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

Rectal Cancer Clinical Trial

— RAPIDO  

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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01558921
• Other study ID #: NL36315.042.11
• Secondary ID: 2010-023957-12
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 21, 2011
• Est. completion date: December 31, 2026

Study information

• Verified date: January 2023
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 920
• Est. completion date: December 31, 2026
• Est. primary completion date: March 8, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Rectal Cancer
• Rectal Neoplasms

Intervention

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

Locations

Country	Name	City	State
Denmark	Aalborg Universitetshospital	Aalborg
Denmark	Odense Universitetshospital	Odense
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	Bronovo Ziekenhuis	Den Haag
Netherlands	HaGaZiekenhuis	Den Haag
Netherlands	Medisch Centrum Haaglanden	Den Haag
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	University Medical Center Groningen	Groningen	Po Box 30001
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	Diakonessenhuis	Utrecht
Netherlands	Isala Klinieken	Zwolle
Norway	Sørlandet Sykehus Kristiansand	Kristiansand
Norway	Oslo Universitetssykehus	Oslo
Slovenia	Institute of Oncology	Ljubljana
Spain	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
Sweden	Södra Älvsborgs Sjukhus	Borås
Sweden	Mälarsjukhuset	Eskilstuna
Sweden	Falu Lasarett	Falun
Sweden	Gävle sjukhus	Gävle
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg
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	Centrallasarett	Västerås
Sweden	Centrallasarettet Växjö	Växjö
United States	Siteman Cancer Center, Washington University Medical School	Saint Louis	Missouri

Sponsors (5)

Lead Sponsor	Collaborator
University Medical Center Groningen	Dutch Cancer Society, Karolinska University Hospital, Leiden University Medical Center, Uppsala University Hospital

Countries where clinical trial is conducted

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

References & Publications (10)

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. Erratum In: Lancet Oncol. 2021 Feb;22(2):e42. — View Citation

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. — View Citation

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. 2022 Dec 26:S0923-7534(22)04784-6. doi: 10.1016/j.annonc.2022.12.012. Online ahead of print. No abstract available. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: Radiother Oncol. 2020 Jun;147:e1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	3 year follow-up after surgery
Secondary	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.	10 year
Secondary	CRM negative rate	Circumferential resection margin > 1 mm	within 30 days
Secondary	pCR rate	Pathological complete response after neo-adjuvant treatment	within 30 days
Secondary	Short and long-term toxicity	Treatment associated toxicity	3 year follow-up
Secondary	Surgical complications	Wound rupture, bleeding, infection, rectal anastomotic leak	3 year follow-up
Secondary	Quality of life QLQ-C30	Quality of life QLQ-C30	3 year after surgery
Secondary	Quality of life QLQ-CR-29+	Quality of life QLQ-CR-29+	3 year after surgery
Secondary	Quality of life QLQ-CIPN20	Quality of life QLQ-CIPN20	3 year after surgery
Secondary	Quality of life LARS	LARS	3 year after surgery

External Links

•   Dutch Colorectal CancerGroup