Critical Appraisal of Approved Chemotherapy Regimens for Advanced Colon Cancer in Ontario, Canada by Akbar Khan, MD, IMD, DHS, FAAO

Abstract

Evidence-based medicine (EBM) is a term often used to describe allopathic medical therapies. Best evidence for a therapy was felt to be obtained by randomized clinical trials which remain the “gold standard” today. Many well-established chemotherapy regimens for metastatic colon cancer claim to be evidence-based, and are government approved and funded in Ontario, Canada. Conversely, natural therapies, off-label non-toxic therapies, and metabolic therapies for cancer remain unproven due to lack of large-scale clinical trials. Many such therapies are backed by lower levels of evidence that suggests they prolong life or enhance quality of life, yet they are not considered evidence-based by the oncology community. A careful analysis of the actual evidence underlying approved regimens for metastatic colorectal cancer raises important questions about the application of EBM in reference to cytotoxic chemotherapy.

Introduction

Evidence based medicine (EBM) is a term often used to describe allopathic medical therapies. This term originated from the work of Sackett and Guyatt and was first described in the medical literature in the Journal of the American Medical Association in 1992 (Evidence-Based Medicine Working Group 1992). Sackett clarified EBM succinctly as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.” (Sackett 1996). Best evidence for a therapy was felt to be obtained by randomized clinical trials (RCT). The RCT remains the “gold standard” to define whether a therapy has clinical benefit that outweighs the harm.

EBM is of critical importance in cancer, as most available allopathic therapies are associated with significant toxicity. It is especially vital to know if maximum tolerated dose cytotoxic chemotherapy is beneficial for patients because death, disability, and reduced quality of life are known side effects of this form of therapy.

In Ontario, Canada, drug regimens are recommended for government funding and approved by the arms-length organization Cancer Care Ontario (CCO). As of this writing, for primary treatment of stage four colorectal cancer, frontline or recurrent, there are 19 approved government-funded chemotherapy-based regimens (Cancer Care Ontario 2021).

1. CAPE (capecitabine)
2. CAPE + BEVA (capecitabine + bevacizumab)
3. FLOX (fluorouracil + leucovorin + oxaliplatin)
4. FOLFIRI (fluorouracil + leucovorin + irinotecan)
5. FOLFIRI + BEVA (fluorouracil + leucovorin + irinotecan + bevacizumab)
6. FOLFIRI + PNTM (fluorouracil + leucovorin + irinotecan + panitumumab)
7. FOLFOXIRI (fluorouracil + leucovorin + oxaliplatin + irinotecan)
8. FU (fluorouracil bolus)
9. FU-CIV (fluorouracil continuous iv)
10. FU (IV-CIV) LCVR (fluorouracil + leucovorin, modified DeGramont regimen)
11. FULCV (DEGRAMONT) (fluorouracil + leucovorin, DeGramont regimen)
12. FULCVR(W) (fluorouracil weekly + leucovorin)
13. FU(W) (fluorouracil weekly)
14. IRIN (irinotecan)
15. IRIN+CETU (irinotecan + cetuximab)
16. IROX (irinotecan + oxaliplatin)
17. MFOLFOX6 (fluorouracil + leucovorin + oxaliplatin)
18. MFOLFOX6+BEVA (fluorouracil + leucovorin + oxaliplatin + bevacizumab)
19. XELOX (capecitabine + oxaliplatin)

Adjuvant post-operative regimens were not explored for the purpose of this review. For all the frontline regimens for stage four colon cancer, the CCO monographs state:

“Evidence Informed: Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives…recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial.”

This statement implies that a systematic analysis of the approved regimens would confirm that they are in fact superior to so-called “alternative” therapies and superior to best supportive care (i.e. no active therapy) based on available clinical evidence. In this situation it would be justifiable for the regimens to receive government-funding and for oncologists to regularly prescribe them despite their substantial risks, with informed patient consent.

All referenced evidence is the best evidence available according to the CCO monograph for the chemotherapy regimen under review. An independent search for further evidence was not carried out. Non-chemo regimens were not reviewed and combination regimens with non-chemo targeted drugs were not reviewed for the purpose of this analysis.

Capecitabine

There are three phase III trials supporting capecitabine, one with 605 patients (Hoff et all 2001), one with 602 patients (Van Cutsem et al 2001), and one with 1987 patients (Twelves et al 2005). All trials compare capecitabine against fluorouracil. Therefore, none of the trials referred to in the CCO regimen monograph establish whether capecitabine improves survival or quality of life.

FLOX – Fluorouracil + Leucovorin + Oxaliplatin

There is a single phase II trial supporting this regimen which enrolled 52 patients (Kato et al 2011). It was a single arm trial (no comparison arm) which looked at response rates and toxicity. Therefore, no conclusion could be drawn whether FLOX improves survival or quality of life.

FOLFIRI – Fluorouracil + Leucovorin + Irinotecan (+/- Bevacizumab)

Several clinical trials supporting this regimen were published. A phase three trial with 387 patients containing a chemo-to-chemo comparison (Douillard et al. 2000), a phase three trial with 813 patients containing a chemo-to-chemo + bevacizumab comparison (Hurwitz et al 2004), a phase three trial with 220 patients containing a chemo-to-chemo comparison (Tournigand et al 2004), and a phase three trial with 1914 patients containing a chemo-to-chemo comparison (Van Cutsem et al 2009). Therefore, none of the trials referred to in the CCO regimen monograph establish whether this regimen improves survival or quality of life.

FOLFOXIRI – Fluorouracil + Leucovorin + Oxaliplatin + Irinotecan

There is a single phase III trial supporting this regimen which enrolled 244 patients. The trial compared the full regimen against the same regimen without oxaliplatin (Falcone et al 2007). There was no placebo arm. Therefore, no conclusion could be drawn whether this regimen improves overall survival or quality of life.

Fluorouracil

Several clinical trials supporting different variations of this regimen were published. A clinical trial of 86 patients in which continuous infusions were compared to bolus doses (Rougier et al 1992), a clinical trial of 184 patients in which continuous infusions were compared to bolus doses (Weinerman et al 1992), a clinical trial of 125 patients in which two dosage schedules of fluorouracil were compared (Budd et al 1987), a clinical trial of 122 patients in which continuous infusion of fluorouracil was compared against fluorouracil + cisplatin (Kemeny, N et al 1990), a randomized trial of 2135 patients in three treatment arms with a control group that received fluorouracil followed by irinotecan (Seymour et al 2007), a phase III trial of 420 patients in which fluorouracil/leucovorin +/- oxaliplatin were compared and quality of life was measured (deGramont et al 2000), a randomized phase III trial of 448 patients comparing two different schedules of fluorouracil combined with leucovorin (deGramont et al 1997), a randomized trial of 372 patients with two arms of different protocols of fluorouracil and leucovorin (Buroker et al 1994),  a randomized trial of 291 patients examining fluorouracil + high dose vs. fluorouracil + low dose leucovorin (Jäger et al 1996) and a randomized trial of 148 patients comparing fluorouracil alone against fluorouracil combined with leucovorin (Nobile et al 1992).

Fluorouracil is one of the oldest chemotherapy drugs approved for treatment of colorectal cancer and is the drug against which many newer drugs are compared. Despite multiple available trials, no conclusion could be drawn whether this regimen improves overall survival or quality of life.

Irinotecan

Several clinical trials of irinotecan were published. Of all the trials, a single trial compared irinotecan chemo against best supportive care (i.e. no active treatment). In this randomized trial of 279 patients who had failed prior fluorouracil, one-year overall survival was evaluated and found to be improved in the chemo arm (36.2%) compared to the supportive care arm (13.8%). The difference was statistically significant. Quality of life was assessed and also favoured the irinotecan arm (Cunningham et al 1998).

IROX – Irinotecan + Oxaliplatin

A clinical trial of 383 patients examined the response rates and survival of patients treated with IROX compared against FOLFOX (Ashley et al 2007). A phase III randomized clinical trial of 628 patients comparing IROX against irinotecan alone found a 2.3 month survival benefit favouring IROX (Haller et al 2008). Since irinotecan alone has been demonstrated to improve survival compared against no treatment, there is a suggestion that IROX may improve overall survival. However, such a comparison is not scientifically rigorous since patients in different trials conducted in different time periods may have separate characteristics (age, race, comorbidities, performance status, drug resistance etc). Therefore, no definite conclusion can be drawn about whether this regimen improves overall survival or quality of life.

mFOLFOX6 – Fluorouracil + Leucovorin + Oxaliplatin followed by Fluorouracil infusion

A phase II trial of 56 patients was conducted with a single chemo arm only (Braun et al. 2003). A phase III trial of 2034 patients was conducted in which FOLFOX was compared against XELOX with no placebo group (Cassidy et al 2011). A randomized trial of 223 patients was conducted in which the patients were divided into three different chemo arms (Hochster et al 2008). A phase II single arm study of 70 patients was conducted of chemo alone (Ryan et al 2003). This regimen is one of the most commonly prescribed regimens for advanced colon cancer. Yet no conclusion can be drawn whether this regimen improves overall survival or quality of life.

XELOX (capecitabine + oxaliplatin)

A phase III trial of 2034 patients was conducted in which FOLFOX was compared against XELOX (Cassidy et al. 2008). A clinical trial of 96 patients was conducted with XELOX alone (Cassidy et al 2004). A randomized phase III trial of 627 patients was conducted in which XELOX was compared to FOLFOX4 (Rothenberg et al 2008). Since there was no placebo arm in any of these trials, no conclusion could be drawn whether the XELOX regimen improves survival or quality of life.

Natural and Metabolic Therapies for Colon Cancer

The author has previously published a case report documenting long-term disease stabilization of stage four colon cancer (liver metastases) using the metabolic therapy dichloroacetate (Khan et al 2016). Dichloroacetate (DCA) induces apoptosis in cancer cells and can act as a cytostatic agent. As of this writing, the patient remains alive and well over 8 years after conventional chemotherapy was stopped. Since life-threatening side effects of DCA have never been documented (Stacpoole et al 1998) in stark contrast to cytotoxic chemotherapy drugs, and since it is inconsistent with the natural history of stage for four colon cancer to spontaneously stabilize for years, it is very plausible that DCA prolonged the survival of this colon cancer patient.

High dose ascorbic acid (vitamin C) has been researched for decades and is supported by extensive pre-clinical data as an effective cancer therapy or adjuvant therapy (Ohno et al 2009). High dose intravenous vitamin C is also associated with tumour regression in advanced cases of colon cancer (El Halabi et al 2018). Survival benefit was also demonstrated in pancreatic cancer in a phase I trial when vitamin C was used as an adjuvant to gemcitabine chemo. Roughly double the survival was observed with added vitamin C compared to gemcitabine alone (Polireddy et al 2017). High dose ascorbic acid does not have life threatening side effects in contrast with chemotherapy. Therefore, it is plausible that ascorbic acid can prolong survival in colon cancer patients.

Low dose naltrexone (LDN) is an unapproved therapy that induces an increase in endogenous levels of methionine-enkephalin, an opioid with demonstrated in vitro anti-cancer effects in colon cancer (Hytrek et al 1996). Schwartz et al (2014) published a case series demonstrating clinical efficacy of LDN combined with natural agents alpha lipoic acid and hydroxycitrate in various cancers including colon. One of the colon cancer patients in the series was reported to be alive and well four years after the diagnosis of widely metastatic disease (Schwartz et al 2014). Therefore, it is plausible that LDN can prolong survival in colon cancer patients.

Despite the limited but convincing evidence cited in these case reports of unapproved non-toxic therapies, they are all considered unproven by the oncology community and do not fall within the definition of evidence-based medicine.

Discussion

Of all the clinical trials of approved colon cancer drug regimens that were reviewed, only one clinical trial conducted in 1998 (single agent irinotecan) established an overall survival benefit compared to placebo/best supportive care. It may be argued that once a chemotherapy drug has been found to improve overall survival, it would only be ethical to design subsequent trials to compare newer drugs against this proven drug. In other words, using placebo would deny patients access to a drug with a known survival benefit. To determining whether this was in fact the justification for other chemo drugs not being compared against placebo, one may simply assess the dates of the trials. Examining the dates of the multiple 5-FU trials, for example, reveals that they were all conducted before the irinotecan trial in question (before it was known that irinotecan improved overall survival). Even so, none of these trials were conducted against placebo. This suggests the above-mentioned ethical dilemma was not the reason these trials were designed without placebo.

Despite limitation of lack of comparison to placebo/best supportive care for all the drug regimens discussed (aside from irinotecan), all are labelled as evidence-based or “evidence-informed”. Specifically, they are all labelled as demonstrating meaningfully improved outcomes including survival and quality of life. The author finds such an overtly contradictory statement deeply troubling. Lessons learned from the opioid crisis, and recent announcements of massive settlements to be paid by pharmaceutical companies to help repair the damage of industry overzealousness (CTV News 2021, USA Today 2021), should serve as an important reminder to sternly question who’s interests are served when suspect standards of care emerge.

Who sits on the expert panels that make the recommendations for chemo approval and government funding?

Is there any motivation to make questionable statements?

Are there undisclosed conflicts of interest among the expert panels?

Are oncologists generally aware that the chemo regimens they prescribe are largely unproven by the standard of demonstrating overall survival benefit?

Are patients unknowingly led to believe that these regimens are likely to help them survive longer?

Are patients truly giving informed consent when they agree to taking these powerful chemotherapy drugs?

Based on this review, a fresh analysis of all the chemo regimens for advanced colon cancer is urgently needed. Such an analysis must be conducted with full disclosure of any conflicts of interest of the expert panels, such as direct or indirect ties to the pharmaceutical industry or industry funding. Experts with conflicts of interest must not be permitted to advise government which drugs to fund or approve. This is of vital importance to enhance patient awareness of the expected outcomes of any proposed chemotherapy regimen. Only then will patients be able to provide truly informed consent in the selection of their chemotherapy regimens.

References

Ashley AC, Sargent DJ, Alberts SR, Grothey A, Campbell ME, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Goldberg RM. Updated efficacy and toxicity analysis of irinotecan and oxaliplatin (IROX) : intergroup trial N9741 in first-line treatment of metastatic colorectal cancer. Cancer. 2007 Aug 1;110(3):670-677.

Braun MS, Adab F, Bradley C, McAdam K, Thomas G, Wadd NJ, Rea D, Philips R, Twelves C, Bozzino J, MacMillan C, Saunders MP, Counsell R, Anderson H, McDonald A, Stewart J, Robinson A, Davies S, Richards FJ, Seymour MT. Modified de Gramont with oxaliplatin in the first-line treatment of advanced colorectal cancer. Br J Cancer. 2003 Oct 6;89(7):1155-1158.

Budd GT, Fleming TR, Bukowski RM, McCracken JD, Rivkin SE, O’Bryan RM, Balcerzak SP, Macdonald JS. 5-Fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest Oncology Group Study. J Clin Oncol. 1987 Feb;5(2):272-277.

Buroker TR, O’Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994 Jan;12(1):14-20.

Cancer Care Ontario. https://www.cancercareontario.ca/en. Accessed April 2021.

Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer. 2011 Jun 28;105(1):58-64.

Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-2012.

Cassidy J, Tabernero J, Twelves C, Brunet R, Butts C, Conroy T, Debraud F, Figer A, Grossmann J, Sawada N, Schöffski P, Sobrero A, Van Cutsem E, Díaz-Rubio E. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol. 2004 Jun 1;22(11):2084-2091.

Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-1418.

CTV News. https://www.ctvnews.ca/health/companies-us-26b-settlement-of-opioid-lawsuits-to-move-ahead-1.5574072 Accessed September 2021.

Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-1047.

de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997 Feb;15(2):808-815.

de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-2947.

El Halabi I, Bejjany R, Nasr R, Mukherji D, Temraz S, Nassar FJ, El Darsa H, Shamseddine A. Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications. Int J Mol Sci. 2018 Sep 13;19(9):2752.

Evidence-Based Medicine Working Group. Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA. 1992 Nov 4;268(17):2420-2425.

Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-1676.

Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, Habboubi N, Garay C, Olivatto LO. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008 Oct 1;26(28):4544-4550.

Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008 Jul 20;26(21):3523-3529. Erratum in: J Clin Oncol. 2008 Oct 1;26(28): 4697.

Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001 Apr 15;19(8):2282-2292.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.

Hytrek SD, McLaughlin PJ, Lang CM, Zagon IS. Inhibition of human colon cancer by intermittent opioid receptor blockade with naltrexone. Cancer Lett. 1996 Mar 29;101(2):159-164.

Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth A. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 1996 Aug;14(8):2274-2279.

Kato T, Nagata N, Fujii M, Takemoto H, Kondo K, Okuyama Y, Tominaga H, Sakamoto J, Mishima H. Multi-center phase II study of FLOX for advanced colorectal cancer patients in Japan: SWIFT 3 study. Anticancer Res. 2011 Dec;31(12):4657-4664.

Kemeny N, Israel K, Niedzwiecki D, Chapman D, Botet J, Minsky B, Vinciguerra V, Rosenbluth R, Bosselli B, Cochran C, et al. Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer. J Clin Oncol. 1990 Feb;8(2):313-318.

Khan A, Andrews D, Blackburn AC. Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy. World J Clin Cases. 2016 Oct 16;4(10):336-343.

Nobile MT, Rosso R, Sertoli MR, Rubagotti A, Vidili MG, Guglielmi A, Venturini M, Canobbio L, Fassio T, Gallo L, et al. Randomised comparison of weekly bolus 5-fluorouracil with or without leucovorin in metastatic colorectal carcinoma. Eur J Cancer. 1992;28A(11):1823-1827.

Ohno S, Ohno Y, Suzuki N, Soma G, Inoue M. High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer. Anticancer Res. 2009 Mar;29(3):809-815.

Polireddy K, Dong R, Reed G, Yu J, Chen P, Williamson S, Violet PC, Pessetto Z, Godwin AK, Fan F, Levine M, Drisko JA, Chen Q. High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. Sci Rep. 2017 Dec 7;7(1):17188.

Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008 Oct;19(10):1720-1726.

Rougier P, Paillot B, LaPlanche A, Morvan F, Seitz JF, Rekacewicz C, Laplaige P, Jacob J, Grandjouan S, Tigaud JM, Fabri MC, Luboinski M, Ducreux M. 5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer. Eur J Cancer. 1997 Oct;33(11):1789-1793.

Ryan DP, Clark JW, Kulke MH, Fuchs CS, Earle CC, Enzinger PC, Stuart K, Catarius KJ, Winkelmann J, Mayer RJ. A phase II study of modified deGramont 5-fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic colorectal cancer. Cancer Invest. 2003;21(4):505-511.

Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996 Jan 13;312(7023):71-72.

Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014 Feb;34(2):973-980.

Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, Thompson L, Griffiths GO, Parmar MK, Stephens RJ; FOCUS Trial Investigators; National Cancer Research Institute Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007 Jul 14;370(9582):143-152.

Stacpoole PW, Henderson GN, Yan Z, James MO. Clinical pharmacology and toxicology of dichloroacetate. Environ Health Perspect. 1998 Aug;106 Suppl 4(Suppl 4):989-994.

Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-237.

Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J,

USA Today. https://www.usatoday.com/story/news/nation/2021/07/21/opioid-settlement-states-detail-26-b-deal-resolve-drug-lawsuits/8046190002/ Accessed August 2021

Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30;352(26):2696-2704.

Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D; First BEAT investigators. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009 Nov;20(11):1842-1847.

Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1;19(21):4097-4106 Weinerman B, Shah A, Fields A, Cripps IC, Wilson K, McCormick R, Temple W, Maroun J, Bogues W, Pater J, et al. Systemic infusion versus bolus chemotherapy with 5-fluorouracil in measurable metastatic colorectal cancer. Am J Clin Oncol. 1992 Dec;15(6):518-523.