Patients With Rectal Cancer: a "Wait-and-see" Approach

Colorectal Carcinoma Clinical Trial

Official title:

Radical External Beam Chemoradiation in Patients With Rectal Cancer: a "Wait-and-see" Approach

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03001362
• Other study ID #: 14-407 GEN
• Status: Recruiting
• Phase: N/A
• Start date: March 2015
• Est. completion date: January 31, 2026

Study information

• Verified date: October 2023
• Source: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Contact: Neil Kopek, M.D.
• Phone: 514-934-4440
• Email: neil.kopek[@]muhc.mcgill.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with histologically proven adenocarcinoma of the rectum will receive pelvic radiotherapy to a dose of 45Gy in 25 fractions with a tumor boost to a dose of 9Gy in 5 fractions (thus total of 54Gy/30Fx to the primary tumor), combined with radio sensitizing chemotherapy. Patients will then be closely monitored, through endoscopy and imaging, for response to treatment and relapse. Salvage oncologic surgery to be offered if there is failure to achieve complete clinical response or in the event of a loco regional relapse.

Description:

The combination of preoperative (chemo)radiotherapy and total mesorectal excision (TME) has been shown to reduce the risk of local recurrence in patients with resectable adenocarcinoma of the rectum. The improved local control rates come at the price of an increased risk of surgical complications, including a postoperative death rate of 2-8 percent which may reach 30 per cent at 6 months in those aged over 85 years, as well as long-term impact on anorectal, urinary and sexual function. Patients with cancers in the low rectum in close proximity to the sphincter muscles, may require a permanent stoma, which can be associated with high psychological morbidity.

Preoperative chemoradiotherapy followed by a delay to resection can produce pathological complete responses. One review of phase II and III studies identified an overall pCR rate of 13.5%, but even higher rates of pCR have been observed with doses of radiotherapy exceeding 45 Gy . Certainly patients who proceed to radical surgery after achieving a pCR with chemo radiation do have favorable long-term outcomes. But do patients whose tumor has already been sterilized by chemo radiotherapy need to proceed with radical surgery?

A number of studies have now emerged highlighting the rationale of a 'wait and see' policy for patients who achieve a complete clinical response (cCR) after chemo radiotherapy. The majority of the clinical data supporting this approach have come from Brazil. The Brazilian data suggests that observation of such patients yields survival rates similar to those of patients who undergo radical surgery with confirmation of pCR. More recent studies from the United Kingdom and the Netherlands appear to support the feasibility of this approach. To date there is no published prospectively collected data of a wait-and-see policy from a North American Centre.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: January 31, 2026
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Pelvic MRI defined disease (at least one of the following):

• mesorectum involved or breached - includes involvement of adjacent organ (s) (T3-T4)

• involvement of muscularis propria (T2)

• extra-mural vascular invasion

• tumour deposit within the mesorectum

• one or more involved mesorectal lymph node

• Patients are considered medically fit for oncologic resection

• ECOG performance status 0 or 1

• No evidence of established metastatic disease (CT chest and abdomen)

• Absolute neutrophil count >1.5x109/L; platelets >100x109/L,

• Serum transaminase <3 x ULN;

• Adequate renal function (Cockroft Gault estimation >50 mL/min)

• Bilirubin <1.5 x ULN

• Ability to comply with oral medication

• Willingness and ability to give informed consent and comply with treatment and follow up schedule

• Age 18 or over

Exclusion Criteria:

• Previous radiotherapy to the pelvis (including brachytherapy)

• Enlarged extramesorectal nodes

• Uncontrolled cardiorespiratory comorbidity (includes patients with inadequately controlled angina or myocardial infarction within 6 months of randomisation)

• T1N0 disease without extra-mural venous invasion

• Unequivocal evidence of metastatic disease (includes resectable metastases)

• Major impairment of bowel function without defunctioning stoma/ileostomy (baseline grade 3 diarrhoea or clinically significant faecal incontinence)

• History of another malignancy within the last 5 years except successfully treated basal cell cancer of skin or carcinoma in situ of uterine cervix.

• Known dihydropyrimidine dehydrogenase deficiency

• Known Gilberts disease (hyperbilirubinaemia)

• Taking warfarin or phenytoin or sorivudine

• Gastrointestinal disorder which would interfere with oral therapy and its bioavailability

• Pregnant, lactating, or pre-menopausal women not using adequate contraception

• Unfit to receive any study treatment or subsequent surgical resection

Related Conditions & MeSH terms

• Colorectal Carcinoma
• Colorectal Neoplasms

Intervention

Radiation:
• Radical external beam radiotherapy
pelvic radiotherapy to a dose of 45 Gy in 25 fractions with a tumor boost to a dose of 9 Gy in 5 fractions (thus total of 54 Gy/30 fractions to the primary tumor), combined with radio sensitizing chemotherapy.

Locations

Country	Name	City	State
Canada	McGill University Health Centre- Cedars Cancer Centre	Montreal	Quebec
Canada	McGill University Health Center-Cedars Cancer Centre	Montréal	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
McGill University Health Centre/Research Institute of the McGill University Health Centre

Country where clinical trial is conducted

Canada, 

References & Publications (24)

Borowski DW, Bradburn DM, Mills SJ, Bharathan B, Wilson RG, Ratcliffe AA, Kelly SB; Northern Region Colorectal Cancer Audit Group (NORCCAG). Volume-outcome analysis of colorectal cancer-related outcomes. Br J Surg. 2010 Sep;97(9):1416-30. doi: 10.1002/bjs.7111. — View Citation

Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. doi: 10.1056/NEJMoa060829. Erratum In: N Engl J Med. 2007 Aug 16;357(7):728. — View Citation

Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006 Oct;93(10):1215-23. doi: 10.1002/bjs.5506. — View Citation

Dalton RS, Velineni R, Osborne ME, Thomas R, Harries S, Gee AS, Daniels IR. A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management? Colorectal Dis. 2012 May;14(5):567-71. doi: 10.1111/j.1463-1318.2011.02752.x. — View Citation

Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006 Oct 1;24(28):4620-5. doi: 10.1200/JCO.2006.06.7629. — View Citation

Gervaz PA, Wexner SD, Pemberton JH. Pelvic radiation and anorectal function: introducing the concept of sphincter-preserving radiation therapy. J Am Coll Surg. 2002 Sep;195(3):387-94. doi: 10.1016/s1072-7515(02)01308-x. No abstract available. — View Citation

Glynne-Jones R, Hughes R. Critical appraisal of the 'wait and see' approach in rectal cancer for clinical complete responders after chemoradiation. Br J Surg. 2012 Jul;99(7):897-909. doi: 10.1002/bjs.8732. Epub 2012 Apr 27. — View Citation

Habr-Gama A, de Souza PM, Ribeiro U Jr, Nadalin W, Gansl R, Sousa AH Jr, Campos FG, Gama-Rodrigues J. Low rectal cancer: impact of radiation and chemotherapy on surgical treatment. Dis Colon Rectum. 1998 Sep;41(9):1087-96. doi: 10.1007/BF02239429. — View Citation

Habr-Gama A, Gama-Rodrigues J, Sao Juliao GP, Proscurshim I, Sabbagh C, Lynn PB, Perez RO. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys. 2014 Mar 15;88(4):822-8. doi: 10.1016/j.ijrobp.2013.12.012. Epub 2014 Feb 1. — View Citation

Habr-Gama A, Perez RO, Nadalin W, Nahas SC, Ribeiro U Jr, Silva E Sousa AH Jr, Campos FG, Kiss DR, Gama-Rodrigues J. Long-term results of preoperative chemoradiation for distal rectal cancer correlation between final stage and survival. J Gastrointest Surg. 2005 Jan;9(1):90-9; discussion 99-101. doi: 10.1016/j.gassur.2004.10.010. — View Citation

Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr, Silva e Sousa AH Jr, Campos FG, Kiss DR, Gama-Rodrigues J. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004 Oct;240(4):711-7; discussion 717-8. doi: 10.1097/01.sla.0000141194.27992.32. — View Citation

Habr-Gama A, Perez RO, Proscurshim I, Campos FG, Nadalin W, Kiss D, Gama-Rodrigues J. Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg. 2006 Dec;10(10):1319-28; discussion 1328-9. doi: 10.1016/j.gassur.2006.09.005. — View Citation

Habr-Gama A. Assessment and management of the complete clinical response of rectal cancer to chemoradiotherapy. Colorectal Dis. 2006 Sep;8 Suppl 3:21-4. doi: 10.1111/j.1463-1318.2006.01066.x. — View Citation

Hartley A, Ho KF, McConkey C, Geh JI. Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials. Br J Radiol. 2005 Oct;78(934):934-8. doi: 10.1259/bjr/86650067. — View Citation

Jorge JM, Wexner SD. Etiology and management of fecal incontinence. Dis Colon Rectum. 1993 Jan;36(1):77-97. doi: 10.1007/BF02050307. — View Citation

Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, van Dam RM, Jansen RL, Sosef M, Leijtens JW, Hulsewe KW, Buijsen J, Beets GL. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011 Dec 10;29(35):4633-40. doi: 10.1200/JCO.2011.37.7176. Epub 2011 Nov 7. — View Citation

Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, Calvo FA, Garcia-Aguilar J, Glynne-Jones R, Haustermans K, Mohiuddin M, Pucciarelli S, Small W Jr, Suarez J, Theodoropoulos G, Biondo S, Beets-Tan RG, Beets GL. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010 Sep;11(9):835-44. doi: 10.1016/S1470-2045(10)70172-8. Epub 2010 Aug 6. — View Citation

Paun BC, Cassie S, MacLean AR, Dixon E, Buie WD. Postoperative complications following surgery for rectal cancer. Ann Surg. 2010 May;251(5):807-18. doi: 10.1097/SLA.0b013e3181dae4ed. — View Citation

Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde CJ; Dutch Colorectal Cancer Group. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007 Nov;246(5):693-701. doi: 10.1097/01.sla.0000257358.56863.ce. — View Citation

Rutten HJ, den Dulk M, Lemmens VE, van de Velde CJ, Marijnen CA. Controversies of total mesorectal excision for rectal cancer in elderly patients. Lancet Oncol. 2008 May;9(5):494-501. doi: 10.1016/S1470-2045(08)70129-3. — View Citation

Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694. — View Citation

Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, Griffiths G, Thompson LC, Parmar M. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20. doi: 10.1016/S0140-6736(09)60484-0. — View Citation

Temple LK, Bacik J, Savatta SG, Gottesman L, Paty PB, Weiser MR, Guillem JG, Minsky BD, Kalman M, Thaler HT, Schrag D, Wong WD. The development of a validated instrument to evaluate bowel function after sphincter-preserving surgery for rectal cancer. Dis Colon Rectum. 2005 Jul;48(7):1353-65. doi: 10.1007/s10350-004-0942-z. — View Citation

van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011 Jun;12(6):575-82. doi: 10.1016/S1470-2045(11)70097-3. Epub 2011 May 17. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of a "wait and see" approach	Rate of failure to achieve CR or the rate of recurrence after achieving CR	One year