Unresolved issuesThe 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
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 RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. study assigning patients to standard preoperative chemoradiation treatment followed by total mesorectal excision and then adjuvant FOLFOXSystemic chemotherapy using a combination of the drugs Leucovorin (folinic acid), Fluorouracil, and Oxaliplatin. versus six cycles of preoperative FOLFOXSystemic chemotherapy using a combination of the drugs Leucovorin (folinic acid), Fluorouracil, and Oxaliplatin. with risk-adjusted use of preoperative radiation therapy.
- The PRODIGE 23, an RCTA study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. 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
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 GPA medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients., 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 ColonThe main part of the large bowel, which absorbs water and electrolytes from undigested food (solid waste). Its four parts are the ascending colon, transverse colon, descending colon and sigmoid colon. RectumThe final section of the large bowel, ending at the anus. 2009 Dec;52(12):1927-34 Abstract available at 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 Abstract available at 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. Abstract available at 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23742033.