Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial.

INTRODUCTION: Although optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant treatment strategy influences the development, location, and timing of metastases in patients diagnosed with high-risk locally advanced rectal cancer included in the Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation (RAPIDO) trial. MATERIAL AND METHODS: Patients were randomly assigned to short-course radiotherapy followed by 18 weeks of CAPOX or FOLFOX4 before surgery (EXP), or long-course chemoradiotherapy with optional postoperative chemotherapy (SC-G). Assessments for metastatic disease were performed pre- and post-treatment, during surgery, and 6, 12, 24, 36, and 60 months postoperatively. From randomisation, differences in the occurrence of DM and first site of metastasis were evaluated. RESULTS: In total, 462 patients were evaluated in the EXP and 450 patients in the SC-G groups. The cumulative probability of DM at 5 years after randomisation was 23% [95% CI 19-27] and 30% [95% CI 26-35] (HR 0.72 [95% CI 0.56-0.93]; P = 0.011) in the EXP and SC-G, respectively. The median time to DM was 1.4 (EXP) and 1.3 years (SC-G). After diagnosis of DM, median survival was 2.6 years [95% CI 2.0-3.1] in the EXP and 3.2 years [95% CI 2.3-4.1] in the SC-G groups (HR 1.39 [95% CI 1.01-1.92]; P = 0.04). First occurrence of DM was most often in the lungs (60/462 [13%] EXP and 55/450 [12%] SC-G) or the liver (40/462 [9%] EXP and 69/450 [15%] SC-G). A hospital policy of postoperative chemotherapy did not influence the development of DM. CONCLUSIONS: Compared to long-course chemoradiotherapy, total neoadjuvant treatment with short-course radiotherapy and chemotherapy significantly decreased the occurrence of metastases, particularly liver metastases.

Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial.

OBJECTIVE: To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years. BACKGROUND: Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial. METHODS: A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed. RESULTS: Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively ( P =0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy ( P =0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P =0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P =0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46-1.26); P =0.29]. CONCLUSIONS: The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.

Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer - The RAPIDO trial.

BACKGROUND AND PURPOSE: The RAPIDO trial demonstrated a decrease in disease-related treatment failure (DrTF) and an increase in pathological complete responses (pCR) in locally advanced rectal cancer (LARC) patients receiving total neoadjuvant treatment (TNT) compared to conventional chemoradiotherapy. This study examines health-related quality of life (HRQL), bowel function, and late toxicity in patients in the trial. MATERIALS AND METHODS: Patients were randomized between short-course radiotherapy followed by pre-operative chemotherapy (EXP), or chemoradiotherapy and optional post-operative chemotherapy (STD). The STD group was divided into patients who did (STD+) and did not (STD-) receive post-operative chemotherapy. Three years after surgery patients received HRQL (EORTC QLQ-C30, QLQ-CR29 and QLQ-CIPN20) and LARS questionnaires. Patients who experienced a DrTF event before the toxicity assessments (6, 12, 24, or 36 months) were excluded from analyses. RESULTS: Of 574 eligible patients, 495 questionnaires were returned (86%) and 453 analyzed (79% completed within time limits). No significant differences were observed between the groups regarding QLQ-C30, QLQ-CR29 or LARS scores. Sensory-related symptoms occurred significantly more often in the EXP group compared to all STD patients, but not compared to STD+ patients. Any toxicity of any grade and grade ≥ 3 toxicity was comparable between the EXP and STD groups at all time-points. Neurotoxicity grade 1-2 occurred significantly more often in the EXP and STD+ group at all time-points compared to the STD- group. CONCLUSION: The results demonstrate that TNT for LARC, yielding improved DrTF and pCRs, does not compromise HRQL, bowel functional or results in more grade ≥3 toxicity compared to standard chemoradiotherapy at three years after surgery in DrTF-free patients.

Re-Irradiation in Patients with Recurrent Rectal Cancer is Safe and Feasible.

BACKGROUND: There is no consensus yet for the best treatment regimen in patients with recurrent rectal cancer (RRC). This study aims to evaluate toxicity and oncological outcomes after re-irradiation in patients with RRC in our center. Clinical (cCR) and pathological complete response (pCR) rates and radicality were also studied. METHODS: Between January 2010 and December 2018, 61 locally advanced RRC patients were treated and analyzed retrospectively. Patients received radiotherapy at a dose of 30.0-30.6 Gy (reCRT) or 50.0-50.4 Gy chemoradiotherapy (CRT) in cases of no prior irradiation because of low-risk primary rectal cancer. In both groups, patients received capecitabine concomitantly. RESULTS: In total, 60 patients received the prescribed neoadjuvant (chemo)radiotherapy followed by surgery, 35 patients (58.3%) in the reRCT group and 25 patients (41.7%) in the long-course CRT group. There were no significant differences in overall survival (p = 0.82), disease-free survival (p = 0.63), and local recurrence-free survival (p = 0.17) between the groups. Patients in the long-course CRT group reported more skin toxicity after radiotherapy (p = 0.040). No differences were observed in late toxicity. In the long-course CRT group, a significantly higher cCR rate was observed (p = 0.029); however, there was no difference in the pCR rate (p = 0.66). CONCLUSIONS: The treatment of RRC patients with re-irradiation is comparable to treatment with long-course CRT regarding toxicity and oncological outcomes. In the reCRT group, less cCR was observed, although there was no difference in pCR. The findings in this study suggest that it is safe and feasible to re-irradiate RRC patients.

Clinical selection strategy for and evaluation of intra-operative brachytherapy in patients with locally advanced and recurrent rectal cancer.

BACKGROUND AND PURPOSE: A radical resection of locally advanced rectal cancer (LARC) or recurrent rectal cancer (RRC) can be challenging. In case of increased risk of an R1 resection, intra-operative brachytherapy (IOBT) can be applied. We evaluated the clinical selection strategy for IOBT. MATERIALS AND METHODS: Between February 2007 and May 2018, 132 LARC/RRC patients who were scheduled for surgery with IOBT standby, were evaluated. By intra-operative inspection of the resection margin and MR imaging, it was determined whether a resection was presumed to be radical. Frozen sections were taken on indication. In case of a suspected R1 resection, IOBT (1 × 10 Gy) was applied. Histopathologic evaluation, treatment and toxicity data were collected from medical records. RESULTS: Tumour was resected in 122 patients. IOBT was given in 42 patients of whom 54.8% (n = 23) had a histopathologically proven R1 resection. Of the 76 IOBT-omitted R0 resected patients, 17.1% (n = 13) had a histopathologically proven R1 resection. In 4 IOBT-omitted patients, a clinical R1/2 resection was seen. In total, correct clinical judgement occurred in 72.6% (n = 88) of patients. In LARC, 58.3% (n = 14) of patients were overtreated (R0, with IOBT) and 10.9% (n = 5) were undertreated (R1, without IOBT). In RRC, 26.5% (n = 9) of patients were undertreated. CONCLUSION: In total, correct clinical judgement occurred in 72.6% (n = 88). However, in 26.5% (n = 9) RRC patients, IOBT was unjustifiedly omitted. IOBT is accompanied by comparable and acceptable toxicity. Therefore, we recommend IOBT to all RRC patients at risk of an R1 resection as their salvage treatment.

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer - Results of the international randomized RAPIDO-trial.

BACKGROUND: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision is widely accepted as the standard of care for high-risk rectal cancer. Adjuvant chemotherapy is advised in several international guidelines, although the survival benefit remains unclear and compliance is poor. The current multidisciplinary approach has led to major improvements in local control, yet the occurrence of distant metastases has not decreased accordingly. The combination of short-course radiotherapy (SCRT) and chemotherapy in the waiting period before surgery might have several benefits, including higher compliance, downstaging and better effect of systemic therapy. METHODS: This is an investigator-initiated, international multicentre randomized phase III trial. High-risk rectal cancer patients were randomized to SCRT followed by chemotherapy (6 cycles CAPOX or alternatively 9 cycles FOLFOX4) and subsequent surgery, or long-course radiotherapy (25-28 × 2-1.8 Gy) with concomitant capecitabine followed by surgery and optional postoperative chemotherapy (8 cycles CAPOX or 12 cycles FOLFOX4) according to local institutions' policy. The primary endpoint is time to disease-related treatment failure. Here, we report the compliance, toxicity and postoperative complications in both study groups. FINDINGS: Between June 2011 and June 2016, 920 patients were enrolled. Of these, 901 were evaluable (460 in the experimental arm and 441 in the standard arm). All patients in the experimental arm received 5 × 5 Gy radiotherapy, and 84% of all patients received at least 75% of the prescribed chemotherapy. In the standard arm, the compliance for CRT was 93% and 58% for postoperative chemotherapy. Toxicity ≥grade 3 occurred in 48% of patients in the experimental arm, compared to 25% of patients in the standard arm during preoperative treatment and 35% of patients during postoperative chemotherapy. No statistically significant differences in surgical procedures or postoperative complications were observed. INTERPRETATION: High compliance (84%) of preoperative systemic treatment could be achieved with the experimental approach. Although considerable toxicity was observed during preoperative therapy, this did not lead to differences in surgical procedures or postoperative complications. Longer follow-up time is needed to assess the primary endpoint and related outcomes.