Patient- and physician-reported radiation-induced toxicity of short-course radiotherapy with a prolonged interval to surgery for rectal cancer.

AIM: A prolonged interval (>4 weeks) between short-course radiotherapy (25 Gy in five fractions) (SCRT-delay) and total mesorectal excision for rectal cancer has been associated with a decreased postoperative complication rate and offers the possibility of organ preservation in the case of a complete tumour response. This prospective cohort study systematically evaluated patient-reported bowel dysfunction and physician-reported radiation-induced toxicity for 8 weeks following SCRT-delay. METHOD: Patients who were referred for SCRT-delay for intermediate risk, oligometastatic or locally advanced rectal cancer were included. Repeated measurements were done for patient-reported bowel dysfunction (measured by the low anterior resection syndrome [LARS] questionnaire and categorized as no, minor or major LARS) and physician-reported radiation-induced toxicity (according to Common Terminology Criteria for Adverse Events version 4.0) before start of treatment (baseline), at completion of SCRT and 1, 2, 3, 4, 6 and 8 weeks thereafter. RESULTS: Fifty-one patients were included; 31 (61%) were men and the median age was 67 years (range 44-91). Patient-reported bowel dysfunction and physician-reported radiation-induced toxicity peaked at weeks 1-2 after completion of SCRT and gradually declined thereafter. Major LARS was reported by 44 patients (92%) at some time during SCRT-delay. Grade 3 radiation-induced toxicity was reported in 17 patients (33%) and concerned predominantly diarrhoea. No Grade 4-5 radiation-induced toxicity occurred. CONCLUSION: During SCRT-delay, almost every patient experiences temporary mild-moderate radiation-induced toxicity and major LARS, but life-threatening toxicity is rare. SCRT-delay is a safe alternative to SCRT-direct surgery that should be proposed when counselling rectal cancer patients on neoadjuvant strategies.

Impact of Dose-Escalated Chemoradiation on Quality of Life in Patients With Locally Advanced Rectal Cancer: 2-Year Follow-Up of the Randomized RECTAL-BOOST Trial.

PURPOSE: Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5 × 3 gray boost + CRT) or standard CRT for 2 years after randomization. METHODS AND MATERIALS: Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test. RESULTS: Patients treated with dose-escalated CRT (boost group, n = 51) experienced a significantly stronger decline in global health at 3 and 6 months (ES -0.4 and ES -0.4), physical functioning at 6 months (ES -1.1), role functioning at 3 and 6 months (ES -0.8 and ES -0.6), and social functioning at 6 months (ES -0.6), compared with patients treated with standard CRT (control group, n = 64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group. CONCLUSIONS: In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved.

Efficacy of Dose-Escalated Chemoradiation on Complete Tumor Response in Patients with Locally Advanced Rectal Cancer (RECTAL-BOOST): A Phase 2 Randomized Controlled Trial.

PURPOSE: Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC. METHODS AND MATERIALS: This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 × 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 × 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521. RESULTS: Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval [CI], 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio [OR] = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade ≥3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR = 1.22; 95% CI, 0.35-4.22). CONCLUSIONS: Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC.

The effect of time interval from chemoradiation to surgery on postoperative complications in patients with rectal cancer.

BACKGROUND: A prolonged time interval between chemoradiation and total mesorectal excision (TME) may render more rectal cancer patients eligible for organ-sparing approaches but may also cause more pelvic fibrosis and surgical morbidity. We estimated the effect of time interval on postoperative complications and other surgical outcomes in rectal cancer patients. METHODS: This is a population-based cohort study using data of the Dutch Colorectal Audit. Rectal cancer patients treated with chemoradiation followed by TME after an interval of 3-20 weeks were selected (n = 6,268). Time interval from completion of chemoradiation to TME was categorized into 3-6, 7-8, 9-10, 11-12 and 13-20 weeks. Outcomes included postoperative complication (any, and stratified by medical and surgical complications), reintervention, intraoperative complication, incomplete resection, positive circumferential margin (CRM) and pathological complete response (pCR). The interval of 7-8 weeks was the reference group. RESULTS: Prolonged time intervals were not associated with a higher risk of a postoperative complication (any, surgical or medical), reintervention, and incomplete resection. Intraoperative complications were however more common after 11-12 weeks than after 7-8 weeks (odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.20-2.69). The interval of 9-10 weeks was associated with less CRM positive resections, and 9-10 and 13-20 weeks with more pCR (relative to 7-8 weeks, OR = 0.74, 95%CI = 0.56-0.98; OR = 1.28, 95%CI = 1.04-1.58; and OR = 1.33, 95%CI = 1.04-1.71, respectively). CONCLUSIONS: Compared with 7-8 weeks, longer time intervals up to 13-20 weeks between chemoradiation and TME are not associated with more postoperative complications or more positive resection margins. Accordingly, prolonging the interval aiming for organ-sparing treatment is safe.

Comparison of pathological complete response rates after neoadjuvant short-course radiotherapy or chemoradiation followed by delayed surgery in locally advanced rectal cancer.

INTRODUCTION: Patients with locally advanced rectal cancer (LARC) who are unfit for chemoradiation (CRT), are often offered short-course radiotherapy followed by delayed surgery (SCRT-delay). This entails a lower radiation dose, no chemotherapy and a shorter treatment period. This may lower their chances for complete tumor response and, as such, organ-sparing approaches. The purpose of this study was to compare the pathological complete response (pCR) rates between neoadjuvant CRT and SCRT-delay in patients with LARC in a nationwide database from the Netherlands. METHODS: In the population based Netherlands Cancer Registry, clinical stage III rectal cancer patients, diagnosed between 2008 and 2014, who underwent CRT or SCTR-delay were selected. pCR (ypT0N0), near pCR (ypT0-1N0), and tumor and nodal downstaging were compared between the treatment groups using multivariable logistic regression analysis. RESULTS: 386 patients underwent SCRT-delay and 3659 patients underwent CRT. The pCR-rate in the SCRT-delay group was significantly lower compared to the CRT-group (6.4% vs. 16.2%, p < 0.001). After adjustment for clinical tumor stage, clinical nodal stage and time interval to surgery, SCRT-delay patients were significantly less likely to reach pCR (adjusted odds ratio 0.3, 95%CI 0.2-0.5). Also, near-pCR (ypT0-1N0) as well as tumor and nodal downstaging was observed less often in the SCRT-delay group. CONCLUSION: Compared to patients treated with neoadjuvant CRT, those receiving SCRT and delayed surgery are less likely to develop pCR. Novel neoadjuvant treatment strategies for patients not fit enough for CRT are needed to increase their eligibility for organ-sparing treatments.

Rotterdam Advanced Multiple Plate: a novel method to measure cold hyperalgesia and allodynia in freely behaving rodents.

BACKGROUND: To investigate the pathophysiology of temperature hypersensitivity in neuropathic pain rodent models, it is essential to be able to quantify the phenotype as objective as possible. Current temperature sensitivity measuring paradigms are performed during exposure to external factors, i.e. light, sound and smell, which modulate behavior significantly. In addition the present outcome measure for temperature hypersensitivity in rodents is the examination of the hind paw lift upon exposure to a certain temperature, which reflects more a reflex-flexion than an experience of pain. NEW METHOD: Therefore the Rotterdam Advanced Multiple Plate (RAMP) was developed to assess cold hyperalgesia and allodynia objectively in freely behaving neuropathic pain rats, which measures the avoidance for certain temperatures and monitoring the location of the rat with an infrared camera while excluding external environmental influences such as light and sound. RESULTS: Compared to sham rats, the spared nerve injury (SNI) rats demonstrated a higher preference for the comfortable plate (27 °C) when the other three plates were set at 5 °C, 14 °C, 17 °C and 19 °C. We were unable to detect heat hyperalgesia and allodynia with the RAMP. COMPARISON WITH EXISTING METHOD: The paw withdrawal method displays similar results during cold hypersensitivity measurements as observed with the RAMP. The SNI group did display heat hypersensitivity during the paw withdrawal test. CONCLUSIONS: The results indicate that the RAMP is able to quantify cold hyperalgesia and allodynia in neuropathic pain rats while resolves some of the problems of conventional temperature sensitivity measuring paradigms in rodents.

Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury.

The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI) model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural) and medial (saphenous) area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP) immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas.