Efficacy of dose-escalated chemoradiation on complete tumour response in patients with locally advanced rectal cancer (RECTAL-BOOST); a phase 2 randomised controlled trial

Purpose Pathological complete tumour response following chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with favourable prognosis and allows organ-sparing treatment strategies. We aimed to investigate the effect of an external radiation boost to the tumour prior to chemoradiation on pathological or sustained clinical complete tumour response in LARC. Methods and materials This multicentre, non-blinded, phase 2, randomised 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 accept or refuse this), whereas patients in the control group are not notified about the randomisation. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of two radiotherapy centres were eligible. Patients were randomised to no boost or an external radiation boost (5 x 3 Gy) without concurrent chemotherapy directly followed by standard pelvic chemoradiation (25 x 2 Gy with concurrent capecitabine). The primary outcome was pathological complete response (pCR, i.e. ypT0N0) in patients with planned surgery at 12 weeks or, as surrogate for pCR, 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 NCTXXXXXX. Results Between Sept 2014 and July 2018, 128 patients were randomised. 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 tumour (31.3% versus 17.2% and 56.3% versus 45.3% respectively), and more patients had a cN2-stage (59.4% versus 70.3% respectively). Rate of pathological or sustained clinical complete tumour response was similar between the groups: 23 of 64 (35.9%, 95%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 (OR=0.94 95%CI 0.46-1.92). Near-complete or complete tumour regression was more common in the intervention group: 34 of 49 (69.4%) versus 24 of 53 (45.3%) in the control group (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). Conclusion Dose escalation with an external radiotherapy boost to the tumour prior to neoadjuvant chemoradiation did not increase the pathological or sustained clinical complete tumour response rate in LARC

MRI-based tumor inter-fraction motion statistics for rectal cancer boost radiotherapy

Background: In patients diagnosed with rectal cancer, dose escalation is currently being investigated in a large number of studies. Since there is little known on gross tumor volume (GTV) inter-fraction motion for rectal cancer, a wide variety in margins is used. Purpose of this study is to quantify GTV inter-fraction motion statistics on different timescales and to give estimates of planning target volume (PTV) margins. Material and methods: Thirty-two patients, diagnosed with rectal cancer, were included. To investigate motion from week-to-week, 16 patients underwent a pretreatment and five weekly MRIs, prior to a radiotherapy (RT) fraction of the chemoradiotherapy treatment. To investigate motion from day-to-day, the remaining 16 patients underwent five daily MRIs before each fraction in one week of RT. GTV was delineated on all scans according to guidelines. Scans were aligned on bony anatomy with the first MRI. For both datasets separately, GTV inter-fraction motion was determined based on center-of-gravity displacement. Therefrom, systematic and random errors were determined in left/right (LR), anterior/posterior and cranial/caudal (CC) direction. PTV margin estimates were calculated and evaluated on GTV coverage. Results: Systematic and random errors were found in the range of 2.3–4.8 mm and 1.5–3.3 mm from week-to-week, and 1.8–4.5 mm and 1.8–4.0 mm from day-to-day, respectively. On both timescales, similar motion patterns were found; the most motion was observed in CC whilst the least motion was observed in LR. On the week-to-week data more systematic and less random motion was observed compared to the day-to-day data. Overall, only slight differences in margin estimates were found. Derived PTV margin estimates were found to give adequate GTV coverage. Conclusion: GTV inter-fraction motion, on a week-to-week and day-to-day timescale, can be accounted for using motion statistics presented in this study

MRI-based tumor inter-fraction motion statistics for rectal cancer boost radiotherapy

Background: In patients diagnosed with rectal cancer, dose escalation is currently being investigated in a large number of studies. Since there is little known on gross tumor volume (GTV) inter-fraction motion for rectal cancer, a wide variety in margins is used. Purpose of this study is to quantify GTV inter-fraction motion statistics on different timescales and to give estimates of planning target volume (PTV) margins. Material and methods: Thirty-two patients, diagnosed with rectal cancer, were included. To investigate motion from week-to-week, 16 patients underwent a pretreatment and five weekly MRIs, prior to a radiotherapy (RT) fraction of the chemoradiotherapy treatment. To investigate motion from day-to-day, the remaining 16 patients underwent five daily MRIs before each fraction in one week of RT. GTV was delineated on all scans according to guidelines. Scans were aligned on bony anatomy with the first MRI. For both datasets separately, GTV inter-fraction motion was determined based on center-of-gravity displacement. Therefrom, systematic and random errors were determined in left/right (LR), anterior/posterior and cranial/caudal (CC) direction. PTV margin estimates were calculated and evaluated on GTV coverage. Results: Systematic and random errors were found in the range of 2.3–4.8 mm and 1.5–3.3 mm from week-to-week, and 1.8–4.5 mm and 1.8–4.0 mm from day-to-day, respectively. On both timescales, similar motion patterns were found; the most motion was observed in CC whilst the least motion was observed in LR. On the week-to-week data more systematic and less random motion was observed compared to the day-to-day data. Overall, only slight differences in margin estimates were found. Derived PTV margin estimates were found to give adequate GTV coverage. Conclusion: GTV inter-fraction motion, on a week-to-week and day-to-day timescale, can be accounted for using motion statistics presented in this study

Health-related quality of life in rectal cancer patients undergoing neoadjuvant chemoradiation with delayed surgery versus short-course radiotherapy with immediate surgery : a propensity score-matched cohort study

Background: Neoadjuvant chemoradiation with delayed surgery (CRT-DS) and short-course radiotherapy with immediate surgery (SCRT-IS) are two commonly used treatment strategies for rectal cancer. However, the optimal treatment strategy for patients with intermediate-risk rectal cancer remains a discussion. This study compares quality of life (QOL) between SCRT-IS and CRT-DS from diagnosis until 24 months after treatment. Methods: In a prospective colorectal cancer cohort, rectal cancer patients with clinical stage T2-3N0-2M0 undergoing SCRT-IS or CRT-DS between 2013 and 2017 were identified. QOL was assessed using EORTC-C30 and EORTC-CR29 questionnaires before the start of neoadjuvant treatment (baseline) and at 3, 6, 12, 18 and 24 months after. Patients were 1:1 matched using propensity sore matching. Between- and within-group differences in QOL domains were analyzed with linear mixed-effects models. Symptoms and sexual interest at 12 and 24 months were compared using logistic regression models. Results: 156 of 225 patients (69%) remained after matching. The CRT-DS group reported poorer emotional functioning at 3, 6, 12, 18 and 24 months (mean difference with SCRT-IS: −9.4, −12.1, −7.3, −8.0 and −7.9 respectively), and poorer global health, physical-, role-, social- and cognitive functioning at 6 months (mean difference with SCRT-IS: −9.1, −9.8, −14.0, −9.2 and −12.6, respectively). Besides emotional functioning, all QOL domains were comparable at 12, 18 and 24 months. Within-group changes showed a significant improvement of emotional functioning after baseline in the SCRT-IS group, whereas only a minor improvement was observed in the CRT-DS group. Symptoms and sexual interest in male patients at 12 and 24 months were comparable between the groups. Conclusions: In rectal cancer patients, CRT-DS may induce a stronger decline in short-term QOL than SCRT-IS. From 12 months onwards, QOL domains, symptoms and sexual interest in male patients were comparable between the groups. However, emotional functioning remained higher after SCRT-IS than after CRT-DS