Search

Background: A pathological complete response (pCR) following chemoradiation (CRT) or short-course radiotherapy (scRT) leads to a favourable prognosis in patients with rectal cancer. Total neo-adjuvant therapy (TNT) doubles the pCR rate, but it is unknown whether oncological outcomes remain favourable and whether the same characteristics are associated with pCR as after CRT., Methods: Comparison between patients with pCR in the RAPIDO trial in the experimental [EXP] (scRT, chemotherapy, surgery, as TNT) and standard-of-care treatment [STD] (CRT, surgery, postoperative chemotherapy depending on hospital policy) groups. Primary and secondary outcomes were time-to-recurrence (TTR), overall survival (OS) and association between patient, tumour, and treatment characteristics and pCR., Results: Among patients with a resection within six months after preoperative treatment, 120/423 (28%) [EXP] and 57/398 (14%) [STD] achieved a pCR. Following pCR, 5-year cumulative TTR and OS rates in the EXP and STD arms were 8% vs. 7% (hazard ratio 1.04, 95%CI 0.32-3.38) and 94% vs. 93% (hazard ratio 1.41, 95%CI 0.51-3.92), respectively. Besides the EXP treatment (odds ratio 2.70, 95%CI 1.83-3.97), pre-treatment carcinoembryonic antigen (CEA) <5, pre-treatment tumour size <40 mm and cT2 were associated with pCR. Distance from the anal verge was the only characteristic with a statistically significant difference in association with pCR between the EXP and STD treatment (P interaction =0.042). pCR rates did not increase with prolonged treatment time., Conclusions: The doubled pCR rate of TNT compared to CRT results in similar oncological outcomes. Characteristics associated with pCR are the EXP treatment, normal CEA, and small tumour size., Competing Interests: Declaration of Competing Interest PJN reports honoraria from Ethicon, Johnson & Johnson, and Amgen. GAPH reports consulting fees from Roche, MSD, Amgen and Novartis; consulting fees and research support to their institution from Bristol Myers Squibb; and research support to their institution from Seerave Foundation. SJDT was fully funded, and AGHR and CJHvdV were partially funded by the EU’s Horizon Skłodowska Curie grant award (H2020MSCAITN2019, grant agreement number 857894; project acronym: CAST). BG reports research support from the Swedish Cancer Society. All other authors have declared no conflicts of interest. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The first authors had full access to all data and had final responsibility for the decision to submit for publication. All other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery., Methods: A narrative review of the most recent relevant literature was conducted., Results: Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients., Conclusion: Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: In rectal cancer, watch and wait for patients with a cCR after neoadjuvant treatment has an established evidence base. However, there is a lack of consensus on the definition and management of a near-cCR. This study aimed to compare outcomes in patients who achieved a cCR at first reassessment versus later reassessment., Methods: This registry study included patients from the International Watch & Wait Database. Patients were categorized as having a cCR at first reassessment or at later reassessment (that is near-cCR at first reassessment) based on MRI and endoscopy. Organ preservation, distant metastasis-free survival, and overall survival rates were calculated. Subgroup analyses were done for near-cCR groups based on the response evaluation according to modality., Results: A total of 1010 patients were identified. At first reassessment, 608 patients had a cCR; 402 had a cCR at later reassessment. Median follow-up was 2.6 years for patients with a cCR at first reassessment and 2.9 years for those with a cCR at later reassessment. The 2-year organ preservation rate was 77.8 (95 per cent c.i. 74.2 to 81.5) and 79.3 (75.1 to 83.7) per cent respectively (P = 0.499). Similarly, no differences were found between groups in distant metastasis-free survival or overall survival rate. Subgroup analyses showed a higher organ preservation rate in the group with a near-cCR categorized exclusively by MRI., Conclusion: Oncological outcomes for patients with a cCR at later reassessment are no worse than those of patients with a cCR at first reassessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Purpose: Reliable predictors of a sustained clinical complete tumour response (cCR) after neoadjuvant therapy in rectal cancer (RC) are lacking. The aim of this study was to determine if the tumour regression grade (TRG) assessed by magnetic resonance imaging (MRI), at the first restaging after neoadjuvant therapy can predict organ preservation, and to estimate the time interval after which surgery should be recommended in patients who remain in near cCR., Materials and Methods: Eighty-three consecutive patients were assessed by MRI as having a cCR (mrTRG 1) or near cCR (mrTRG 2) after neoadjuvant therapy. Cox proportional hazards regression models and Kaplan-Meier survival analyses were used to determine associations between resection-free survival (RFS) and mrTRG at the first restaging, and in relation to mrTRG with a landmark period. mrTRG and pathological findings were compared in operated patients., Results: mrTRG 2 at the first restaging significantly predicted poorer RFS during follow up. The best prediction of RFS was mrTRG at landmark 16 weeks after termination of radiotherapy; 42 out of 49 patients (86%) evaluated as mrTRG 1 had cCR at one year of follow up. In contrast, 12 out of 15 patients (80%) evaluated as mrTRG 2 had clinical signs of tumour and were recommended surgery., Conclusions: The first mrTRG, and to an even greater extent mrTRG at landmark 16 weeks predicts RFS. Patients who remain mrTRG 2 at 5-6 months after radiotherapy with signs of tumour should be recommended surgery. These findings may help in patient counselling and surgical decision-making., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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/m 2 orally twice daily on days 1-14, oxaliplatin 130 mg/m 2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m 2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m 2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m 2 intravenously and fluorouracil 600 mg/m 2 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/m 2 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer., Methods and Design: Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life., Discussion: Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer., Trial Registration: ClinicalTrials.gov NCT01558921.

In the past decade many changes in neoadjuvant treatment for patients with rectal cancer have taken place and are expected to impact complete response rates. The aim of this study was to investigate the impact on pathological, and overall, complete response rates in a nationwide population-based cohort, in relation to changes in neoadjuvant treatment and the start of a Watch & Wait (WoW) study. A nationwide register study using prospectively collected data from the Swedish Colorectal Cancer Register between 2009 and 2020. Patients with rectal cancer stage I-III with a ypT0N0 in the resected specimen after neoadjuvant treatment and clinical complete responders from the yearly inclusion data of the national WoW study were included. Temporal changes in pathological and overall complete response rates were analysed, and differences in neoadjuvant treatment regimens over time and per region were studied. Between 2009 and 2020 the pathological complete response rate for rectal cancer remained similar (Mann-Kendall tau of 0.091, p = 0.68) while the overall complete response rate increased significantly from 3.0% to 9.6% (Mann-Kendall tau of 0.818, p < 0.001). The pathological complete response rate for patients receiving short course radiotherapy followed by chemotherapy was reduced by 50% after the introduction of the WoW study. During the studied time period the overall complete response rate increased significantly presumably due to changes in national neoadjuvant treatment regimens. Since the start of the national WoW study clinical complete response seem to partly replace pathological complete response. [ABSTRACT FROM AUTHOR]