Evolving Concepts toward Individualized Treatment of Squamous Cell Carcinoma of the Anus

Treatment of squamous cell carcinoma of the anus has evolved over the last 5 decades from radical surgery to combined chemoradiation therapy. Radiation treatment techniques have dramatically improved with the development of more powerful computers, algorithms and treatment machines. The clinical impact of the modern radiation treatment techniques, such as intensity-modulated radiotherapy and volumetric modulated arc therapy, is discussed. The standard-of-care regimen still is concurrent Mitomycin C, 5-fluorouracil and high-dose radiation, as was conceived 45 years ago. Variants of this schedule are discussed in this chapter. International guidelines have been generated and implemented. Whereas concurrent chemoradiation therapy is the treatment of choice for locally advanced tumors, early tumors are probably adequately controlled with either reduced dose chemoradiation therapy or radiation therapy alone. Prognostic factors, such as high-risk human papillomavirus, epidermal growth factor receptor and immune response, will be highlighted. The role of surgery in primary care is limited to local excision of T1N0 tumors ≤ 1 cm of the anal margin. Salvage radical surgery is limited to locoregional recurrent, non-metastasized and resectable tumors after chemoradiation therapy. In addition, new treatment modalities, such as targeted therapy and immunotherapy, will be discussed. Current research aims at refining prognostic subgroups to further individualize treatment strategy, implementing quality assurance protocols in international trials and investigating the molecular profile of squamous cell carcinoma of the anus, in order to identify new treatment avenues. This will hopefully change the landscape of anal cancer treatment in the future

Tumour ADC measurements in rectal cancer: effect of ROI methods on ADC values and interobserver variability

OBJECTIVES: To assess the influence of region of interest (ROI) size and positioning on tumour ADC measurements and interobserver variability in patients with locally advanced rectal cancer (LARC). METHODS: Forty-six LARC patients were retrospectively included. Patients underwent MRI including DWI (b0,500,1000) before and 6-8 weeks after chemoradiation (CRT). Two readers measured mean tumour ADCs (pre- and post-CRT) according to three ROI protocols: whole-volume, single-slice or small solid samples. The three protocols were compared for differences in ADC, SD and interobserver variability (measured as the intraclass correlation coefficient; ICC). RESULTS: ICC for the whole-volume ROIs was excellent (0.91) pre-CRT versus good (0.66) post-CRT. ICCs were 0.53 and 0.42 for the single-slice ROIs versus 0.60 and 0.65 for the sample ROIs. Pre-CRT ADCs for the sample ROIs were significantly lower than for the whole-volume or single-slice ROIs. Post-CRT there were no significant differences between the whole-volume ROIs and the single-slice or sample ROIs, respectively. The SDs for the whole-volume and single-slice ROIs were significantly larger than for the sample ROIs. CONCLUSIONS: ROI size and positioning have a considerable influence on tumour ADC values and interobserver variability. Interobserver variability is worse after CRT. ADCs obtained from the whole tumour volume provide the most reproducible results. Key Points • ROI size and positioning influence tumour ADC measurements in rectal cancer • ROI size and positioning influence interobserver variability of tumour ADC measurements • ADC measurements of the whole tumour volume provide the most reproducible results • Tumour ADC measurements are more reproducible before, rather than after, chemoradiation treatment • Variations caused by ROI size and positioning should be taken into account when using ADC as a biomarker for tumour response

Tumour ADC measurements in rectal cancer: effect of ROI methods on ADC values and interobserver variability

OBJECTIVES: To assess the influence of region of interest (ROI) size and positioning on tumour ADC measurements and interobserver variability in patients with locally advanced rectal cancer (LARC). METHODS: Forty-six LARC patients were retrospectively included. Patients underwent MRI including DWI (b0,500,1000) before and 6-8 weeks after chemoradiation (CRT). Two readers measured mean tumour ADCs (pre- and post-CRT) according to three ROI protocols: whole-volume, single-slice or small solid samples. The three protocols were compared for differences in ADC, SD and interobserver variability (measured as the intraclass correlation coefficient; ICC). RESULTS: ICC for the whole-volume ROIs was excellent (0.91) pre-CRT versus good (0.66) post-CRT. ICCs were 0.53 and 0.42 for the single-slice ROIs versus 0.60 and 0.65 for the sample ROIs. Pre-CRT ADCs for the sample ROIs were significantly lower than for the whole-volume or single-slice ROIs. Post-CRT there were no significant differences between the whole-volume ROIs and the single-slice or sample ROIs, respectively. The SDs for the whole-volume and single-slice ROIs were significantly larger than for the sample ROIs. CONCLUSIONS: ROI size and positioning have a considerable influence on tumour ADC values and interobserver variability. Interobserver variability is worse after CRT. ADCs obtained from the whole tumour volume provide the most reproducible results. Key Points • ROI size and positioning influence tumour ADC measurements in rectal cancer • ROI size and positioning influence interobserver variability of tumour ADC measurements • ADC measurements of the whole tumour volume provide the most reproducible results • Tumour ADC measurements are more reproducible before, rather than after, chemoradiation treatment • Variations caused by ROI size and positioning should be taken into account when using ADC as a biomarker for tumour response

An Evaluation and Implementation of Rule-Based Home Energy Management System Using the Rete Algorithm

In recent years, sensors become popular and Home Energy Management System (HEMS) takes an important role in saving energy without decrease in QoL (Quality of Life). Currently, many rule-based HEMSs have been proposed and almost all of them assume “IF-THEN” rules. The Rete algorithm is a typical pattern matching algorithm for IF-THEN rules. Currently, we have proposed a rule-based Home Energy Management System (HEMS) using the Rete algorithm. In the proposed system, rules for managing energy are processed by smart taps in network, and the loads for processing rules and collecting data are distributed to smart taps. In addition, the number of processes and collecting data are reduced by processing rules based on the Rete algorithm. In this paper, we evaluated the proposed system by simulation. In the simulation environment, rules are processed by a smart tap that relates to the action part of each rule. In addition, we implemented the proposed system as HEMS using smart taps

Role of Local Excision for Suspected Regrowth in a Watch and Wait Strategy for Rectal Cancer

Simple Summary Rectal cancer patients with a clinical complete response to neoadjuvant treatment are eligible for Watch and Wait as an alternative to total mesorectal excision. However, in patients with local regrowth, major surgery is still the standard of care. The present study evaluates the role of local excision for suspected local regrowth in a large Watch and Wait cohort, in terms of long-term outcomes. This study shows excellent overall survival and a good organ preservation rate. Patients who developed locoregional recurrence after initial local excision for regrowth were all successfully treated with salvage surgery. This study shows that local excision can provide maintenance of organ preservation without an obvious compromise in surgical or oncological safety. Local excision for suspected regrowth in patients following Watch and Wait can be a safe alternative for total mesorectal excision in selected patients with a strong wish to preserve their rectum. Rectal cancer patients with a clinical complete response to neoadjuvant (chemo)radiation are eligible for Watch and Wait (W&W). For local regrowth, total mesorectal excision (TME) is considered the standard of care. This study evaluated local excision (LE) for suspected local regrowth. From 591 patients prospectively entered into a national W&W registry, 77 patients with LE for regrowth were included. Outcomes analyzed included histopathologic findings, locoregional recurrence, long-term organ preservation, and colostomy-free and overall survival. In total, 27/77 patients underwent early LE (= 6 months). Median follow-up was 53 (39-69) months. In 28/77 patients the LE specimen was histopathologically classified as ypT0 (including 9 adenomas); 11/77 were ypT1, and 38/77 were ypT2-3. After LE, 13/77 patients with ypT2-3 and/or irradical resection underwent completion TME. Subsequently, 14/64 patients without completion TME developed locoregional recurrence, and were successfully treated with salvage TME. Another 8/77 patients developed distant metastases. At 5 years, overall organ preservation was 63%, colostomy-free survival was 68%, and overall survival was 96%. There were no differences in outcomes between early or late LE. In W&W for rectal cancer, LE can be considered as an alternative to TME for suspected regrowth in selected patients who wish to preserve their rectum or avoid colostomy in distal rectal cancer

Outcomes and potential impact of a virtual hands-on training program on MRI staging confidence and performance in rectal cancer

Objectives: To explore the potential impact of a dedicated virtual training course on MRI staging confidence and performance in rectal cancer. // Methods: Forty-two radiologists completed a stepwise virtual training course on rectal cancer MRI staging composed of a pre-course (baseline) test with 7 test cases (5 staging, 2 restaging), a 1-day online workshop, 1 month of individual case readings (n = 70 cases with online feedback), a live online feedback session supervised by two expert faculty members, and a post-course test. The ESGAR structured reporting templates for (re)staging were used throughout the course. Results of the pre-course and post-course test were compared in terms of group interobserver agreement (Krippendorf’s alpha), staging confidence (perceived staging difficulty), and diagnostic accuracy (using an expert reference standard). // Results: Though results were largely not statistically significant, the majority of staging variables showed a mild increase in diagnostic accuracy after the course, ranging between + 2% and + 17%. A similar trend was observed for IOA which improved for nearly all variables when comparing the pre- and post-course. There was a significant decrease in the perceived difficulty level (p = 0.03), indicating an improved diagnostic confidence after completion of the course. // Conclusions: Though exploratory in nature, our study results suggest that use of a dedicated virtual training course and web platform has potential to enhance staging performance, confidence, and interobserver agreement to assess rectal cancer on MRI virtual training and could thus be a good alternative (or addition) to in-person training. // Clinical relevance statement: Rectal cancer MRI reporting quality is highly dependent on radiologists’ expertise, stressing the need for dedicated training/teaching. This study shows promising results for a virtual web-based training program, which could be a good alternative (or addition) to in-person training. // Key Points: • Rectal cancer MRI reporting quality is highly dependent on radiologists’ expertise, stressing the need for dedicated training and teaching. • Using a dedicated virtual training course and web-based platform, encouraging first results were achieved to improve staging accuracy, diagnostic confidence, and interobserver agreement. • These exploratory results suggest that virtual training could thus be a good alternative (or addition) to in-person training

Global variation in the long-term outcomes of ypT0 rectal cancers

Background Colorectal cancer mortality presents world-wide variation. In rectal cancers presenting a complete/nearly-complete tumor response (ypT0/ypTis) following neoadjuvant treatment, the features correlated to nodal metastases and relapses still need to be defined. Methods An international cohort study enrolling ypT0/ypTis rectal cancers surgically treated from 2012 to 2017 was conducted. A propensity matching was used to balance nodal-positive and nodal-negative patients and statistical analyses were performed to investigate survivals, using a bootstrap model for internal validation. The features correlated with nodal metastasis were studied. Countries with participating centers were ranked using the World Bank (WBI), Human Development (HDI) and Global Gender Gap (GGG) indexes to compare survivals. Results 680 ypT0/ypTis from 52 European, Australian, Indian and American Institutions were analyzed. Mean follow-up was of 30.4 months. 96.5% were treated with total mesorectal excision, 7.2% were nodal-positive and 8.8% relapsed. Distal cancers (HR 0.71 95%CI: 0.56-0.91) and nodal metastasis and nodal metastasis (HR 3.85 95%CI:1.12–13.19) correlated with worse DFS, whereas a younger age was of borderline significance (HR 0.95 95%CI:0.91–0.99). The bootstrap analysis validated the model on 5000 repetitions. A short-course radiotherapy (OR 0.18 95%CI:0.09–0.37) correlated with the occurrence of nodal metastasis. Those countries classified in the low/medium-WBI, medium-HDI and lower-GGG ranks documented worse DFS curves (respectively p < 0.0001, p < 0.0001 and p 0.0002). However, the clinical stages were similar and patients from medium-HDI countries received more adjuvant chemotherapy than the others (p < 0.0001). Conclusion Sub-groups at risk for relapses and nodal metastasis were identified. A global variation exists also when benchmarking a rectal cancer complete regression

Size and depth of residual tumor after neoadjuvant chemoradiotherapy in rectal cancer – implications for the development of new imaging modalities for response assessment

With the shift towards organ preserving treatment strategies in rectal cancer it has become increasingly important to accurately discriminate between a complete and good clinical response after neoadjuvant chemoradiotherapy (CRT). Standard of care imaging techniques such as CT and MRI are well equipped for initial staging of rectal tumors, but discrimination between a good clinical and complete response remains difficult due to their limited ability to detect small residual vital tumor fragments. To identify new promising imaging techniques that could fill this gap, it is crucial to know the size and invasion depth of residual vital tumor tissue since this determines the requirements with regard to the resolution and imaging depth of potential new optical imaging techniques. We analyzed 198 pathology slides from 30 rectal cancer patients with a Mandard tumor regression grade 2 or 3 after CRT that underwent surgery. For each patient we determined response pattern, size of the largest vital tumor fragment or bulk and the shortest distance from the vital tumor to the luminal surface. The response pattern was shrinkage in 14 patients and fragmentation in 16 patients. For both groups combined, the largest vital tumor fragment per patient was smaller than 1mm for 38% of patients, below 0.2mm for 12% of patients and for one patient as small as 0.06mm. For 29% of patients the vital tumor remnant was present within the first 0.01mm from the luminal surface and for 87% within 0.5mm. Our results explain why it is difficult to differentiate between a good clinical and complete response in rectal cancer patients using endoscopy and MRI, since in many patients submillimeter tumor fragments remain below the luminal surface. To detect residual vital tumor tissue in all patients included in this study a technique with a spatial resolution of 0.06mm and an imaging depth of 8.9mm would have been required. Optical imaging techniques offer the possibility of detecting majority of these cases due to the potential of both high-resolution imaging and enhanced contrast between tissue types. These techniques could thus serve as a complimentary tool to conventional methods for rectal cancer response assessment