Rectal CancerPhase 3RAPIDONCT01558921
Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial
A Phase 3 study testing M1 scheme and standard long course chemoradiotherapy in people with Rectal Cancer, run by University Medical Center Groningen at 56 sites in 7 countries.
Trial summary
Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rectal Cancer
- What is being tested?
- M1 scheme and standard long course chemoradiotherapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 920 participants
- Where
- 56 sitesin 7 countries
- Study dates
- 21 Jun 2011to 31 Dec 2026
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Primary tumour characteristics:
- Histological proof of newly diagnosed primary adenocarcinoma of the rectum
- Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (clinical T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to tumor node metastasis (TNM-Classification version 5)), clinical T4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Positive Mesorectal Fascia (MRF+), i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes (LN), > 1 cm (lat LN+)
Who cannot join
- Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen
- Presence of metastatic disease or recurrent rectal tumour
- Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis
- Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years
- Known Dihydro-Pyrimidine Dehydrogenase (DPD) deficiency
- Any contraindications to MRI (e.g. patients with pacemakers)
Show all 13Show fewer
- Medical or psychiatric conditions that compromise the patient's ability to give informed consent
- Concurrent uncontrolled medical conditions
- Any investigational treatment for rectal cancer within the past month
- Pregnancy or breast feeding
- Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract
- Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months
- Patients with symptoms or history of peripheral neuropathy
Trial locations and contacts
56 sites in 7 countries.
56 sites in 7 countries
Netherlands28 sites
Noordwest Ziekenhuisgroep
Alkmaar
Amsterdam UMC, location AMC
Amsterdam
Amsterdam UMC, location VUMC
Amsterdam
Nki / Avl
Amsterdam
Onze Lieve Vrouwe Gasthuis
Amsterdam
Wilhelmina Ziekenhuis
Assen
Amphia Ziekenhuis
Breda
Reinier de Graaf Groep
Delft
Deventer Hospital
Deventer
Catharina ZIekenhuis
Eindhoven
Het Groene Hart Ziekenhuis
Gouda
University Medical Center Groningen
Groningen, PO BOX 30001, 9700 RB
Martini Ziekenhuis
Groningen
Universitair Medisch Centrum Groningen
Groningen
de Tjongerschans
Heerenveen
Ziekenhuisgroep Twente
Hengelo
Spaarne Ziekenhuis
Hoofddorp
Medisch Centrum Leeuwarden
Leeuwarden
Radiotherapeutisch Instituut Friesland
Leeuwarden
Leiden University Medical Center
Leiden
Alrijne Ziekenhuis
Leiderdorp
UMC Nijmegen St Radboud
Nijmegen
Antonius Ziekenhuis
Sneek
Bronovo Ziekenhuis
The Hague
HaGaZiekenhuis
The Hague
Medisch Centrum Haaglanden
The Hague
Diakonessenhuis
Utrecht
Isala Klinieken
Zwolle
Sweden17 sites
Södra Älvsborgs Sjukhus
Borås
Mälarsjukhuset
Eskilstuna
Falu Lasarett
Falun
Gävle sjukhus
Gävle
Sahlgrenska Universitetssjukhuset
Gothenburg
Kalmar Hospital
Kalmar
Centralsjukhuset i Karlstad
Karlstad
Linköpings Universitet
Linköping
Universitetssjukhuset i Lund
Lund
Universitetssjukhuset ÖREBRO
Örebro
Skaraborgs Sjukhus
Skövde
Karolinska Universitetssjukhuset
Stockholm
Sundsvalls Sjukhus
Sundsvall
Norrlands Universitetssjukhus
Umeå
Akademiska Sjukhuset
Uppsala
Centrallasarett
Västerås
Centrallasarettet Växjö
Vaxjo
Spain5 sites
Hospital Vall d'Hebron
Barcelona
ICO Hospital Duran I Reynals
L'Hospitalet de Llobregat
Consorcio Hospital General Universitario Valencia
Valencia
Hospital Clínico Universitario de Valencia
Valencia
Hospital Universitari i Politècnic la Fe
Valencia
Denmark2 sites
Aalborg Universitetshospital
Aalborg
Odense Universitetshospital
Odense
Norway2 sites
Sørlandet Sykehus Kristiansand
Kristiansand
Oslo Universitetssykehus
Oslo
United States1 site
Siteman Cancer Center, Washington University Medical School
St Louis, Missouri, 63110
About this study
Official title: Randomized Multicentre Phase III Study of Short Course Radiation Therapy Followed by Prolonged Pre-operative Chemotherapy and Surgery in Primary High Risk Rectal Cancer Compared to Standard Chemoradiotherapy and Surgery and Optional Adjuvant Chemotherapy.
Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant chemoradiotherapy). The neoadjuvant chemoradiotherapy has been demonstrated to improve local control, but had no effect on the overall survival. Different studies in patients with rectal cancer studying the effect of adjuvant post operative chemotherapy did not result in an improved survival. This may be due the fact that rectal cancer surgery (TME) is associated with a high complication rate so substantial proportion of patients cannot receive chemotherapy postoperatively. An alternative approach is to administer the systemic therapy preoperative. To guarantee control of the rectum tumor short-course radiotherapy (5 days) is given, as different studies showed local control of the tumor for a long time. During this waiting period the patient is in a good condition to receive an optimal dose of chemotherapy. The investigators hypothesize that with this proposed protocol both the local tumour and possible micrometastases are effectively treated and that this will result in an increased survival. The investigators will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.
Read the detailed description
Patients will be randomized between an experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine/ 5-fluorouracil and oxaliplatin) and surgery and a control group (arm A) with long course chemoradiotherapy followed by surgery. In arm A adjuvant chemotherapy is allowed according to the local protocol of the institution. In both groups the rectal tumour will be removed by TME surgery or more extensive surgery if required because of tumour extent.
- Conditions
- Rectal Cancer
- Being tested
- M1 scheme, standard long course chemoradiotherapy
- Keywords
- rectal cancer, radiotherapy, chemotherapy, 5x5, capecitabine, oxaliplatin, CAPOX, FOLFOX, folinic acid, fluorouracil
- Medical subject headings
- Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
M1 schemeOther
short course 5x5Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX
standard long course chemoradiotherapyOther
long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group.
| Study group | Role | What they receive |
|---|---|---|
| B: 5x5Gy -> CAPOX -> surgery | Experimental | experimental group (arm B) M1 scheme: 5 fractions of 5 Gy external beam radiation (5x5Gy) followed by CAPOX followed by TME surgery Receives: Other: M1 scheme |
| A: 5 weeks chemoradiation -> surgery | Active comparator | control group (arm A) standard long course chemoradiotherapy followed by TME surgery Receives: Other: standard long course chemoradiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients With Disease Related Treatment Failure (DrTF)
DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait \& watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier.
Measured: 3 years follow-up after surgery
Secondary outcomes (9)
Number of Patients Completing the Prescribe Neo-adjuvant Treatment Dose
Number of patients in the experimental arm receiving 5 fractions of x 5 Gy (5x5Gy) radiotherapy followed by at least 75% of the prescribed chemotherapy.
In the standard arm receiving the prescribed chemoradiotherapy.
Measured: 30 days after neoadjuvant treatment
Number of Patients With Negative CRM Negative
Number of patients with a Circumferential Resection Margin (CRM) > 1 mm
Measured: 30 days after surgery
Number of Patients With a Pathological Complete Response (pCR)
Number of patients with a Pathological Complete Response (pCR) after neo-adjuvant treatment
Measured: 30 days after surgery
Number of Patients With Surgical Complications
Number of patients with surgical complications: wound rupture, bleeding, infection, rectal anastomotic leak
Measured: 30 days after surgery
Quality of Life QLQ-C30 Scores
Quality of life QLQ-C30 core questionnaire EORTC quality-of-life instrument for use in international clinical trials in oncology A total Quality of Life Questionnaire (QLQ) score can range from 0 to 88, higher score means worse outcome.
Measured: 3 year after surgery
Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20)
Quality of life EORTC-QLQ-CIPN20. International EORTC questionnaire to assess Chemotherapy-Induced Peripheral Neuropathy (CIPN).
A total QLQ-CIPN20 score can range from 0 to 100, higher score means worse outcome. Chemotherapy-induced peripheral neuropathy (CIPN) is a common phenomenon, often resulting in serious limitations in daily functioning and compromised quality of life.
Measured: 3 year after surgery
Quality of Life LARS Scores
Low Anterior Resection Syndrome (LARS) scores in patients without a stoma three years after curative surgery Patient reported score (5 questions). 0-12 no LARS, 21-29 Minor LARS, 30-42 Major LARS.
Higher scores mean a worse outcome.
Measured: 3 year after surgery
Number of Patients With a Locoregional Recurrence
Number of patients with a locoregional recurrence (LRR) after an R0/R1 resection
Measured: 5 years after surgery
Overall Survival
Overall survival will be computed as the time between randomization and colorectal cancer or treatment related death. Patients lost to follow-up will be censored the last date of patient visit.
In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour.
Measured: 10 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Mar 2012 (estimated)
- Study start21 Jun 2011
- Primary completion8 Mar 2020
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for Rectal CancerStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- standard arm: 5.5 weeks chemoradiation -\> surgery -\> optional chemotherapy experimental arm: 5x5Gy -\> 12 wks chemotherapy -\> surgery
- Masking
- None (open label)
- Enrolment
- 920 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- Karolinska University Hospital, Leiden University Medical Center, Uppsala University Hospital, Dutch Cancer Society
- Responsible party
- Principal investigator, B. van Etten, MD, PhD, University Medical Center Groningen
- Investigators
- B. van Etten, MD, PhD, Principal investigator, University Medical Center Groningen, Department of Surgery, Groningen, The NetherlandsB. Glimelius, MD, PhD, Principal investigator, Akademiska Sjukhuset, Department of Oncology, Uppsala, SwedenG. A. Hospers, MD, PhD, Principal investigator, University Medical Center Groningen, Department of Medical Oncology, Groningen, The NetherlandsP. Nilsson, MD, PhD, Principal investigator, Karolinska Universitetssjukhuset, Stockholm, SwedenC. J. van de Velde, MD, PhD, Principal investigator, Leiden University Medical Center, Department of Surgery, Leiden, The NetherlandsC.A.M. Marijnen, MD, PhD, Principal investigator, Netherlands Cancer Institute, Amsterdam, the Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01558921
- Sponsor's protocol ID
- NL36315.042.11
- Other IDs
- 2010-023957-12
- Acronym
- RAPIDO
- Status last verified
- Apr 2026
- First submitted
- 18 Mar 2012
- Last updated
- 1 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Nilsson PJ, van Etten B, Hospers GA, Pahlman L, van de Velde CJ, Beets-Tan RG, Blomqvist L, Beukema JC, Kapiteijn E, Marijnen CA, Nagtegaal ID, Wiggers T, Glimelius B. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer. 2013 Jun 7;13:279. doi: 10.1186/1471-2407-13-279.
PubMed 23742033Giunta EF, Bregni G, Pretta A, Deleporte A, Liberale G, Bali AM, Moretti L, Troiani T, Ciardiello F, Hendlisz A, Sclafani F. Total neoadjuvant therapy for rectal cancer: Making sense of the results from the RAPIDO and PRODIGE 23 trials. Cancer Treat Rev. 2021 May;96:102177. doi: 10.1016/j.ctrv.2021.102177. Epub 2021 Mar 16.
PubMed 33798955Jimenez-Fonseca P, Salazar R, Valenti V, Msaouel P, Carmona-Bayonas A. Is short-course radiotherapy and total neoadjuvant therapy the new standard of care in locally advanced rectal cancer? A sensitivity analysis of the RAPIDO clinical trial. Ann Oncol. 2022 Aug;33(8):786-793. doi: 10.1016/j.annonc.2022.04.010. Epub 2022 Apr 22.
PubMed 35462008Glynne-Jones R, Harrison M. Should the RAPIDO schedule represent standard of care in locally advanced rectal cancer? Ann Oncol. 2022 Aug;33(8):745-746. doi: 10.1016/j.annonc.2022.05.002. Epub 2022 May 12. No abstract available.
PubMed 35568280Patel A, Spychalski P, Corrao G, Jereczek-Fossa BA, Glynne-Jones R, Garcia-Aguilar J, Kobiela J. Neoadjuvant short-course radiotherapy with consolidation chemotherapy for locally advanced rectal cancer: a systematic review and meta-analysis. Acta Oncol. 2021 Oct;60(10):1308-1316. doi: 10.1080/0284186X.2021.1953137. Epub 2021 Jul 24.
PubMed 34308767Papaccio F, Rosello S, Huerta M, Gambardella V, Tarazona N, Fleitas T, Roda D, Cervantes A. Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer. Cancers (Basel). 2020 Dec 3;12(12):3611. doi: 10.3390/cancers12123611.
PubMed 33287114Ozturk SK, Martinez CG, Mens D, Verhoef C, Tosetto M, Sheahan K, de Wilt JHW, Hospers GAP, van de Velde CJH, Marijnen CAM, van der Post RS, Nagtegaal ID. Lymph node regression after neoadjuvant chemoradiotherapy in rectal cancer. Histopathology. 2024 May;84(6):935-946. doi: 10.1111/his.15134. Epub 2024 Jan 8.
PubMed 38192084Nilsson PJ, van Etten B, Hospers GAP, Marijnen CAM, Meershoek-Klein Kranenberg E, Roodvoets AGH, van de Velde CJH, Glimelius B. Comment on the RAPIDO Trial Point-Counterpoint Debate. Dis Colon Rectum. 2024 Feb 1;67(2):e126. doi: 10.1097/DCR.0000000000003138. Epub 2023 Oct 26. No abstract available.
PubMed 37889954Polack M, van Pelt GW, van den Heuvel DH, Klein-Kranenbarg EM, Roodvoets AGH, Putter H, Crobach ASLP, Nagtegaal ID, Peeters KCMJ, Tollenaar RAEM, van Krieken JHJM, Mesker WE. The tumour-stroma ratio as predictive aid towards a biopsy-based treatment strategy in rectal carcinoma. Histopathology. 2025 Jul;87(1):44-57. doi: 10.1111/his.15423. Epub 2025 Apr 4.
PubMed 40183423van der Valk MJM, Marijnen CAM, van Etten B, Dijkstra EA, Hilling DE, Kranenbarg EM, Putter H, Roodvoets AGH, Bahadoer RR, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes AMR, de Groot DJA, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; Collaborative investigators. 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. Radiother Oncol. 2020 Jun;147:75-83. doi: 10.1016/j.radonc.2020.03.011. Epub 2020 Mar 30.
PubMed 32240909Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. 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. Lancet Oncol. 2021 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6. Epub 2020 Dec 7.
PubMed 33301740Dijkstra EA, Hospers GAP, Kranenbarg EM, Fleer J, Roodvoets AGH, Bahadoer RR, Guren MG, Tjalma JJJ, Putter H, Crolla RMPH, Hendriks MP, Capdevila J, Radu C, van de Velde CJH, Nilsson PJ, Glimelius B, van Etten B, Marijnen CAM. Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer - The RAPIDO trial. Radiother Oncol. 2022 Jun;171:69-76. doi: 10.1016/j.radonc.2022.04.013. Epub 2022 Apr 18.
PubMed 35447283Dijkstra EA, Zwart WH, Putter H, Marijnen CAM, Nilsson PJ, van de Velde CJH, van Etten B, Hospers GAP, Glimelius B. Authors' reply-A sensitivity analysis of the RAPIDO clinical trial. Ann Oncol. 2023 Apr;34(4):446-447. doi: 10.1016/j.annonc.2022.12.012. Epub 2022 Dec 26. No abstract available.
PubMed 36581138Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH, Putter H, Berglund A, Cervantes A, Crolla RMPH, Hendriks MP, Capdevila J, Edhemovic I, Marijnen CAM, van de Velde CJH, Glimelius B, van Etten B; Collaborative Investigators. 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. Ann Surg. 2023 Oct 1;278(4):e766-e772. doi: 10.1097/SLA.0000000000005799. Epub 2023 Jan 20.
PubMed 36661037Bahadoer RR, Hospers GAP, Marijnen CAM, Peeters KCMJ, Putter H, Dijkstra EA, Kranenbarg EM, Roodvoets AGH, van Etten B, Nilsson PJ, Glimelius B, van de Velde CJH; collaborative investigators. Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial. Eur J Cancer. 2023 May;185:139-149. doi: 10.1016/j.ejca.2023.02.027. Epub 2023 Mar 7.
PubMed 36996624
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Multicentre Phase III Study of Short Course Radiation Therapy Followed by Prolonged Pre-operative Chemotherapy and Surgery in Primary High Risk Rectal Cancer Compared to Standard Chemoradiotherapy and Surgery and Optional Adjuvant Chemotherapy.
- ClinicalTrials.gov ID
- NCT01558921
- Acronym / sponsor ID
- RAPIDO / NL36315.042.11
- Conditions
- Rectal Cancer
- Keywords
- rectal cancer, radiotherapy, chemotherapy, 5x5, capecitabine, oxaliplatin, CAPOX, FOLFOX
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 920 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- Karolinska University Hospital, Leiden University Medical Center, Uppsala University Hospital, Dutch Cancer Society
- Study start
- 21 Jun 2011 (actual)
- Primary completion
- 8 Mar 2020 (actual)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 20 Mar 2012 (estimated)
- Results
- Posted 1 May 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant chemoradiotherapy). The neoadjuvant chemoradiotherapy has been demonstrated to improve local control, but had no effect on the overall survival. Different studies in patients with rectal cancer studying the effect of adjuvant post operative chemotherapy did not result in an improved survival. This may be due the fact that rectal cancer surgery (TME) is associated with a high complication rate so substantial proportion of patients cannot receive chemotherapy postoperatively. An alternative approach is to administer the systemic therapy preoperative. To guarantee control of the rectum tumor short-course radiotherapy (5 days) is given, as different studies showed local control of the tumor for a long time. During this waiting period the patient is in a good condition to receive an optimal dose of chemotherapy. The investigators hypothesize that with this proposed protocol both the local tumour and possible micrometastases are effectively treated and that this will result in an increased survival. The investigators will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.
Detailed description
Patients will be randomized between an experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine/ 5-fluorouracil and oxaliplatin) and surgery and a control group (arm A) with long course chemoradiotherapy followed by surgery. In arm A adjuvant chemotherapy is allowed according to the local protocol of the institution. In both groups the rectal tumour will be removed by TME surgery or more extensive surgery if required because of tumour extent.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- standard arm: 5.5 weeks chemoradiation -> surgery -> optional chemotherapy experimental arm: 5x5Gy -> 12 wks chemotherapy -> surgery
| Arm | Type | Receives |
|---|---|---|
| B: 5x5Gy -> CAPOX -> surgery | Experimental | Other: M1 schemeexperimental group (arm B) M1 scheme: 5 fractions of 5 Gy external beam radiation (5x5Gy) followed by CAPOX followed by TME surgery |
| A: 5 weeks chemoradiation -> surgery | Active comparator | Other: standard long course chemoradiotherapycontrol group (arm A) standard long course chemoradiotherapy followed by TME surgery |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Histological proof of newly diagnosed primary adenocarcinoma of the rectum
- Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (clinical T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to tumor node metastasis (TNM-Classification version 5)), clinical T4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Positive Mesorectal Fascia (MRF+), i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes (LN), > 1 cm (lat LN+)
Key exclusion criteria (13 listed)
- Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen
- Presence of metastatic disease or recurrent rectal tumour
- Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis
- Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years
- Known Dihydro-Pyrimidine Dehydrogenase (DPD) deficiency
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| M1 schemeshort course 5x5Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX | Other | B: 5x5Gy -> CAPOX -> surgery |
| standard long course chemoradiotherapylong course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group. | Other | A: 5 weeks chemoradiation -> surgery |
Primary outcome
Number of Patients With Disease Related Treatment Failure (DrTF)
Time frame: 3 years follow-up after surgery
DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait \& watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier.
9 secondary outcomes
Number of Patients Completing the Prescribe Neo-adjuvant Treatment Dose
Time frame: 30 days after neoadjuvant treatment
Number of Patients With Negative CRM Negative
Time frame: 30 days after surgery
Number of Patients With a Pathological Complete Response (pCR)
Time frame: 30 days after surgery
Number of Patients With Surgical Complications
Time frame: 30 days after surgery
Quality of Life QLQ-C30 Scores
Time frame: 3 year after surgery
Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20)
Time frame: 3 year after surgery
Quality of Life LARS Scores
Time frame: 3 year after surgery
Number of Patients With a Locoregional Recurrence
Time frame: 5 years after surgery
Overall Survival
Time frame: 10 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23742033Nilsson PJ, van Etten B, Hospers GA, Pahlman L, van de Velde CJ, Beets-Tan RG, Blomqvist L, Beukema JC, Kapiteijn E, Marijnen CA, Nagtegaal ID, Wiggers T, Glimelius B. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer. 2013 Jun 7;13:279. doi: 10.1186/1471-2407-13-279.
- Background: PubMed 33798955Giunta EF, Bregni G, Pretta A, Deleporte A, Liberale G, Bali AM, Moretti L, Troiani T, Ciardiello F, Hendlisz A, Sclafani F. Total neoadjuvant therapy for rectal cancer: Making sense of the results from the RAPIDO and PRODIGE 23 trials. Cancer Treat Rev. 2021 May;96:102177. doi: 10.1016/j.ctrv.2021.102177. Epub 2021 Mar 16.
- Background: PubMed 35462008Jimenez-Fonseca P, Salazar R, Valenti V, Msaouel P, Carmona-Bayonas A. Is short-course radiotherapy and total neoadjuvant therapy the new standard of care in locally advanced rectal cancer? A sensitivity analysis of the RAPIDO clinical trial. Ann Oncol. 2022 Aug;33(8):786-793. doi: 10.1016/j.annonc.2022.04.010. Epub 2022 Apr 22.
- Background: PubMed 35568280Glynne-Jones R, Harrison M. Should the RAPIDO schedule represent standard of care in locally advanced rectal cancer? Ann Oncol. 2022 Aug;33(8):745-746. doi: 10.1016/j.annonc.2022.05.002. Epub 2022 May 12. No abstract available.
- Background: PubMed 34308767Patel A, Spychalski P, Corrao G, Jereczek-Fossa BA, Glynne-Jones R, Garcia-Aguilar J, Kobiela J. Neoadjuvant short-course radiotherapy with consolidation chemotherapy for locally advanced rectal cancer: a systematic review and meta-analysis. Acta Oncol. 2021 Oct;60(10):1308-1316. doi: 10.1080/0284186X.2021.1953137. Epub 2021 Jul 24.
- Background: PubMed 33287114Papaccio F, Rosello S, Huerta M, Gambardella V, Tarazona N, Fleitas T, Roda D, Cervantes A. Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer. Cancers (Basel). 2020 Dec 3;12(12):3611. doi: 10.3390/cancers12123611.
- Background: PubMed 38192084Ozturk SK, Martinez CG, Mens D, Verhoef C, Tosetto M, Sheahan K, de Wilt JHW, Hospers GAP, van de Velde CJH, Marijnen CAM, van der Post RS, Nagtegaal ID. Lymph node regression after neoadjuvant chemoradiotherapy in rectal cancer. Histopathology. 2024 May;84(6):935-946. doi: 10.1111/his.15134. Epub 2024 Jan 8.
- Background: PubMed 37889954Nilsson PJ, van Etten B, Hospers GAP, Marijnen CAM, Meershoek-Klein Kranenberg E, Roodvoets AGH, van de Velde CJH, Glimelius B. Comment on the RAPIDO Trial Point-Counterpoint Debate. Dis Colon Rectum. 2024 Feb 1;67(2):e126. doi: 10.1097/DCR.0000000000003138. Epub 2023 Oct 26. No abstract available.
- Background: PubMed 40183423Polack M, van Pelt GW, van den Heuvel DH, Klein-Kranenbarg EM, Roodvoets AGH, Putter H, Crobach ASLP, Nagtegaal ID, Peeters KCMJ, Tollenaar RAEM, van Krieken JHJM, Mesker WE. The tumour-stroma ratio as predictive aid towards a biopsy-based treatment strategy in rectal carcinoma. Histopathology. 2025 Jul;87(1):44-57. doi: 10.1111/his.15423. Epub 2025 Apr 4.
- Results publication: PubMed 32240909van der Valk MJM, Marijnen CAM, van Etten B, Dijkstra EA, Hilling DE, Kranenbarg EM, Putter H, Roodvoets AGH, Bahadoer RR, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes AMR, de Groot DJA, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; Collaborative investigators. 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. Radiother Oncol. 2020 Jun;147:75-83. doi: 10.1016/j.radonc.2020.03.011. Epub 2020 Mar 30.
- Results publication: PubMed 33301740Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. 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. Lancet Oncol. 2021 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6. Epub 2020 Dec 7.
- Results publication: PubMed 35447283Dijkstra EA, Hospers GAP, Kranenbarg EM, Fleer J, Roodvoets AGH, Bahadoer RR, Guren MG, Tjalma JJJ, Putter H, Crolla RMPH, Hendriks MP, Capdevila J, Radu C, van de Velde CJH, Nilsson PJ, Glimelius B, van Etten B, Marijnen CAM. Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer - The RAPIDO trial. Radiother Oncol. 2022 Jun;171:69-76. doi: 10.1016/j.radonc.2022.04.013. Epub 2022 Apr 18.
- Dutch Colorectal CancerGroupLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
B. van Etten, MD, PhD principal investigator
University Medical Center Groningen, Department of Surgery, Groningen, The Netherlands
B. Glimelius, MD, PhD principal investigator
Akademiska Sjukhuset, Department of Oncology, Uppsala, Sweden
G. A. Hospers, MD, PhD principal investigator
University Medical Center Groningen, Department of Medical Oncology, Groningen, The Netherlands
56 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing M1 scheme and standard long course chemoradiotherapy in people with Rectal Cancer, run by University Medical Center Groningen at 56 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 1 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 56 sites in Netherlands, Sweden, Spain, Denmark, Norway and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 May 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients With Disease Related Treatment Failure (DrTF) (time frame: 3 years follow-up after surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01558921, which also lists 25 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2026.