Clinical trial NCT01558921: Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial
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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Rectal Cancer
Keywords: rectal cancer
radiotherapy
chemotherapy
5x5
capecitbine
oxaliplatin
CAPOX
FOLFOX
folinic acid
fluorouracil
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Karolinska University Hospital
name: Leiden University Medical Center
name: Uppsala University Hospital
name: Dutch Cancer Society
First posted: 2012-03-20
Enrollment: 920
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: standard arm: 5.5 weeks chemoradiation -\> surgery -\> optional chemotherapy experimental arm: 5x5Gy -\> 12 wks chemotherapy -\> surgery
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Disease related Treatment Failure (DrTF)
timeFrame: 3 year follow-up after surgery
Secondary outcomes:
measure: Overall survival
timeFrame: 10 year
measure: CRM negative rate
timeFrame: within 30 days
measure: pCR rate
timeFrame: within 30 days
measure: Short and long-term toxicity
timeFrame: 3 year follow-up
measure: Surgical complications
timeFrame: 3 year follow-up
measure: Quality of life QLQ-C30
timeFrame: 3 year after surgery
measure: Quality of life QLQ-CR-29+
timeFrame: 3 year after surgery
measure: Quality of life QLQ-CIPN20
timeFrame: 3 year after surgery
measure: Quality of life LARS
timeFrame: 3 year after surgery
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Siteman Cancer Center, Washington University Medical School
state: Missouri
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
state: Po Box 30001
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUMC
city: Amsterdam
country: Netherlands
facility: Nki / Avl
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Groep
city: Den Haag
country: Netherlands
facility: Bronovo Ziekenhuis
city: Den Haag
country: Netherlands
facility: HaGaZiekenhuis
city: Den Haag
country: Netherlands
facility: Medisch Centrum Haaglanden
city: Deventer
country: Netherlands
facility: Deventer Hospital
city: Eindhoven
country: Netherlands
facility: Catharina ZIekenhuis
city: Gouda
country: Netherlands
facility: Het Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Heerenveen
country: Netherlands
facility: de Tjongerschans
city: Hengelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leeuwarden
country: Netherlands
facility: Radiotherapeutisch Instituut Friesland
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Leiderdorp
country: Netherlands
facility: Alrijne Ziekenhuis
city: Nijmegen
country: Netherlands
facility: UMC Nijmegen St Radboud
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Zwolle
country: Netherlands
facility: Isala Klinieken
city: Kristiansand
country: Norway
facility: Sørlandet Sykehus Kristiansand
city: Oslo
country: Norway
facility: Oslo Universitetssykehus
city: Ljubljana
country: Slovenia
facility: Institute of Oncology
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: L'HOSPITALET de LLOBREGAT
country: Spain
facility: ICO Hospital Duran I Reynals
city: Valencia
country: Spain
facility: Consorcio Hospital General Universitario Valencia
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic la Fe
city: Borås
country: Sweden
facility: Södra Älvsborgs Sjukhus
city: Eskilstuna
country: Sweden
facility: Mälarsjukhuset
city: Falun
country: Sweden
facility: Falu Lasarett
city: Gävle
country: Sweden
facility: Gävle sjukhus
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Kalmar
country: Sweden
facility: Kalmar Hospital
city: Karlstad
country: Sweden
facility: Centralsjukhuset i Karlstad
city: Linköping
country: Sweden
facility: Linköpings Universitet
city: Lund
country: Sweden
facility: Universitetssjukhuset i Lund
city: Skövde
country: Sweden
facility: Skaraborgs Sjukhus
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
city: Sundsvall
country: Sweden
facility: Sundsvalls Sjukhus
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Västerås
country: Sweden
facility: Centrallasarett
city: Växjö
country: Sweden
facility: Centrallasarettet Växjö
city: Örebro
country: Sweden
facility: Universitetssjukhuset ÖREBRO
Study officials:
affiliation: University Medical Center Groningen, Department of Surgery, Groningen, The Netherlands
name: B. van Etten, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Akademiska Sjukhuset, Department of Oncology, Uppsala, Sweden
name: B. Glimelius, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen, Department of Medical Oncology, Groningen, The Netherlands
name: G. A. Hospers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska Universitetssjukhuset, Stockholm, Sweden
name: P. Nilsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center, Department of Surgery, Leiden, The Netherlands
name: C. J. van de Velde, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Netherlands Cancer Institute, Amsterdam, the Netherlands
name: C.A.M. Marijnen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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.
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.
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.
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.
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.
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.
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. 2023 Apr;34(4):446-447. doi: 10.1016/j.annonc.2022.12.012. Epub 2022 Dec 26. No abstract available.