Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial

NCT ID: NCT01558921

Last Updated: 2023-01-13

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 920 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-21
• Study Completion Date: 2026-12-31

Brief 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 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/5FU 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

B: 5x5Gy -> CAPOX -> surgery

experimental group (arm B) M1 scheme

Group Type: EXPERIMENTAL

M1 scheme

Intervention Type: OTHER

short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX

A: 5 weeks chemoradiation -> surgery

control group (arm A) standard long course chemoradiotherapy

Group Type: ACTIVE_COMPARATOR

standard long course chemoradiotherapy

Intervention Type: OTHER

long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group.

Interventions

M1 scheme

short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX

Intervention Type: OTHER

standard long course chemoradiotherapy

long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

Primary tumour characteristics:

1. Histological proof of newly diagnosed primary adenocarcinoma of the rectum

2. Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to TNM version 5), cT4b, 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 MRF, i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes, > 1 cm (lat LN+)

Exclusion Criteria

1. 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

2. Presence of metastatic disease or recurrent rectal tumour

3. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn¡¦s disease or active ulcerative Colitis

4. 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

5. Known DPD deficiency

6. Any contraindications to MRI (e.g. patients with pacemakers)

7. Medical or psychiatric conditions that compromise the patient's ability to give informed consent

8. Concurrent uncontrolled medical conditions

9. Any investigational treatment for rectal cancer within the past month

10. Pregnancy or breast feeding

11. Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract

12. 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

13. Patients with symptoms or history of peripheral neuropathy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: collaborator

Uppsala University Hospital

OTHER

Sponsor Role: collaborator

Dutch Cancer Society

OTHER

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: lead

Responsible Party

B. van Etten, MD, PhD

Dr. B. van Etten, surgical oncologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

B. van Etten, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen, Department of Surgery, Groningen, The Netherlands

B. Glimelius, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Akademiska Sjukhuset, Department of Oncology, Uppsala, Sweden

G. A. Hospers, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen, Department of Medical Oncology, Groningen, The Netherlands

P. Nilsson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Karolinska Universitetssjukhuset, Stockholm, Sweden

C. J. van de Velde, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center, Department of Surgery, Leiden, The Netherlands

C.A.M. Marijnen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Netherlands Cancer Institute, Amsterdam, the Netherlands

Locations

Siteman Cancer Center, Washington University Medical School

St Louis, Missouri, United States

Aalborg Universitetshospital

Aalborg, , Denmark

Odense Universitetshospital

Odense, , Denmark

University Medical Center Groningen

Groningen, PO BOX 30001, Netherlands

Noordwest Ziekenhuisgroep

Alkmaar, , Netherlands

Amsterdam UMC, location AMC

Amsterdam, , Netherlands

Amsterdam UMC, location VUMC

Amsterdam, , Netherlands

Nki / Avl

Amsterdam, , Netherlands

Onze Lieve Vrouwe Gasthuis

Amsterdam, , Netherlands

Wilhelmina Ziekenhuis

Assen, , Netherlands

Amphia Ziekenhuis

Breda, , Netherlands

Reinier de Graaf Groep

Delft, , Netherlands

Deventer Hospital

Deventer, , Netherlands

Catharina ZIekenhuis

Eindhoven, , Netherlands

Het Groene Hart Ziekenhuis

Gouda, , Netherlands

Martini Ziekenhuis

Groningen, , Netherlands

Universitair Medisch Centrum Groningen

Groningen, , Netherlands

de Tjongerschans

Heerenveen, , Netherlands

Ziekenhuisgroep Twente

Hengelo, , Netherlands

Spaarne Ziekenhuis

Hoofddorp, , Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Radiotherapeutisch Instituut Friesland

Leeuwarden, , Netherlands

Leiden University Medical Center

Leiden, , Netherlands

Alrijne Ziekenhuis

Leiderdorp, , Netherlands

UMC Nijmegen St Radboud

Nijmegen, , Netherlands

Antonius Ziekenhuis

Sneek, , Netherlands

Bronovo Ziekenhuis

The Hague, , Netherlands

HaGaZiekenhuis

The Hague, , Netherlands

Medisch Centrum Haaglanden

The Hague, , Netherlands

Diakonessenhuis

Utrecht, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Sørlandet Sykehus Kristiansand

Kristiansand, , Norway

Oslo Universitetssykehus

Oslo, , Norway

Institute of Oncology

Ljubljana, , Slovenia

Hospital Vall d'Hebron

Barcelona, , Spain

ICO Hospital Duran I Reynals

L'Hospitalet de Llobregat, , Spain

Consorcio Hospital General Universitario Valencia

Valencia, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Hospital Universitari i Politècnic la Fe

Valencia, , Spain

Södra Älvsborgs Sjukhus

Borås, , Sweden

Mälarsjukhuset

Eskilstuna, , Sweden

Falu Lasarett

Falun, , Sweden

Gävle sjukhus

Gävle, , Sweden

Sahlgrenska Universitetssjukhuset

Gothenburg, , Sweden

Kalmar Hospital

Kalmar, , Sweden

Centralsjukhuset i Karlstad

Karlstad, , Sweden

Linköpings Universitet

Linköping, , Sweden

Universitetssjukhuset i Lund

Lund, , Sweden

Universitetssjukhuset ÖREBRO

Örebro, , Sweden

Skaraborgs Sjukhus

Skövde, , Sweden

Karolinska Universitetssjukhuset

Stockholm, , Sweden

Sundsvalls Sjukhus

Sundsvall, , Sweden

Norrlands Universitetssjukhus

Umeå, , Sweden

Akademiska Sjukhuset

Uppsala, , Sweden

Centrallasarettet Växjö

Vaxjo, , Sweden

Centrallasarett

Västerås, , Sweden

Countries

United States; Denmark; Netherlands; Norway; Slovenia; Spain; Sweden

References

van 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.

Reference Type: BACKGROUND

PMID: 32240909 (View on PubMed)

Bahadoer 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.

Reference Type: BACKGROUND

PMID: 33301740 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23742033 (View on PubMed)

Dijkstra 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.

Reference Type: BACKGROUND

PMID: 35447283 (View on PubMed)

Giunta 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.

Reference Type: BACKGROUND

PMID: 33798955 (View on PubMed)

Jimenez-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.

Reference Type: BACKGROUND

PMID: 35462008 (View on PubMed)

Glynne-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.

Reference Type: BACKGROUND

PMID: 35568280 (View on PubMed)

Patel 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.

Reference Type: BACKGROUND

PMID: 34308767 (View on PubMed)

Papaccio 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.

Reference Type: BACKGROUND

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Dijkstra 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.

Reference Type: BACKGROUND

PMID: 36581138 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

http://www.dccg.nl/trial/rapido

Dutch Colorectal CancerGroup

Other Identifiers

2010-023957-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL36315.042.11

Identifier Type: -

Identifier Source: org_study_id