Unresolved issues[edit source]
The optimal protocol for neoadjuvant therapy, including the role of chemotherapy cycles at systemic doses, has not been determined. One observational study reported clinical complete response rates of up to 48% with the administration of extra chemotherapy in the wait period after chemoradiotherapy.
Studies currently underway[edit source]
Several randomised controlled trials (RCTs) are currently underway that should help to inform management of rectal cancer. In particular, the role of short-course versus long-course neoadjuvant treatment and the role of neoadjuvant chemotherapy cycles are two key areas for which additional prospective trial data will become available. Trials include (but are not limited to):
- The Stockholm III study of short-course versus long-course radiation treatment.. This trial randomised 657 patients between 1998 and 2010 to one of three arms: short-course radiation treatment with immediate surgery (within a week), short-course radiation treatment with delayed surgery (4–8 weeks), or long-course RT with surgery within 4–8 weeks. Survival outcomes are yet to be reported.
- The PROSPECT/N1048 trial, a phase III RCT study assigning patients to standard preoperative chemoradiation treatment followed by total mesorectal excision and then adjuvant FOLFOX versus six cycles of preoperative FOLFOX with risk-adjusted use of preoperative radiation therapy.
- The PRODIGE 23, an RCT comparing neoadjuvant chemoradiation with capecitabine then 6 months of adjuvant chemotherapy, with six cycles of FOLFIRINOX chemotherapy prior to chemoradiation, then 3 months of adjuvant chemotherapy. The adjuvant chemotherapy can be either mFOLFOX6 or capecitabine.
- The phase III RAPIDO trial, which randomises patients with high risk rectal cancer (T4 and/or N2, other high risk features) to neoadjuvant chemoradiation with capecitabine then optional postoperative chemotherapy, or short course radiation treatment plus six cycles of neoadjuvant CAPOX without postoperative chemotherapies.
Future research priorities[edit source]
Future research priorities should include the validation of biomarkers to help guide management of rectal cancer. These may include both prognostic and predictive biomarkers to help determine the level of intensity of therapy as well as the most appropriate drug selection. In ideal circumstances treatment could be tailored to the individual on the basis of clinical, tumour and biomarker characteristics.
More robust methods to determine clinical complete response after neoadjuvant therapy are needed to help better help to better stratify patients into those who require surgery and those who can possibly be treated with an organ preservation strategy or ‘watch and wait’ protocols.
Multiple developments have occurred over the last two decades with respect to the management of curable rectal cancer resulting in greater locoregional disease control. Ongoing studies will help inform the best anti-cancer agents to use in the neoadjuvant disease setting, and the optimal timing of radiotherapy and surgery.
- Habr-Gama A, Perez RO, Sabbaga J, Nadalin W, São Julião GP, Gama-Rodrigues J. Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period. Dis Colon Rectum 2009 Dec;52(12):1927-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19934911.
- Pettersson D, Lörinc E, Holm T, Iversen H, Cedermark B, Glimelius B, et al. Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br J Surg 2015 Jul;102(8):972-8; discussion 978 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26095256.
- ClinicalTrials.gov Identifier: NCT01515787. PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery. Available from: https://clinicaltrials.gov/ct2/show/NCT01515787.
- Nilsson PJ, van Etten B, Hospers GA, Påhlman L, van de Velde CJ, Beets-Tan RG, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer 2013 Jun 7;13:279 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23742033.