The analysis was conducted on 220 consecutive patients with CRC who received FOLFOX-4 postoperatively or because of cancer relapse. Of these, 41 patients with rectal cancer had preoperatively received radio(chemo)therapy (study group) and the remaining 179 with CRC had not (control group). The RDI of oxaliplatin at 8 and 16 weeks was calculated. Results: The median RDI of oxaliplatin at 8 weeks was 95.91% in the study group and 96.15% in the control group (p = 0.79). The corresponding percentages at 16 weeks were 87.6 and 86.5%, respectively (p = 0.55). It was found that within 0–8 weeks, 26.9% of the patients in the study group and 26.3% in the control group had grade 3+ toxicity, hypersensitivity reactions, or granulocyte colony-stimulating factor administration (p = 0.94). The corresponding percentages for 0–16 weeks were 44.8 and 43.9%, respectively (p = 0.92). Conclusions: We found no association between preoperative radio(chemo)therapy and the RDI of FOLFOX-4. We failed to explain the inferior efficacy of postoperative chemotherapy in patients with rectal cancer who had preoperatively received irradiation compared to those with CRC who had not.

In advising the optimal management for older patients, health care professionals try to balance the risks from frailty, vulnerability, and comorbidity against the patient's ultimate prognosis, potential functional outcomes and quality of life (QOL). At the same time it is important to involve the patient and incorporate their preferences. But how can we present and balance the potential downside of radical radiotherapy and risks of unsalvageable recurrence against the potential risks of postoperative morbidity and mortality associated with radical surgery? There are currently no nationally approved and evidence-based guidelines available to ensure consistency in discussions with older adults or frail and vulnerable patients. In this overview we hope to provide an insightful discussion of the relevant issues and options currently available. (C) 2018 Elsevier Ltd. All rights reserved.

Short-course radiotherapy (5 × 5 Gy) in rectal cancer is routinely being used preoperatively, either immediately before surgery or with surgery performed 6–8 weeks later. Acute toxicity, mostly grade I, occurred over the period of 5 × 5 Gy deliveries in about 25% of the patients, grade III complications in 0–3%. Most of the post-radiation toxicity occurs 3–7 days after the completion of radiotherapy in 27–41% of the patients; grade III side effects occurred in 2% to 5% of the patients. 5 × 5 Gy given immediately before surgery cases slightly increase in minor postoperative complications compared with surgery alone or when surgery is delayed after 5 × 5 Gy. Short-course preoperative radiotherapy causes several chronic functional problems. However, these problems do not seriously affect quality of life. Preoperative 5 × 5 Gy radiotherapy enhances severity of low anterior resection syndrome; after median 14.6 years of follow-up, major syndrome was observed in 56% of patients in the 5 × 5 Gy plus surgery group compared to 35% in the surgery only group, P < 0.01. In young women, 5 × 5 Gy to the pelvis results in radiation-induced menopause and infertility. Preoperative radiotherapy was associated with reduced vaginal dimensions, vaginal dryness, dyspareunia and lack of desire. Preoperative 5 × 5 Gy radiotherapy increases males sexual dysfunctions (ejaculation disorders and erectile functioning) caused by surgery. Scatter radiation dose at the testicles may result in a permanent infertility and in a risk of hypogonadism.

Individualized risk assessment for patients with rectal cancer might allow a better selection of patients who will benefit from postoperative treatment and intensified follow-up. The developed nomograms can contribute to better individual risk prediction for local recurrence, distant metastases and overall survival for patients operated on rectal cancer. This makes decision support in the consulting room feasible. Background In many European countries, short-term 5 × 5 Gy radiotherapy has become the standard preoperative treatment of patients with resectable rectal cancer. Individualized risk assessment might allow a better selection of patients who will benefit from postoperative treatment and intensified follow-up. Patients and methods From patient's data from three European rectal cancer trials (N = 2881), we developed multivariate cox nomograms reflecting the risk for local recurrence (LR), distant metastases (DM) and overall survival (OS). Evaluated variables were age, gender, tumour distance from the anal verge, the use of radiotherapy, surgical technique (total mesorectal excision/conventional surgery), surgery type (low anterior resection/abdominoperineal resection), time from randomization to surgery, residual disease (R0 versus R1 + 2), pT-stage, pN-stage and surgical complications. Results Pathological T- and N-status are of vital importance for an accurate prediction of LR, DM and OS. Short-course radiotherapy reduces the rate of LR. The developed nomograms are capable of predicting events with a validation c-index of 0.79 (LR), 0.76 (DM) and 0.75 (OS). The proposed stratification in risk groups allowed significant distinction between Kaplan–Meier curves for outcome. Conclusion The developed nomograms can contribute to better individual risk prediction for LR, DM and OS for patients operated on rectal cancer. The practicality of the defined risk groups makes decision support in the consulting room feasible, assisting physicians to select patients for adjuvant therapy or intensified follow-up.

Purpose Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patient’s sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. Methods Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. Findings The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5–15% had pCR and were disease free after 2 years (excellent prognosis), 65–75% had no pCR but were disease free (good prognosis) and 15–30% had neither pCR nor 2yDFS (poor prognosis). Interpretation Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies.

BACKGROUND:In elderly and comorbid patients with rectal cancer, radical surgery is associated with significant perioperative mortality. Data suggest that a watch-and-wait approach where a complete clinical response is obtained after neoadjuvant chemoradiotherapy might be oncologically safe.OBJECTIVE

Rectal cancers can be categorized into three clinical subgroups: early, intermediate, and those locally advanced. For the latter two cases, preoperative radiotherapy is recommended. An advanced type of cancer is diagnosed whenever a cT3 lesion threatens or invades mesorectal fascia or when a cT4 tumor overgrows into organs not readily resectable. For the intermediate-risk group, tumor shrinkage before surgery is not needed and preoperative radiotherapy is aimed at reducing the risk of local recurrence. There are two types of preoperative radiation treatment commonly accepted as standard for the intermediate risk group: (1) short-course (5 fractions of 5 Gy over 1 week) radiotherapy (RT) with surgery carried out within the next 5 days and (2) long-course chemoradiation (conventionally fractionated RT consisting of 25–28 fractions of 1.8 or 2 Gy over 5–5.5 weeks concomitantly used with 5-fluorouracil or capecitabine) with surgery carried out 6–8 weeks thereafter.

Background and purpose The aim of this randomised trial was to investigate whether hyperthermia (HT) combined with interstitial brachytherapy (ISBT) has any influence on local control (LC), disease-free survival (DFS), or acute and late side effects in patients with advanced cervical cancer. Materials and methods After radiochemotherapy, consecutive patients with cervical cancer (FIGO stage II–III) were randomly assigned to two treatment groups, either ISBT alone or ISBT combined with interstitial hyperthermia (ISHT). A total of 205 patients were included in the statistical analysis. Once a week, HT, at a temperature above 42.5°C, was administered for 45min before and during the HDR BT. Results The median follow-up time was 45months (range 3–72months). An effect of hyperthermia was not detected for disease-free survival (DFS) (log-rank test: p =0.178) or for local control (LC) ( p =0.991). According to Cox's analysis, HT did not significantly influence failure or interactions with potential prognostic factors for LC or DFS. Statistical differences were not observed for the distribution of early and late complications between the HT and non HT groups. Conclusions ISHT is well-tolerated and does not affect treatment-related early or late complications. Improvements in DFS and LC were not observed following the addition of ISHT to ISBT.

Background and purpose A previous prospective trial reported that three-dimensional conformal postoperative radiotherapy (PORT) for pN2 NSCLC patients using a limited clinical target volume (CTV) had a late morbidity rate and pulmonary function that did not differ from those observed in pN1 patients treated with surgery without PORT. The aim of this study was to assess locoregional control and localization of failure in patients treated with PORT. Materials and methods The pattern of locoregional failure was evaluated retrospectively in 151 of 171 patients included in the PORT arm. The CTV included the involved lymph node stations and those with a risk of invasion >10%. Competing risk analysis was used to assess the incidence of locoregional failure and its location outside the CTV. Results Overall survival at 5years was 27.1% with a median follow-up of 67months for 40 living patients. The 5-year cumulative incidence of locoregional failure was 19.4% (95% CI: 18.2–20.5%) including a failure rate of 2% (95% CI: 0–17%) in locations outside or at the border of the CTV. Conclusions The use of limited CTV was associated with acceptable risk of geographic miss. Overall locoregional control was similar to that reported by other studies using PORT for pN2 patients.

Purpose To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer. Methods Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment. Results 49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II. Conclusions The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.

Aim The 1-cm rule of distal bowel clearance in patients with low-lying rectal cancer undergoing anterior resection is based mainly on pathological data showing distal intramural spread. Because clinical data are contradictory, a review that includes only cancers located ≤ 5 or ≤ 6 cm from the anal verge was carried out. Method A systematic review of the literature identified seven studies that presented results in relation to a margin of ≤ 1 cm (n = 293) vs > 1 cm (n = 315). In six studies, pre- or postoperative radiotherapy was implemented, and in one study patients were treated with surgery alone. Three studies, all implementing radiotherapy, reported results related to a margin of ≤ 5 mm (n = 51) vs > 5 mm (n = 125). Results In none of the studies were the differences in local recurrence rate between the small and large margin groups statistically significant. The pooled analysis of six studies, in which patients received perioperative radiotherapy, showed a 1.2% [95% confidence interval (Cl) −4.5–7.0%] higher local recurrence rate in the ≤ 1 cm margin group compared with the > 1 cm margin group (P = 0.6). The corresponding figures for the ≤ 5 mm cut-off point were 0.5% (95% CI −7.6–8.7%, P = 0.9). The 5-year local recurrence rate in the only study in which radiotherapy had not been used was 8.6% higher in the ≤ 1 cm margin group compared with the > 1 cm margin group (P = 0.09). Conclusion Clinical evidence does not support the 1-cm rule in patients with low-lying rectal cancer undergoing pre- or postoperative radiotherapy.

Background Whether there is any benefit derived from adding oxaliplatin to fluoropyrimidine-based preoperative chemoradiation is currently unknown in cases of advanced cT3 or cT4 tumours. Our aim was to evaluate this issue by analysing a randomized trial, which compared two schedules of preoperative treatment (chemoradiation vs. 5 × 5 Gy with 3 cycles of consolidation chemotherapy) for cT4 or fixed cT3 rectal cancer. Patients and methods Delivery of oxaliplatin was mandatory to the first part of the study. For the second part, its delivery in both treatment-assigned groups was left to the discretion of the local investigator. We analysed a subgroup of 272 patients (136 in the oxaliplatin group and 136 in the fluorouracil-only group) from institutions that had omitted oxaliplatin in the second part of the study. Results Circumferential resection margin negative (CRM−) status rate was 68% in the oxaliplatin group and 70% in the fluorouracil-only group, p = 0.72. The pathological complete response rate (pCR) was correspondingly 14% vs. 7%, p = 0.10. Following multivariable analysis, when comparing the CRM− status in the oxaliplatin group to the fluorouracil-only group, the odds ratio was 0.79 (95 CI 0.35–1.74), p = 0.54; there being no interaction between concomitant chemoradiation and 5 × 5 Gy with consolidation chemotherapy; p interaction = 0.073. For pCR, the corresponding results were 0.47 (95 CI 0.19–1.16), p = 0.10, p interaction = 0.84. Conclusion No benefit was found of adding oxaliplatin in terms of CRM nor pCR rates for either concomitant or sequential settings in preoperative radiochemotherapy for very advanced rectal cancer.