Tegafur/gimeracil/oteracil
Tegafur/gimeracil/oteracil is an oral fluoropyrimidine. The European Medicines Agency has granted marketing authorisation for tegafur/gimeracil/oteracil as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic colorectal cancer who are unable to continue treatment with another fluoropyrimidine due to hand-foot syndrome or cardiovascular toxicity that developed in the adjuvant or metastatic setting. Tegafur/gimeracil/oteracil is not currently approved in the US. Tegafur is an oral prodrug of fluorouracil, while gimeracil and oteracil are modulators of fluorouracil activity. Gimeracil is a dihydropyrimidine dehydrogenase inhibitor that prevents degradation of fluorouracil, and oteracil is an orotate phosphoribosyltransferase (OPRT) inhibitor that decreases the activity of fluorouracil in normal gastrointestinal mucosa (reducing gastrointestinal toxicity). A phase 3 trial in patients with stage 3 colorectal cancer is ongoing.[363]ClinicalTrials.gov. SOX versus XELOX as adjuvant chemotherapy for stage III colorectal cancer patients. ClinicalTrials.gov identifier: NCT03448549. Mar 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03448549
Botensilimab plus balstilimab
The FDA has granted fast-track designation to the combination of botensilimab (an investigational monoclonal antibody directed at multi-functional cytotoxic T-lymphocyte-associated protein-4 [CTLA-4]) plus balstilimab (an investigational monoclonal antibody directed at programmed cell death protein-1 [PD-1]) in patients with nonmicrosatellite instability-high/deficient mismatch repair metastatic colorectal cancer with no active liver involvement. In the phase 1B study that was conducted in more than 350 patients, clinical response was observed in nine solid tumour cancers when botensilimab was used alone or in combination with balstilimab. A global, randomised phase 2 trial in nonmicrosatellite instability-high metastatic colorectal cancer is in progress.[364]ClinicalTrials.gov. A study of botensilimab and balstilimab for the treatment of colorectal cancer. Apr 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT05608044
Phosphodiesterase-5 inhibitors
Phosphodiesterase-5 inhibitors are being investigated for repurposing for colorectal cancer prevention.[365]Huang W, Sundquist J, Sundquist K, et al. Use of phosphodiesterase 5 inhibitors is associated with lower risk of colorectal cancer in men with benign colorectal neoplasms. Gastroenterology. 2019 Sep;157(3):672-81.e4.
https://www.gastrojournal.org/article/S0016-5085(19)40892-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31103628?tool=bestpractice.com
[366]Cullinane C, Brett A, Devane L, et al. The protective role of phosphodiesterase inhibitors in preventing colorectal cancer and advanced colorectal polyps: a systematic review and meta-analysis. Colorectal Dis. 2023 Oct;25(10):1949-59.
http://www.ncbi.nlm.nih.gov/pubmed/37635321?tool=bestpractice.com
[367]Huang W, Sundquist J, Sundquist K, et al. Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer. Nat Commun. 2020 Jun 24;11(1):3191.
https://www.nature.com/articles/s41467-020-17028-4
http://www.ncbi.nlm.nih.gov/pubmed/32581298?tool=bestpractice.com
In one nationwide population-based study of men with a diagnosis of benign colorectal neoplasm, phosphodiesterase-5 inhibitor use was associated with a greater reduction in advanced-stage colorectal cancer risk than early-stage colorectal cancer risk; however, the difference was not significant.[365]Huang W, Sundquist J, Sundquist K, et al. Use of phosphodiesterase 5 inhibitors is associated with lower risk of colorectal cancer in men with benign colorectal neoplasms. Gastroenterology. 2019 Sep;157(3):672-81.e4.
https://www.gastrojournal.org/article/S0016-5085(19)40892-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31103628?tool=bestpractice.com
One systematic review and meta-analysis reported that phosphodiesterase-5 inhibitor ever-users had a significantly lower incidence of colorectal cancer than never-users (odds ratio 0.88, 95% confidence interval 0.79 to 0.98, P=0.02).[366]Cullinane C, Brett A, Devane L, et al. The protective role of phosphodiesterase inhibitors in preventing colorectal cancer and advanced colorectal polyps: a systematic review and meta-analysis. Colorectal Dis. 2023 Oct;25(10):1949-59.
http://www.ncbi.nlm.nih.gov/pubmed/37635321?tool=bestpractice.com
Further studies are warranted to investigate this association.
Transanal total mesorectal excision
Transanal total mesorectal excision (TaTME) is an emerging minimally invasive procedure in which the rectum is dissected transanally according to TME principles. The transanal approach is intended to overcome technical difficulties associated with distal rectal dissection. Long-term, large-scale follow-up data regarding survival, local recurrence, oncological safety, and functional results are awaited; ongoing audit and prospective trials are recommended.[368]Bjørn MX, Perdawood SK. Transanal total mesorectal excision--a systematic review. Dan Med J. 2015 Jul;62(7):A5105.
https://ugeskriftet.dk/dmj/transanal-total-mesorectal-excision-systematic-review
http://www.ncbi.nlm.nih.gov/pubmed/26183050?tool=bestpractice.com
[369]Lau SYC, Choy KT, Yang TWW, et al. Defining the learning curve of transanal total mesorectal excision: a systematic review and meta-analysis. ANZ J Surg. 2022 Mar;92(3):355-64.
http://www.ncbi.nlm.nih.gov/pubmed/34676655?tool=bestpractice.com
[370]Butterworth JW, Butterworth WA, Meyer J, et al. A systematic review and meta-analysis of robotic-assisted transabdominal total mesorectal excision and transanal total mesorectal excision: which approach offers optimal short-term outcomes for mid-to-low rectal adenocarcinoma? Tech Coloproctol. 2021 Nov;25(11):1183-98.
http://www.ncbi.nlm.nih.gov/pubmed/34562160?tool=bestpractice.com
Radiolabelled microspheres
Hollow spheres filled with yttrium-90 (Y-90) are used in an interventional radiology procedure known as selective internal radiation therapy (SIRT) or radioembolisation. The procedure targets high doses of radiation directly to unresectable liver metastases. Studies in colorectal cancer report mixed results; some demonstrated improved progression-free survival and an overall survival benefit, others demonstrated no improvement in either disease progression or overall survival.[371]Townsend AR, Chong LC, Karapetis C, et al. Selective internal radiation therapy for liver metastases from colorectal cancer. Cancer Treat Rev. 2016 Nov;50:148-54.
http://www.ncbi.nlm.nih.gov/pubmed/27690234?tool=bestpractice.com
[372]van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016 May 20;34(15):1723-31.
https://ascopubs.org/doi/full/10.1200/JCO.2015.66.1181
http://www.ncbi.nlm.nih.gov/pubmed/26903575?tool=bestpractice.com
[373]Van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004 Nov 1;88(2):78-85.
http://www.ncbi.nlm.nih.gov/pubmed/15499601?tool=bestpractice.com
[374]Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001 Dec;12(12):1711-20.
http://www.ncbi.nlm.nih.gov/pubmed/11843249?tool=bestpractice.com
[375]Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 Aug 10;28(23):3687-94.
https://ascopubs.org/doi/full/10.1200/JCO.2010.28.5643
http://www.ncbi.nlm.nih.gov/pubmed/20567019?tool=bestpractice.com
[376]Mulcahy MF, Mahvash A, Pracht M, et al. Radioembolization with chemotherapy for colorectal liver metastases: a randomized, open-label, international, multicenter, phase III trial. J Clin Oncol. 2021 Sep 20;JCO2101839.
https://ascopubs.org/doi/10.1200/JCO.21.01839?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/34541864?tool=bestpractice.com
One systematic review comprising 11 retrospective and three prospective studies on Y-90 radioembolisation reported overall survival of about 9 months, suggesting that there was no significant improvement in overall survival over previous studies.[377]d'Andrea E, Russi M, Pacilio M, et al. Yttrium-90 radioembolization of colorectal cancer liver metastases: a systematic review of clinical evidence. Am J Clin Oncol. 2022 Apr 1;45(4):175-81.
http://www.ncbi.nlm.nih.gov/pubmed/35320818?tool=bestpractice.com
Combined analysis of three multicentre, randomised, phase 3 trials found that the addition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone.[378]Wasan HS, Gibbs P, Sharma NK, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 Sep;18(9):1159-71.
https://www.doi.org/10.1016/S1470-2045(17)30457-6
http://www.ncbi.nlm.nih.gov/pubmed/28781171?tool=bestpractice.com
The study concluded that, to further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed.