MRI Simulation-guided Boost in Short-course Preoperative Radiotherapy for Unresectable Rectal Cancer

Rectal Neoplasms Clinical Trial

— SUNRISE  

Official title:

MRI Simulation-guided Boost in Short-course Preoperative Radiotherapy (SCPRT) Followed by Consolidation Chemotherapy Versus Long Course Chemoradiation for Unresectable Rectal Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03714490
• Other study ID #: NCC201807007
• Status: Recruiting
• Phase: Phase 2
• Start date: October 23, 2018
• Est. completion date: September 30, 2025

Study information

• Verified date: May 2024
• Source: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Contact: Jing Jin, M.D.
• Phone: 86-010-87788503
• Email: jinjing[@]csco.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Improvements in downstaging are required when using preoperative chemoradiation for unresectable rectal cancer. There is therefore a need to explore more effective schedules. The study arm will receive MRI simulation-guided boost in short-course preoperative radiotherapy followed by consolidation chemotherapy , which may enhance the shrinkage of tumor comparing with the concurrent chemoradiation.

Description:

The study is a prospective phase II randomized multicenter trial. The purpose of this study is to compare short-term radiotherapy with MRI simulation-guided boost followed by consolidation chemotherapy(Experimental group) with preoperative long-term chemoradiotherapy(Control group) for middle-lower unresectable locally advanced rectal cancer evaluated by MRI. The primary endpoint is the rate of R0 resection and cCR, and the secondary objectives are local recurrence-free survival, distant metastasis-free survival, disease-free survival and overall survival at 3-year and 5-year follow up. Furthermore, pathological complete response rate, the acute and late toxicity profile and quality of life (QOL) after 3 years follow-up are secondary endpoints. The exploratory end point includes the circulating tumor DNA, and other potential biomarkers from tumor tissue and blood sample for treatment response and survival predicting. For each group, a plan for collection of serum/plasma/feces at baseline and different stages during or after treatment and for obtaining fresh tumor tissue for freezing prior to treatment was defined in the protocol.

The SUNRISE-trial has been designed by National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, and the hypothesis is R0 resection rate in Experimental group was superior to that in Control group.

Interim analysis design: As a phase II trial, the safety of experimental intervention is a major concern. We took the toxicity data from STELLAR, a phase III randomized study led by our center, as a reference. The incidence of G3 and above side effects in the short course radiotherapy with sequential neoadjuvant chemotherapy group was 28%, and that in the standard long-course concurrent chemoradiotherapy control group was 5%. Considering that boost dose may increase toxicity, if severe toxicity in the study group significantly exceeds that in the control group by more than 35%, it is up to the principal investigator to decide whether to modify the study protocol or terminate the study. The sample size of the interim analysis was calculated by the Z-pooled test, with α=0.05 (one-sided test), 1-β=0.90, using PASS 11 software. The frequency of the toxicity of G3 and above should be compared when neoadjuvant therapy was completed in 21 patients enrolled in each group.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: September 30, 2025
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Biopsy proven rectal adenocarcinoma;

• Distance between tumour and anal verge= 10cm;

• Locally advanced tumour;(AJCC Cancer Staging:T3, T4 or N+)

• Mesorectal fascia(MRF)+ or T4b evaluated by pelvic MRI;

• Eastern Cooperative Oncology Group(ECOG) performance score = 1;

• Written informed consent;

• Mentally and physically fit for chemotherapy;

• Adequate blood counts: White blood cell count =3.5 x 109/L Haemoglobin levels =100g/L Platelet count =100 x 109/L Creatinine levels =1.0× upper normal limit(UNL) Urea nitrogen levels =1.0× upper normal limit(UNL) Alanine aminotransferase(ALT) =1.5× upper normal limit(UNL) Aspartate aminotransferase(AST) =1.5× upper normal limit(UNL) Alkaline phosphatase(ALP) =1.5× upper normal limit(UNL) Total bilirubin(TBIL) =1.5× upper normal limit(UNL)

• No excision of tumor, chemotherapy or other anti-tumor treatment after the diagnosis.

Exclusion Criteria:

• Distant metastases;

• Recurrent rectal cancer;

• Active Crohn's disease or ulcerative colitis;

• Concomitant malignancies;(except basocellular carcinoma or in-situ cervical carcinoma)

• Allergic to Fluorouracil or Platinum drugs;

• Contraindications to MRI for any reason;

• Concurrent uncontrolled medical condition;

• Pregnancy or breast feeding;

• Known malabsorption syndromes or lack of physical integrity of upper gastrointestinal tract;

• Symptoms or history of peripheral neuropathy

Related Conditions & MeSH terms

• Rectal Neoplasms

Intervention

Radiation:
• SCPRT
Short-course preoperative radiotherapy(SCPRT), which consists of 5 Gy x 5f and 4Gy for boost on the GTV with MRI-simulation alone.
• CRT
Long-term chemoradiotherapy(CRT), which consists of a long-term chemoradiation (2 Gy x 25 with capecitabine) preoperatively.

Drug:
• CAPOX
Patients will receive consolidation chemotherapy after 7-10 days of SCPRT completed, given in 3 week cycle of capecitabine 1000 mg/m2 twice daily, day 1-14 combined with oxaliplatin 130 mg/m2 once. In total, 4 cycles of neoadjuvant chemotherapy are scheduled before surgery.

Locations

Country	Name	City	State
China	Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Country where clinical trial is conducted

China, 

References & Publications (11)

Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Pahlman L, Wiig JN, Bystrom P, Bujko K, Glimelius B. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 2008 Aug 1;26(22):3687-94. doi: 10.1200/JCO.2007.15.3858. — View Citation

Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, Michalski W, Oledzki J, Kusnierz J, Zajac L, Bednarczyk M, Szczepkowski M, Tarnowski W, Kosakowska E, Zwolinski J, Winiarek M, Wisniowska K, Partycki M, Beczkowska K, Polkowski W, Stylinski R, Wierzbicki R, Bury P, Jankiewicz M, Paprota K, Lewicka M, Cisel B, Skorzewska M, Mielko J, Bebenek M, Maciejczyk A, Kapturkiewicz B, Dybko A, Hajac L, Wojnar A, Lesniak T, Zygulska J, Jantner D, Chudyba E, Zegarski W, Las-Jankowska M, Jankowski M, Kolodziejski L, Radkowski A, Zelazowska-Omiotek U, Czeremszynska B, Kepka L, Kolb-Sielecki J, Toczko Z, Fedorowicz Z, Dziki A, Danek A, Nawrocki G, Sopylo R, Markiewicz W, Kedzierawski P, Wydmanski J; Polish Colorectal Study Group. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016 May;27(5):834-42. doi: 10.1093/annonc/mdw062. Epub 2016 Feb 15. — View Citation

Burbach JP, den Harder AM, Intven M, van Vulpen M, Verkooijen HM, Reerink O. Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: a systematic review and meta-analysis. Radiother Oncol. 2014 Oct;113(1):1-9. doi: 10.1016/j.radonc.2014.08.035. Epub 2014 Oct 1. — View Citation

Caravatta L, Padula GD, Picardi V, Macchia G, Deodato F, Massaccesi M, Sofo L, Pacelli F, Rotondi F, Cecere G, Sallustio G, Di Lullo L, Piscopo A, Mignogna S, Bonomo P, Cellini N, Valentini V, Morganti AG. Concomitant boost radiotherapy and multidrug chemotherapy in the neoadjuvant treatment of locally advanced rectal cancer: results of a phase II study. Acta Oncol. 2011 Nov;50(8):1151-7. doi: 10.3109/0284186X.2011.582880. Epub 2011 Aug 18. — View Citation

Chen W, Zheng R, Zeng H, Zhang S, He J. Annual report on status of cancer in China, 2011. Chin J Cancer Res. 2015 Feb;27(1):2-12. doi: 10.3978/j.issn.1000-9604.2015.01.06. — View Citation

Engels B, Platteaux N, Van den Begin R, Gevaert T, Sermeus A, Storme G, Verellen D, De Ridder M. Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer: report on late toxicity and outcome. Radiother Oncol. 2014 Jan;110(1):155-9. doi: 10.1016/j.radonc.2013.10.026. Epub 2013 Nov 12. — View Citation

Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rodel C, Cervantes A, Arnold D; ESMO Guidelines Committee. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv22-iv40. doi: 10.1093/annonc/mdx224. No abstract available. Erratum In: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv263. — View Citation

Lee JH, Kim DY, Nam TK, Yoon SC, Lee DS, Park JW, Oh JH, Chang HJ, Yoon MS, Jeong JU, Jang HS. Long-term follow-up of preoperative pelvic radiation therapy and concomitant boost irradiation in locally advanced rectal cancer patients: a multi-institutional phase II study (KROG 04-01). Int J Radiat Oncol Biol Phys. 2012 Nov 15;84(4):955-61. doi: 10.1016/j.ijrobp.2012.01.045. Epub 2012 Apr 24. — View Citation

Li JL, Ji JF, Cai Y, Li XF, Li YH, Wu H, Xu B, Dou FY, Li ZY, Bu ZD, Wu AW, Tham IW. Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: a phase II trial. Radiother Oncol. 2012 Jan;102(1):4-9. doi: 10.1016/j.radonc.2011.07.030. Epub 2011 Sep 6. — View Citation

Teo MTW, McParland L, Appelt AL, Sebag-Montefiore D. Phase 2 Neoadjuvant Treatment Intensification Trials in Rectal Cancer: A Systematic Review. Int J Radiat Oncol Biol Phys. 2018 Jan 1;100(1):146-158. doi: 10.1016/j.ijrobp.2017.09.042. Epub 2017 Sep 29. — View Citation

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108. doi: 10.3322/caac.21262. Epub 2015 Feb 4. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	circulating tumor DNA, single cells, Cytokines and other potential biomarkers such as T-cell receptor	The exploratory end point for predicting of treatment response and survival. The circulating tumor DNA test by sequencing will includes KRAS, NRAS, BRAF,PI3K,TP53,PTEN, EGFR, NEGF etc (509-gene panel). And Measuring change in T cell receptor sub-types during treatment.Single cells test by cytof. Cytokines test by the Olink Proteomics panel.	3-year
Primary	R0(microscopically margin-negative) resection and cCR rate	The composite outcome of R0 (microscopically margin-negative) resection and cCR, that is, the combined rate of radical resection and cCR management after neoadjuvant treatment.	1-month after surgery completed
Secondary	local recurrence-free survival	the time from surgery to local recurrence	3-year and 5-year
Secondary	distant metastasis-free survival	the time from diagnosis to metastasis	3-year and 5-year
Secondary	disease-free survival	the time from surgery to recurrence	3-year and 5-year
Secondary	overall survival	the time from diagnosis to death	3-year and 5-year
Secondary	pathological complete response rate	pathological complete response in surgery specimen	1-month after surgery completed
Secondary	clinical complete response rate	clinical complete response evaluated by MDT	3-month after neoadjuvant treatment
Secondary	the acute toxicity profile	the frequency of acute adverse events during and after treatment in 1-month, including gastrointestinal (vomiting, diarrhea and incontinence), dermatitis, and hematologic toxicity evaluated weekly by the Common Terminology Criteria 4.0.	1-month
Secondary	the late toxicity profile	the late toxicity after treatment completion for 1-month, the frequency of late adverse events after 1-month of treatment, including gastrointestinal function, fistula, and hematologic toxicity, evaluated regularly by LENT-SOMA scoring systems.	3-year
Secondary	general quality of life (QoL) by QLQ-30	general quality of life of patients evaluated by questionaire of EORTC QLQ-C30. The higher score in total indicates the worse quality of life in general.	3-year
Secondary	QoL by QLO-CR29	quality of life related to colorectal disease of patients evaluated by questionaire of EORTC QLQ-CR29. The higher score in total of this module indicates the worse quality of life by colorectal module.	3-year
Secondary	Sum of sustained clinical complete response rate and R0 resection rate	the rate of sustained clinical complete response plus rate of R0 resection	12 months after neoadjuvant therapy