Neoadjuvant chemotherapy regimen
Fluoropyrimidine-based chemotherapy is the standard choice of radiation sensitiser for use in combination with radiation treatment. Intravenous and oral routes of administration are used.
Other approaches that are not currently standard treatment for rectal cancer, but are either under investigation or have been proposed for evaluation, include:
- the addition of oxaliplatin
- neoadjuvant systemic chemotherapy cycles given without radiation
- targeted therapies such as bevacizumab, panitumumab and cetuximab.
Overview of evidence (non-systematic literature review)[edit source]
No systematic reviews were undertaken for this topic. Practice points were based on selected published evidence. See Guidelines development process.
Intravenous or oral fluoropyrimidine[edit source]
Continuous infusional therapy is preferred over bolus injection for fluoropyrimidine-based chemotherapy, based on a 1994 study investigating bolus versus infusional adjuvant chemoradiation in 644 patients with rectal cancer, which reported that infusional 5-fluorouracil (5-FU) increased time to relapse and improved overall survival.
5FU has been the standard backbone of chemotherapy in the management of both colon and rectal cancer. Capecitabine, an oral 5FU analogue, is a prodrug that is converted systemically by the enzyme thymidine phosphorylase to 5FU. Compared with infusional 5FU, it is associated with a higher risk of hand-foot syndrome, but a lower risk of neutropenia.
- A 2012 German study in 392 evaluable patients compared capecitabine or infusional 5FU with radiation treatment in the neoadjuvant setting. This was a non-inferiority study and capecitabine was found to be non-inferior for overall survival at 5 years (76% versus 67%, non-inferiority p = 0.0004).)
- The larger US National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 study randomised 1608 patients to one of four arms: infusional 5FU with or without oxaliplatin, or capecitabine with or without oxaliplatin. Comparing groups receiving the 5FU- and capecitabine-based regimens, there were no statistically significantly differences in rates of sphincter preservation, pathological complete response, locoregional control or 5-year overall survival.
Because of the risk of toxicity, and given that capecitabine is an oral cytotoxic agent self-administered at home, patients should be carefully selected, where possible, to ensure appropriate compliance with the drug in order to avoid serious toxicity from inadvertent dosing errors.
Infusional fluoropyrimidine is preferable to bolus fluoropyrimidine for use in combination with radiation treatment for rectal cancer.
Oral capecitabine or intravenous infusional 5FU are both acceptable agents to combine with radiation treatment for rectal cancer.
If capecitabine is considered, patients should be carefully selected to minimise risk of non-compliance or overdosing.
Neoadjuvant oxaliplatin[edit source]
Oxaliplatin is a platinum analogue commonly used in metastatic colorectal cancer. Multiple trials have investigated its use combined with neoadjuvant radiation treatment and fluoropyrimidine in rectal cancer. Several large-scale phase III RCTs have produced somewhat conflicting results with respect to efficacy These studies have also demonstrated greater toxicity when adding oxaliplatin to fluoropyrimidine. Oxaliplatin is commonly associated with myelosuppression and peripheral neuropathy.
There have been several negative studies:
- The STAR-01 trial from Italy randomised 747 patients to standard chemoradiation with or without weekly oxaliplatin. Pathological complete response, sphincter preservation, and overall survival were not significantly different between treatment arms.
- The ACCORD 12/0405 PRODIGE 2 trial (n=598) compared capecitabine with and without oxaliplatin in combination with radiation treatment. It reported no significant differences in rates of pathological complete response, sphincter preservation, local control or overall survival.
- The PETACC-6 trial (n=1094) compared capecitabine with and without oxaliplatin, both before and after surgery. It reported no difference in rates of disease-free survival and overall survival with or without oxaliplatin.
- The four-arm NSABP R-04 compared infusional 5FU alone, 5FU with oxaliplatin, capecitabine alone and capecitabine with oxaliplatin. The addition of oxaliplatin was not associated with any differences in rates of locoregional control, disease-free survival or overall survival.
- A Chinese study (n=206) randomised patients to receive preoperative radiotherapy with either capecitabine or capecitabine and oxaliplatin with all patients receiving post-operative adjuvant mFOLFOX. This study found no difference in pathological complete remission, local recurrence, disease free survival and overall survival. Three year distant metastatic rate was improved with the experimental arm (16.5% vs 28.2%, p=0.045).
Other large studies have yielded positive results for the role of oxaliplatin:
- The German CAO/ARO/AIO-04 trial (n=1236 assessable patients) used a non-standard schedule of neoadjuvant infusional 5FU in both arm and gave oxaliplatin both before and after surgery in the experimental arm. The oxaliplatin group showed improved rates of pathological complete response and 3-year disease-free survival (75.9% versus 71.2%, p=0.03), representing an absolute 4.7% gain. It is not known whether this benefit is due to the neoadjuvant, or adjuvant oxaliplatin, or both.
- A three-arm Chinese trial (FOWARC) randomised 495 patients (475 evaluable) to radiotherapy with either infusional 5FU or mFOLFOX6, or to mFOLFOX6 without radiation treatment. All arms received postoperative chemotherapy. The neoadjuvant mFOLFOX6 group showed a higher rates of pathological complete response (27.5% versus 14% for 5FU plus radiation treatment and 6% for chemotherapy alone) and a higher rate of tumour downstaging, but a similar sphincter preservation rate. Survival data are not yet available.
A 2013 meta-analysis assessing short-term outcomes, which included four RCTs, similarly found that the addition of oxaliplatin improved pathological complete response rate and reduced the rate of perioperative metastases, but increased toxicity, with no differences in the rates of R0 resection, sphincter preservation or surgical complications. A subsequent meta-analysis (currently only available in abstract form), which included the same studies and an additional RCT, reported similarly that the addition of oxaliplatin increased the proportion of patients who achieved pathological complete response after neoadjuvant treatment, but was again associated with higher toxicity.
Neoadjuvant systemic chemotherapy[edit source]
One management strategy currently under investigation is the use of initial systemic chemotherapy in the neoadjuvant setting. This approach facilitates the early delivery of systemic doses of chemotherapy, and may treat potential micrometastatic disease early rather than after radiation treatment and surgery.
Additionally, the role of chemotherapy alone, without radiation treatment, is under question – ideally avoiding short-term and late toxicities related to radiotherapy. A small number of prospective studies have investigated this approach: either neoadjuvant chemotherapy without radiation treatment, or combined with radiation treatment in various sequences. Most are small single-arm studies combining capecitabine or 5FU with oxaliplatin; several of the chemotherapy-alone studies also include bevacizumab (see Targeted therapies, below). A retrospective analysis of the US National Cancer Database, which compared patients with stage II/II rectal cancer reported that patients who received neoadjuvant multiagent chemotherapy had an inferior overall survival than those who received neoadjuvant chemoradiotherapy. This strategy cannot be recommended outside of a clinical trial.
The role of neoadjuvant systemic chemotherapy is still under investigation and is not regarded as routine.
Targeted therapies[edit source]
The use of targeted therapies such as bevacizumab, panitumumab and cetuximab as neoadjuvant therapy in the management of rectal cancer has not been investigated in phase III RCTs.
Bevacizumab is a humanised monoclonal antibody targeting vascular endothelial growth factor. It is routinely used in the treatment of metastatic colorectal cancer. Multiple studies, mostly small single-arm phase II trials have investigated its use in the neoadjuvant setting for rectal cancer. A 2011 systematic review reported good pathological complete response rates with the use of neoadjuvant bevacizumab, but also some concerns regarding perioperative morbidity. Currently bevacizumab is not recommended in the neoadjuvant or adjuvant disease setting for rectal cancer, excepting metastatic disease.
Cetuximab and panitumumab are monoclonal antibodies targeting epidermal growth factor receptor. Efficacy in colorectal cancer is limited to patients with wild-type K-ras. These are also used routinely in the management of metastatic disease. There are several small, largely single-arm phase II studies. The largest study, the EXPERT-C trial, is a phase II RCT including 165 patients who received neoadjuvant CAPOX chemotherapy and chemoradiation, followed by adjuvant CAPOX, with or without cetuximab (both neoadjuvant and adjuvant). Sixty per cent of assessable tumours were K-ras wild-type. The addition of cetuximab improved radiological response but, importantly, not the primary endpoint of pathological complete response, and was associated with increased toxicity. Subsequent analysis did not demonstrate improvement in progression-free survival or overall survival,
- O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994 Aug 25;331(8):502-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8041415.
- Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012 Jun;13(6):579-88 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22503032.
- O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol 2014 Jun 20;32(18):1927-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24799484.
- Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, et al. Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial. J Natl Cancer Inst 2015 Nov;107(11) Available from: http://www.ncbi.nlm.nih.gov/pubmed/26374429.
- Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 2011 Jul 10;29(20):2773-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21606427.
- Aschele C, Cionini L, Lonardi S, et al. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. J Clin Oncol ;2011; 29: 2773-80.
- Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010 Apr 1;28(10):1638-44 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20194850.
- Francois, E; Gourgou-Bourgade, S; Azria, D; Conroy, T; Bouche, O; Doyen, J, et al. ACCORD12/0405-Prodige 2 phase III trial neoadjuvant treatment in rectal cancer: Results after 5 years of follow-up. J Clin Oncol 34, 2016 (suppl 4S; abstr 490) ;http://meetinglibrary.asco.org/content/160015-173.
- Schmoll, H; Haustermans, K; Price, T; Nordlinger, B; Hofheinz, R; Daisne, J, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: Disease-free survival results at interim analysis. J Clin Oncol 32:5s, 2014 (suppl; abstr 3501) Available from: http://meetinglibrary.asco.org/content/134502-144.
- Schmoll, H; Stein, A; Hofheinz, R; Price, T; Nordlinger, B; Daisne, J, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin vs. capecitabine alone in locally advanced rectal cancer: final analyses. Ann Oncol (2016) 27 (suppl 6): doi: 10.1093/annonc/mdw370.16 Available from: http://annonc.oxfordjournals.org/content/27/suppl_6/467PD.short?rss=1.
- Jiao D, Zhang R, Gong Z, Liu F, Chen Y, Yu Q, et al. Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study. Chin J Cancer Res 2015 Dec;27(6):588-96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26752933.
- Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 2012 Jun 1;30(16):1926-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22529255.
- Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, et al. Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial. J Clin Oncol 2016 Sep 20;34(27):3300-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27480145.
- An X, Lin X, Wang FH, Goodman K, Cai PQ, Kong LH, et al. Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: a meta analysis. Eur J Cancer 2013 Mar;49(4):843-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23063351.
- Wyrwicz L, Temnyk M, Spalek M. The addition of oxaliplatin increases pathological complete response: a meta-analysis of randomized controlled trials on radiochemotherapy in rectal cancer. Ann Oncol (2016) 27 (suppl 2): ii65 Available from: http://annonc.oxfordjournals.org/content/27/suppl_2/ii65.3.short?rss=1#.
- Cassidy RJ, Liu Y, Patel K, Zhong J, Steuer CE, Kooby DA, et al. Can we eliminate neoadjuvant chemoradiotherapy in favor of neoadjuvant multiagent chemotherapy for select stage II/III rectal adenocarcinomas: Analysis of the National Cancer Database. Cancer 2016 Oct 25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27780316.
- Fornaro L, Caparello C, Vivaldi C, Rotella V, Musettini G, Falcone A, et al. Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: a systematic review. World J Gastroenterol 2014 May 28;20(20):6081-91 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24876730.
- Sclafani F, Gonzalez D, Cunningham D, Hulkki Wilson S, Peckitt C, Giralt J, et al. RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial. Eur J Cancer 2014 May;50(8):1430-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24582914.
- Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol 2012 May 10;30(14):1620-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22473163.