International Validation of the EORTC QLQ-ANL27, a Field Study to Test the Anal Cancer-Specific Health-Related Quality-of-Life Questionnaire.

PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) health-related quality of life questionnaire for anal cancer (QLQ-ANL27) supplements the EORTC cancer generic measure (QLQ-C30) to measure concerns specific to people with anal cancer treated with chemoradiotherapy. This study tested the psychometric properties and acceptability of the QLQ-ANL27. METHODS AND MATERIALS: People with anal cancer were recruited from 15 countries to complete the QLQ-C30 and QLQ-ANL27 and provide feedback on the QLQ-ANL27. Item responses, scale structure (multitrait scaling, factor analysis), reliability (internal consistency and reproducibility) and sensitivity (known group comparisons and responsiveness to change) of the QLQ-ANL27 were evaluated. RESULTS: Data from 382 people were included in the analyses. The EORTC QLQ-ANL27 was acceptable, comprehensive, and easy to complete, taking an average 8 minutes to complete. Psychometric analyses supported the EORTC QLQ-ANL27 items and reliability (Cronbach's α ranging from 0.71-0.93 and test-retest coefficients above 0.7) and validity of the scales (particularly nonstoma bowel symptoms and pain/discomfort). Most scales distinguished people according to treatment phase and performance status. Bowel (nonstoma), pain/discomfort, and vaginal symptoms were sensitive to deteriorations over time. The stoma-related scales remained untested because of low numbers of people with a stoma. Revisions to the scoring and question ordering of the sexual items were proposed. CONCLUSIONS: The QLQ-ANL27 has good psychometric properties and is available in 16 languages for people treated with chemoradiotherapy for anal cancer. It is used in clinical trials and has a potential role in clinical practice.

Neoadjuvant Chemotherapy without Radiation in Colorectal Cancer.

In colon cancer, primary surgery followed by postoperative chemotherapy represents the standard of care. In rectal cancer, the standard of care is preoperative radiotherapy or chemoradiation, which significantly reduces local recurrence but has no impact on subsequent metastatic disease or overall survival. The administration of neoadjuvant chemotherapy (NACT) before surgery can increase the chance of a curative resection and improves long-term outcomes in patients with liver metastases. Hence, NACT is being explored in both primary rectal and colon cancers as an alternative strategy to shrink the tumor, facilitate a curative resection, and simultaneously counter the risk of metastases. Yet, this lack of clarity regarding the precise aims of NACT (downstaging, maximizing response, or improving survival) is hindering progress. The appropriate cytotoxic agents, the optimal regimen, the number of cycles, or duration of NACT prior to surgery or in the postoperative setting remains undefined. Several potential strategies for integrating NACT are discussed with their advantages and disadvantages.

Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients.

Whilst anal cancer accounts for less than 1% of all new cancer cases, incidence rates have increased by up to 70% in the last 30 years with the majority of cases driven by human papilloma virus (HPV) infection. Standard treatment for localised anal cancer is chemoradiotherapy (CRT). Localised progression is the predominant pattern of relapse but well under 50% of cases are salvaged by surgery, predominantly because confirming recurrence within post-radiation change is very challenging. Identifying cancer-associated circulating cells (CCs) in peripheral blood could offer a corroborative method of monitoring treatment efficacy and identifying relapse early. To study this, nucleated cells were isolated from the blood of patients with anal cancer prior to, during, and after CRT and processed through the Amnis® ImageStream®X Mk II Imaging Flow Cytometer, without prior enrichment, using Pan-cytokeratin (PCK), CD45 antibodies and making use of the DNA dye DRAQ5. Analysis was undertaken using IDEAS software to identify those cells that were PCK-positive and DRAQ5-positive as well as CD45-negative; these were designated as CCs. CCs were identified in 7 of 8 patients; range 60-876 cells per mL of blood. This first report of the successful identification of CCs in anal cancer patients raises the possibility that liquid biopsies will find a future role as a prognostic/diagnostic tool in this patient group.

International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct.

PURPOSE: To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen. PATIENTS AND METHODS: Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m2 (day 1) plus FU 1,000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner. RESULTS: We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; P = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; P = .014). CONCLUSION: This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.

How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement.

Various methods categorize tumour response after neoadjuvant therapy, including down-staging and tumour regression grading. Response categories allow comparison of different treatments within clinical trials and predict outcome. A reproducible response categorization could identify subgroups with high or low risk for the most appropriate subsequent treatments, like watch and wait. Lack of standardization and interpretation difficulties currently limit the usability of these approaches. In this review we describe these difficulties for the evaluation of chemoradiation in rectal cancer. An alternative approach of tumour response is based on patterns of residual disease, including fragmentation. We summarise the evidence behind this alternative method of response categorisation, which explains a number of very relevant clinical discrepancies. These issues include differences between downstaging and tumour regression, high local regrowth in advanced tumours during watchful waiting procedures, the importance of resection margins, the limited value of post-treatment biopsies and the relatively poor outcome of patients with a near complete pathological response. Recognition of these patterns of response can allow meaningful development of novel biomarkers in the future.

Should we favour the use of 5 × 5 preoperative radiation in rectal cancer.

The management of patients with "locally advanced rectal cancer" (LARC) is evolving from the original aim of reducing local recurrence. Current practice recognises the importance of surgical technique, high-quality preoperative imaging, and integration of neoadjuvant systemic chemotherapy. Contemporary protocols focus on improving survival and avoiding radical surgery with organ preservation strategies. Both short course preoperative radiotherapy (SCPRT) with immediate surgery and long-course chemoradiation (LCCRT) are standard neoadjuvant strategies, both demonstrating similar efficacy in preventing local recurrence, distant metastases and improving disease-free survival (DFS). SCPRT is highly cost-effective with high compliance rates, hence is gaining traction in Europe and East Asia, partly because of inherent flexibility in timing and the ability to add neoadjuvant systemic chemotherapy as there is a delay to surgery. SCPRT is currently not being exploited to its full extent - particularly in the USA where uptake is approximately 1% of neoadjuvant treatments for rectal cancer. We analyse the use of induction, concurrent and consolidation chemotherapy with SCPRT in a total neoadjuvant therapy (TNT) approach.

The Management and Prevention of Anal Squamous Cell Carcinoma.

Our aim is to discuss the current established management of care and associated prevention strategies of anal squamous cell carcinoma (SCCA). In general, the development of SCCA is commonly linked to a prior history of HPV. Unfortunately, HPV vaccination continues to be underutilized in the United States versus other countries. Increased acknowledgment of the importance of HPV vaccination as an anticancer vaccine should be encouraged. The present standard of care is primary chemoradiotherapy (CRT), which results in a high level of disease control for small, early-stage SCCA. More advanced cancers still fare poorly with this treatment, and the disease relapses locoregionally in the majority of cases (30%-50% of patients), resulting in an abdominoperineal resection. Current treatment recommendations are associated with substantial morbidity; alternative radiation doses and/or novel combinations of agents with CRT are needed to improve quality of life and oncologic outcomes. Cytotoxic chemotherapy remains the standard of care for treatment-naïve patients with metastatic disease, with a possible new treatment paradigm of carboplatin/weekly paclitaxel. In addition, immune checkpoint inhibition appears to have a promising role in the setting of patients with refractory disease. Several clinical trials with immunotherapeutic and vaccine approaches for locally advanced and metastatic anal cancer are ongoing, as are HPV-agnostic umbrella trials. Whenever possible, clinical trial enrollment is always encouraged for further therapeutic development in the setting of a rare cancer, given the potentially substantial global impact for other HPV-associated malignancies.

MRI heterogeneity analysis for prediction of recurrence and disease free survival in anal cancer.

BACKGROUND: The aim of this study was to evaluate the role of image heterogeneity analysis of standard care magnetic resonance imaging (MRI) in patients with anal squamous cell carcinoma (ASCC) to predict chemoradiotherapy (CRT) outcome. The ability to predict disease recurrence following CRT has the potential to inform personalized radiotherapy approaches currently being explored in novel clinical trials. METHODS: An IRB waiver was obtained for retrospective analysis of standard care MRIs from ASCC patients presenting between 2010 and 2014. Whole tumor 3D volume-of-interest (VOI) was outlined on T2-weighted (T2w) and diffusion weighted imaging (DWI) of the pre- and post-treatment scans. Independent imaging features most predictive of disease recurrence were added to the baseline clinico-pathological model and the predictive value of respective extended models was calculated using net reclassification improvement (NRI) algorithm. Cross-validation analysis was carried out to determine percentage error reduction with inclusion of imaging features to the baseline model for both endpoints. RESULTS: Forty patients who underwent 1.5 T pelvic MRI at baseline and following completion of CRT were included. A combination of two baseline MR heterogeneity features (baseline T2w energy and DWI coefficient of variation) was most predictive of disease recurrence resulting in significant NRI (p = 0 < 0.001). This was confirmed in cross-validation analysis with 34.8% percentage error reduction for the primary endpoint and 18.1% reduction for the secondary endpoint with addition of imaging variables to baseline model. CONCLUSION: MRI heterogeneity analysis offers complementary information, in addition to clinical staging, in predicting outcome of CRT in anal SCC, warranting validation in larger datasets.

Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review.

INTRODUCTION: There is a paucity of data on incidence and mechanisms of long-term gastrointestinal consequences after chemoradiotherapy for anal cancer. Most of the adverse effects reported were based on traditional external beam radiotherapy whilst only short-term follow-ups have been available for intensity-modulated radiotherapy, and there is lack of knowledge about consequences of dose-escalation radiotherapy. METHOD: A systematic literature review. RESULTS: Two thousand nine hundred and eighty-five titles (excluding duplicates) were identified through the search; 130 articles were included in this review. The overall incidence of late gastrointestinal toxicity was reported to be 7-64.5%, with Grade 3 and above (classified as severe) up to 33.3%. The most commonly reported late toxicities were fecal incontinence (up to 44%), diarrhea (up to 26.7%), and ulceration (up to 22.6%). Diarrhea, fecal incontinence and buttock pain were associated with lower scores in radiotherapy specific quality of life scales (QLQ-CR29, QLQ-C30, and QLQ-CR38) compared to healthy controls. Intensity-modulated radiation therapy appears to reduce late toxicity. CONCLUSION: Late gastrointestinal toxicities are common with severe toxicity seen in one-third of the patients. These symptoms significantly impact on patients' quality of life. Prospective studies with control groups are needed to elucidate long-term toxicity.

Optimal management of localized rectal cancer in older patients.

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.

Toxicity, Tolerability, and Compliance of Concurrent Capecitabine or 5-Fluorouracil in Radical Management of Anal Cancer With Single-dose Mitomycin-C and Intensity Modulated Radiation Therapy: Evaluation of a National Cohort.

PURPOSE: Chemoradiation therapy (CRT) with mitomycin C (MMC) and 5-fluorouracil (5-FU) is established as the standard of care for the radical treatment of patients with anal squamous cell carcinoma (ASCC). The use of the oral fluoropyrimidine-derivative capecitabine is emerging as an alternative to 5-FU despite limited evidence of its tolerability and toxicity. METHODS AND MATERIALS: A national cohort evaluation of ASCC management within the United Kingdom National Health Service was undertaken from February to July 2015. The toxicity rates were prospectively recorded. For the present analysis, we report data from ASCC patients who underwent intensity modulated RT and a single dose of MMC with either 5-FU (5-FU/MMC) or capecitabine (capecitabine/MMC). All were treated with radical intent and intensity modulated radiation therapy (IMRT) was delivered in accordance with UK guidance. RESULTS: Of the 242 patients received from 40 centers across the United Kingdom, 147 met the inclusion criteria; 52 of whom were treated with capecitabine/MMC and 95 with 5-FU/MMC. No treatment-related deaths and no overall difference were found in the proportion of patients experiencing any grade ≥3 toxicity between the capecitabine and 5-FU groups (45% vs 55%; P = .35). However, significantly fewer patients in the capecitabine/MMC group experienced grade 3 hematologic toxicity (4% vs 27%; P = .001). A lower proportion of patients completed their planned chemotherapy course in the capecitabine cohort, although this did not reach statistical significance (81% vs 90%; P = .21). The median RT duration was 38 days (interquartile range 38-39) for both groups. No difference was found in the 1-year oncologic outcomes. CONCLUSIONS: Capecitabine/MMC resulted in similar levels of grade 3/4 toxicity overall compared with 5-FU/MMC as CRT for ASCC, although differences were found in the patterns of observed toxicities, with less hematologic toxicity with capecitabine. Further studies of capecitabine/MMC are required to understand the acute toxicity profile and long-term oncologic outcomes of this combination with intensity modulated RT for ASCC.

Development and external validation of a nomogram and online tool to predict bowel dysfunction following restorative rectal cancer resection: the POLARS score.

OBJECTIVE: Bowel dysfunction is common following a restorative rectal cancer resection, but symptom severity and the degree of quality of life impairment is highly variable. An internationally validated patient-reported outcome measure, Low Anterior Resection Syndrome (LARS) score, now enables these symptoms to be measured. The study purpose was: (1) to develop a model that predicts postoperative bowel function; (2) externally validate the model and (3) incorporate these findings into a nomogram and online tool in order to individualise patient counselling and aid preoperative consent. DESIGN: Patients more than 1 year after curative restorative anterior resection (UK, median 54 months; Denmark (DK), 56 months since surgery) were invited to complete The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 version3 (EORTC QLQ-C30 v3), LARS and Wexner incontinence scores. Demographics, tumour characteristics, preoperative/postoperative treatment and surgical procedures were recorded. Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, risk factors for bowel dysfunction were independently assessed by advanced linear regression shrinkage techniques for each dataset (UK:DK). RESULTS: Patients in the development (UK, n=463) and validation (DK, n=938) datasets reported mean (SD) LARS scores of 26 (11) and 24 (11), respectively. Key predictive factors for LARS were: age (at surgery); tumour height, total versus partial mesorectal excision, stoma and preoperative radiotherapy, with satisfactory model calibration and a Mallow's Cp of 7.5 and 5.5, respectively. CONCLUSIONS: The Pre-Operative LARS score (POLARS) is the first nomogram and online tool to predict bowel dysfunction severity prior to anterior resection. Colorectal surgeons, gastroenterologist and nurse specialists may use POLARS to help patients understand their risk of bowel dysfunction and to preoperatively highlight patients who may require additional postoperative support.

Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer.

For patients with high-risk stage II or stage III colon cancer, adjuvant chemotherapy with fluoropyrimidine monotherapy reduces the risk of recurrence and death by approximately 20-30%. Additional improvements have been reported in three phase 3 colon cancer trials when oxaliplatin was added to fluoropyrimidines, although the effect was mainly on disease-free survival. However, patients with rectal cancer were specifically excluded from these landmark studies because of potential toxicity and the confounding impact of radiotherapy and chemoradiation. Hence, despite evidence from smaller individual postoperative adjuvant phase 3 trials, meta-analyses, retrospective analyses, reviews, and population studies, the precise benefit of adjuvant chemotherapy for patients with rectal cancer following radiotherapy or chemoradiation remains unclear. Consequently, clinical guidelines offer inconsistent recommendations for the management of this patient population. In this Review, we suggest that the available data do not robustly support the routine use of postoperative adjuvant chemotherapy for patients with rectal cancer treated with preoperative chemoradiation. We discuss sources of bias and offer potential reasons to explain this observation, as well as propose a recommended schema for a randomised phase 3 trial that might potentially answer this question definitively.

3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer.

The primary treatment of pancreatic cancer was the topic of the 3rd St. Gallen Conference 2016. A multidisciplinary panel reviewed the current evidence and discussed controversial issues in a moderated consensus session. Here we report on the key expert recommendations. It was generally accepted that radical surgical resection followed by adjuvant chemotherapy offers the only evidence-based treatment with a chance for cure. Initial staging should classify localised tumours as resectable or unresectable (i.e. locally advanced pancreatic cancer) although there remains a large grey-zone of potentially resectable disease between these two categories which has recently been named as borderline resectable, a concept which was generally accepted by the panel members. However, the definition of these borderline-resectable (BR) tumours varies between classifications due to their focus on either (i) technical hurdles (e.g. the feasibility of vascular resection) or (ii) oncological outcome (e.g. predicting the risk of a R1 resection and/or occult metastases). The resulting expert discussion focussed on imaging standards as well as the value of pretherapeutic laparoscopy. Indications for biliary drainage were seen especially before neoadjuvant therapy. Following standard resection, the panel unanimously voted for the use of adjuvant chemotherapy after R0 resection and considered it as a reasonable standard of care after R1 resection, even though the optimal pathologic evaluation and the definition of R0/R1 was the issue of an ongoing debate. The general concept of BR tumours was considered as a good basis to select patients for preoperative therapy, albeit its current impact on the therapeutic strategy was far less clear. Main focus of the conference was to discuss the limits of surgical resection and to identify ways to standardise procedures and to improve curative outcome, including adjuvant and perioperative treatment.