Helpt u ons aan 500 donateurs?

17 september 2018: lees ook het ervaringsverhaal van meneer Cor C. 

Lees ook: 

https://kanker-actueel.nl/studiepublicaties-van-niet-toxische-middelen-en-behandelingen-uit-literatuurlijst-van-arts-bioloog-drs-engelbert-valstar-gerelateerd-aan-vormen-van-darmkanker.html

en wellicht ook dit artikel: 

https://kanker-actueel.nl/NL/probiotica-melkzuurbacterien-vooraf-en-na-operaties-bij-darmkanker-voorkomen-ernstige-infecties-bevorderen-sneller-herstel-en-zorgen-voor-kortere-ziekenhuisopname.html

Update 5 januari 2020: Vergelijkingsstudie van kortstondige radiotherapie gevolgd door chemotherapie vóór TME = totale mesorectale excisie versus preoperatieve chemoradiotherapie, TME en optionele adjuvante chemotherapie bij lokaal gevorderde rectumkanker toont aan dat een totale preoperatieve aanpak veel beter post operatieve uitzaaiingen op afstand voorkomt. Hoewel er statistisch geen verschil zat in overall overleving blijkt het verschil in effectiviteit van de behandelingen op uitzaaiingen op afstand op 3-jaars meting 23,7% versus 30,4%.

Met ongeveer 450 patiënten per groep zagen de auteurs een verbeterde pathologische complete respons en minder ziektegerelateerde mislukte behandelingen in hun experimentele (TNT) groep, voornamelijk als gevolg van minder metastasen op afstand in de experimentele groep (86/128 [67%] versus in de standaardgroep (123/152 [81%].

De onderzoekers stellen dan ook dat deze bevindingen de experimentele benadering van totale neoadjuvante therapie als standaardzorg voor deze patiëntenpopulatie algemeen standaard zou moeten zijn en worden.

Het volledige studierapport is gepubliceerd in The Lancet en moet voor betaald worden: 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 (abstract onderaan artikel)

27 april 2018: Bron: EJSO - European Journal of Surgical Oncology

Patiënten met lokaal gevorderde rectumkanker (LARC) (stadium III, dus hoog risico op een recidief) die om wat voor reden dan ook (meestal slechte lichamelijke conditie) ongeschikt zijn voor de standaard behandeling chemoradiatie (CRT), worden vaak een korter durende periode radiotherapie aangeboden gevolgd door een zogeheten SCRT-delay = kortdurende bestraling met een vertraagde operatie, dus niet dirct na de bestraling. Deze SCRT-delay behandeling houdt een lagere stralingsdosis in, geen chemotherapie en een kortere behandelingsperiode. Een Nederlandse studie heeft op basis van de landelijke registratiedatabase geanalyseerd wat in de periode van 2008 tot 2014 de verschillen waren in bereikte pathologische complete remissies (pCR = klinisch kankervrij) tussen een volledige CRT en de SCRT-delay behandeling bij patiënten met lokaal gevorderde rectumkanker (endeldarmkanker) LARC.

En die resultaten blijken voor de SCRT-delay beduidend slechter dan voor de CRT.

Van de 386 patiënten die een SCRT-delay behandeling hadden gehad bereikte slechts 6,4 procent een pathologische complete remissie tegenover 16,2 van de 3659 patiënten die een volledige CRT hadden gehad. (6.4% vs. 16.2%, p < 0.001)

Na correctie voor tumorstadium, aangetaste lymfklieren en periode voor operatie plaatsvond, hadden patiënten die een SCRT-delay behandeling hadden gehad statistisch significant minder kans om een pCR te bereiken (aangepaste oddsratio 0,3, 95% BI 0,2-0,5).

Ik moet zeggen dat dit toch wel hele lage percentages zijn voor zulke belastende behandelingen.

En is ook wel in contrast met deze Poolse studie al uit 2006 Doen ze het dan in Nederland zo slecht? Ik begrijp niet waarom de verschillen tussen bovengenoemde Poolse studie en de Nederlandse studie de resultaten zo ver uit elkaar liggen. rectal-cancer-preoperative-radiotherapy-short-vs-long-course-8-638

Uit het studierapport: Comparison of pathological complete response rates after neoadjuvant short-course radiotherapy or chemoradiation followed by delayed surgery in locally advanced rectal cancer dat gratis is in te zien hier enkele grafieken. Het abstract staat daaronder met referentielijst.

Table 1 geeft de karakteristieken van de patienten weer. Daaronder table 2 die de resultaten op pathologische complete remissies weergeeft.

Table 1Baseline characteristics of selected rectal cancer patients from the Netherlands Comprehensive Cancer Organisation (IKNL).
SCRT-delay

N = 391 (%)		CRT

N = 3659 (%)
Mean age in years ± SD 76 ± 9 63 ± 10
Sex
 Male 198 (50.6) 2338 (63.9)
 Female 193 (49.4) 1321 (36.1)
Tumor distance
 ≤5 cm 176 (45.0) 1680 (45.9)
 6–10 cm 146 (37.3) 1324 (36.2)
 ≥11 cm 43 (11.0) 437 (11.9)
 Missing 26 (6.6) 218 (6.0)
cT-stage
 2 13 (3.3) 143 (3.9)
 3 298 (76.2) 2769 (75.7)
 4 80 (20.5) 747 (20.4)
cN-stage
 0 37 (9.5) 192 (5.2)
 1 216 (55.2) 1569 (42.9)
 2 133 (34.0) 1840 (50.3)
 Missing 5 (1.3) 58 (1.6)
Median time interval (IQR) 9.1 (6.9–12.0) 9.4 (8.0–11.3)
Time interval categorical
 ≤7 weeks 106 (27.1) 533 (14.6)
 8–9 weeks 87 (22.3) 1090 (29.8)
 10–11 weeks 72 (18.4) 1034 (28.3)
 ≥12 weeks 126 (32.2) 1002 (27.4)
Surgical procedure
 TEM/TAE 5 (1.3) 18 (0.5)
 LAR 146 (37.3) 1768 (48.3)
 APR 169 (43.2) 1498 (40.9)
 Intersphincteric resection 10 (2.6) 34 (0.9)
 Hartmann resection 56 (14.3) 270 (7.4)
 Sigmoid resection 1 (0.3) 3 (0.1)
 Extended TME 4 (1.0) 68 (1.9)
Vital status
 Alive 268 (68.5) 3021 (82.6)
 Dead 123 (31.5) 638 (17.4)
Median years follow-up (IQR) 2.4 (1.5–3.5) 3.2 (2.0–4.7)
View Table in HTML

APR: abdominoperineal resection; CRT: chemoradiation; LAR: low anterior resection; SCRT: short-course radiotherapy.

TAE: transanal excision; TEM: Transanal endoscopic microsurgery; TME: total mesorectal excision.

Table 2Differences in pathology outcomes between short-course radiotherapy and delayed surgery (SCRT-delay) and chemoradiation (CRT).
SCRT-delay

N = 391 (%)		CRT

N = 3659 (%)		p-value
pCR (ypT0-N0) 25 (6.4) 592 (16.2) <0.001
Near-pCR (ypT0–1 N0) 43 (11.0) 755 (20.6) <0.001
Tumor downstaging (ypT < cT) 182 (46.8) 2079 (58.1) <0.001
Nodal downstaging (ypN < cN) 225 (58.1) 2618 (72.4) <0.001
ypT-stage <0.001
 0 31 (7.9) 673 (18.4)
 1 21 (5.4) 210 (5.7)
 2 99 (25.3) 934 (25.5)
 3 206 (52.7) 1581 (43.2)
 4 32 (8.2) 183 (5.0)
 Missing 2 (0.5) 78 (2.1)
ypN-stage <0.001
 0 215 (55.0) 2413 (65.9)
 1 109 (27.9) 805 (22.0)
 2 63 (16.1) 400 (10.9)
 Missing 4 (1.0) 41 (1.1)
Median no. of examined lymph nodes (IQR) 14 (11–19) 12 (9–16) <0.001a
Median lymph node ratio (IQR)b 0 (0–0.09) 0 (0–0.14) <0.001a
View Table in HTML

CRT: chemoradiation; pCR: pathological complete response; SCRT: short-course radiotherapy.

aBased on a Mann-Whitney U test.
bThe number of positive lymph nodes divided by number of examined lymph nodes.
Hier het abstract met conclusies plus referentielijst.

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.

Source: EJSO - European Journal of Surgical Oncology 

DOI: https://doi.org/10.1016/j.ejso.2018.03.014

 

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.

Discussion

Pathological compete response rates are lower in patients treated with neoadjuvant short-course radiotherapy with delayed surgery than in patients treated with neoadjuvant chemoradiation for locally advanced rectal cancer. This is far from unexpected, since the administered biological effective radiation dose is lower in SCRT. SCRT followed by surgery within 10 days does not induce downstaging, let alone pCR [19]. Moreover, since chemotherapy is eliminated, the lack of a radiosensitizing agent may reduce radiotherapy efficacy [20]. A prolonged interval to surgery increases the pCR rate [, ]. In previous studies the pCR rates following SCRT-delay range from 4.4% to 25%, with intervals to surgery from 4 up to 19 weeks [, , , , , , , , ]. A systematic review found an average increase in pCR rate of 10% in the delayed-surgery group compared to immediate surgery (3–12% and 0–0.4%, respectively) [21]. The Stockholm III trial showed that prolonging the interval to surgery from 1 week to 4–8 weeks increases pCR rates from 2.1% to 11.8% [16]. No differences were found in local recurrence, recurrence-free survival and 5-year overall survival [30]. A comparison between SCRT-delay and CRT for cT1-4 N0-3 tumors showed clinical complete response (cCR) rates of 20% and 34% after a median interval to response evaluation of 10.3 and 8.9 weeks, respectively. cCR was only achieved in cT2N0 and cT3N0 tumors [31]. Similar effects on cT3 tumors have been published [, ]. In our study, pCR rate was 6.5% after SCRT-delay, with a mean interval to surgery of 9.1 weeks. This relatively low pCR rate may be attributed to higher tumors stages (Stage III or cT4N0) in our study population.

In contrast to literature, we did not observe a higher pCR rates when interval to surgery was increased within the CRT group. This corresponds to the results of the phase III randomized GRECCAR-6 trial, where no benefit of a prolonged interval beyond a minimal interval of 11 weeks was found [32].

We observed a lower proportion of near-pCR (ypT0-1) in the SCRT-delay group than in the CRT group. Near-pCR is relevant when local excision as an alternative treatment option is considered, for example for frail patients, to reduce acute and long-term morbidity of surgery, such as anastomotic leakage, bleeding, urinary, and fecal incontinence [, , ].

A higher pathological nodal stage, a higher mean number of examined lymph nodes and a higher mean metastatic/examined lymph nodes ratio (LNR) were observed in the SCRT-delay group compared to the CRT-group. An increase in lymph node yield after neoadjuvant therapy for locally advanced rectal cancer is associated with improved cancer-specific and 5-year survival and lower local recurrence rates [, ]. However, in tumors with (near) pCR a lower number of lymph nodes is found [38]. A high LNR is prognostic for decreased overall and disease-free survival, even in patients with fewer than 12 lymph nodes examined [39]. These findings suggest that prognosis after SCRT-delay for LARC might be worse than after CRT, but the clinical relevance of LNR is still under debate.

To the best of our knowledge, this is the first large, nationwide study that describes the difference in pathological response rates between chemoradiation and short-course radiotherapy in LARC. A limitation of our study is the missing information about involvement of the mesorectal fascia (MRF). According to Dutch Guidelines, SCRT might have been justified in cT3N1 patients with a wide margin (>1 mm) to the MRF. An increased interval to surgery could have increased pCR rates in this group. However, since cT3N1 MRF- patients require immediate surgery after SCRT and we selected an interval to surgery of more than 4 weeks, we assumed most of the cT3N1 in our dataset had an involved MRF and thus needed CRT.

The group of patients that receive SCRT-delay instead of CRT is not clearly defined. Studies have shown that treatment deviation is more common in elderly patients [, , , , , , ], with age and comorbidities being predictive factors for altered treatment [, , ]. Since rectal cancer incidence increases with age and the general population is getting older, clinicians increasingly consider alternative, less aggressive treatment options for the frail LARC patient. More importantly, since per- and postoperative morbidity and mortality rates are increased in the older patient due to complications [, , , ] and postoperative complications have a larger negative impact on physical- and role functioning in older patients [49], organ preservation would be favorable in this particular population. However, if SCRT-delay is mostly offered to elderly patients, and pCR rates are lower after SCRT-delay, elderly treated with SCRT-delay have a lower probability to become eligible for organ-sparing approaches. Novel neoadjuvant treatment strategies for frail patients are needed in order to increase their eligibility for organ-sparing treatments, while focusing on a balance between morbidity on the one hand and optimal function and cure rates on the other. Current studies investigate a combination of short-course radiotherapy and chemotherapy, resulting in increased pCR rates [, , , , ]. However, the risk of toxicity associated with this strategy is likely to be unacceptable in the frail rectal cancer patient. Future studies should look into new treatment modalities where therapy doses can be increased to a level where response rates are higher and toxicity is still tolerable.

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.

Disclosures

None.

Funding

None.

Conflict of interest

None.

Acknowledgements

The authors thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice.

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  50. Nilsson, P.J., van Etten, B., Hospers, G.A., Pahlman, L., van de Velde, C.J., Beets-Tan, R.G. et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer–the RAPIDO trial. BMC Cancer. 2013; 13: 279
1AC and SH contributed equally to the manuscript.
© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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.

ARTICLES| VOLUME 22, ISSUE 1, P29-42, JANUARY 01, 2021

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

Published:December 07, 2020DOI:https://doi.org/10.1016/S1470-2045(20)30555-6

Summary

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 stage cT4a or cT4b, extramural vascular invasion, clinical nodal 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.

 


PlumX Metrics

Summary

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 stage cT4a or cT4b, extramural vascular invasion, clinical nodal 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.

darmkanker, TME, Totale mesorectale Exicisi. operatie, CRT - chemoradiotherapie, verkorte radiotherapie, uitgestelde operatie


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