Timing of Therapies - CancerChoices

We’re busy updating our review of timing of therapies and will provide a rating when that’s complete. While we’re working, we share a summary from our predecessor website, Beyond Conventional Cancer Therapies. The information we share here was last updated in November 2021.

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Timing of Therapies: Chronomodulation and Metronomic Dosing

Chronomodulation

Chronomodulation, or chronomodulated chemotherapy, involves administering chemotherapy drugs at optimal times of day when cancer cells may be more susceptible and/or when normal cells are less likely to be damaged by treatment. The intended outcome is to make treatment more effective with fewer side effects.

Integrative oncologist and CancerChoices advisor Keith Block, MD, has been a pioneer of chronomodulated chemotherapy in the United States. A brief excerpt from his description:

Gold standard research supports the use of chronomodulated chemotherapy. For example, for metastatic colon cancer patients, studies show that administering chemotherapy at the optimal time can halve toxicity and double treatment response. For advanced metastatic ovarian cancer, a study in the journal Cancer reported that optimal timing of chemotherapy can reduce toxic side effects by 50 percent and quadruple five-year survival. This is a four-fold improvement! (Four times as many patients were alive at the five-year mark). The same study demonstrated a 75 percent reduction in the need to cut the treatment dose!¹Block KI. When it comes to chemotherapy, timing’s everything. Block Center for Integrative Cancer Therapy. June 29, 2012. Viewed August 22, 2018.

Key Points

Before using this therapy, consult your oncology team about interactions with other treatments and therapies. Also make sure this therapy is safe for use with any other medical conditions you may have.
Chronomodulation, or chronomodulated chemotherapy, involves administering chemotherapy drugs at optimal times of day when cancer cells may be more susceptible and/or when normal cells are less likely to be damaged by treatment.
Clinical evidence suggests some positive benefits of chronomodulated chemotherapy in treating the cancer and reducing the rate and severity of adverse reactions.
Early evidence is finding that prolonged, repetitive and more frequent low doses of chemotherapy drugs (metronomic chemotherapy) interferes with a process in cancer growth and reduces the cancer’s ability to become resistant.
Used in two integrative programs and protocols.

Practical obstacles may make administering chemotherapy based on chronomodulation less available. Giving drugs at odd times of the day or night (such as a colorectal cancer chemotherapy regimen of administration at 4am, 5am and 4pm) can be difficult to schedule, for example.²Baker D. Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity? Advances in Pharmacy. 2004 Jul;2(3):222-228. US insurers may not reimburse for chronotherapy expenses.³Block KI. Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States. Chronobiology International. 2002;19(1):275–287.

The patients’ sex, genetic background, and lifestyle may influence responses and drug schedule tolerability.⁴Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035; Ortiz-Tudela E, Mteyrek A, Ballesta A, Innominato PF, Lévi F. Cancer chronotherapeutics: experimental, theoretical, and clinical aspects. Handbook of Experimental Pharmacology. 2013;(217):261-88.

Dr. Block and colleagues provide guidance on chronomodulating cancer treatment in their article Making Circadian Cancer Therapy Practical.⁵Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Improving Circadian Rhythms

Your treatment and wellness outcomes can benefit from achieving more normal circadian (sleep and rest) patterns.⁶Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86. If your circadian rhythms are disrupted by chemotherapy, chronomodulated therapy may not be as effective. Chemotherapy-induced fatigue and weight loss—both of which are related to poor sleep quality—early in therapy may impair the benefits of chonomodulated therapy on survival and time to progression.⁷Innominato PF, Giacchetti S et al. Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer. Cancer. 2013 Jul 15;119(14):2564-73.

Dr. Block offers practical suggestions for promoting beneficial circadian function through diet, through activity, and through mind-body approaches. These approaches are described in detail in an article by Dr. Block and his colleagues, Making Circadian Cancer Therapy Practical.⁸Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Their guidance on what and when to eat (click the + sign to view):

Treating the Cancer

Working against cancer growth or spread, improving survival, or working with other treatments or therapies to improve their anticancer action

Clinical Evidence

General Cancer

Evidence shows benefit with acute lymphoblastic leukemia, ovarian cancer, endometrial uterine cancer, metastatic colorectal cancer, metastatic transitional cell carcinoma, bladder cancer, progressive metastatic renal cell carcinoma, breast carcinoma, lung carcinoma, hormone-refractory metastatic prostate cancer and genitourinary tract cancer.

Higher rates of complete and partial remissions compared to those getting continuous infusion chemotherapy⁹Elliott WJ. Timing treatment to the rhythm of disease: a short course in chronotherapeutics. Postgraduate Medicine. 2001 Aug;110(2):119-22, 125-6, 129.
Improved tumor response¹⁰Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.
Improved outcomes and survival with metastasis¹¹Baker D. Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity? Advances in Pharmacy. 2004 Jul;2(3):222-228.
Influenced all phenotype markers important for tolerability and efficacy of fluoropyrimidine drugs¹²Jacobs BA, Deenen MJ et al. Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers. British Journal of Clinical Pharmacology. 2016 Sep;82(3):706-16.
Higher tumor response, fewer dose-limiting toxicities allowing for higher treatment doses, and longer median progression-free survival and survival among previously untreated metastatic colorectal cancer with chronomodulated delivery of 5-FU, FA, and 1-OHP compared to constant delivery in a small RCT¹³Lévi FA, Zidani R et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Journal of the National Cancer Institute. 1994 Nov 2;86(21):1608-17.

Bladder Cancer

Of the 35 evaluable patients with widespread metastatic transitional cell carcinoma of the bladder, 57 percent showed an objective response¹⁴Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.

Colorectal Cancer

Greater objective response, progression-free survival and median survival, with higher doses of oxaliplatin, fluorouracil and 1-folinic acid tolerated in people with previously untreated metastatic colorectal cancer¹⁵Lévi FA, Zidani R et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Journal of the National Cancer Institute. 1994 Nov 2;86(21):1608-17.
Prolonged median overall survival in men, but not always in women¹⁶Innominato PF, Roche VP et al. The circadian timing system in clinical oncology. Annals of Medicine. 2014 Jun;46(4):191-207; Giacchetti S, Dugué PA et al. Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis. Annals of Oncology. 2012 Dec;23(12):3110-6; Lévi F. Chronotherapeutics: the relevance of timing in cancer therapy. Cancer Causes & Control. 2006 May;17(4):611-21; Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035; Liao C, Li J, Bin Q, Cao Y, Gao F. Chronomodulated chemotherapy versus conventional chemotherapy for advanced colorectal cancer: a meta-analysis of five randomized controlled trials. International Journal of Colorectal Disease. 2010 Mar;25(3):343-50; Mormont MC, Waterhouse J et al. Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clinical Cancer Research. 2000;6(8):3038–3045.
Higher rates of complete and partial remissions compared to those getting continuous infusion chemotherapy¹⁷Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.
Improved tumor response (but also with greater bone metastases and and relapse from surgically treated metastases attributed to failed randomization)¹⁸Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.
Longer median time to treatment failure compared to constant-rate infusion¹⁹Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997;350(9079):681–686.
No difference in survival in four-day chronomodulated combination of 5-fluorouracil and oxaliplatin versus two-day FOLFOX2²⁰Giacchetti S, Bjarnason G et al. First line infusion of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer: 4-day chronomodulated (FFL4–10) versus 2-day FOLFOX2. A multicenter randomized phase III trial of the Chronotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC 05963). Journal of Clinical Oncology. 2004 Jul 15;22(14_suppl):3526-3526.
Improved tolerability and near doubling of anticancer activity with oxaliplatin and 5-FU-leucovorin given through chronomodulated vs. constant-rate administration²¹Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035.
Improved outcomes and survival with metastasis²²Lévi F, Karaboué A et al. Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability. Cancer Chemother Pharmacol. 2011;67(2):339–348; Garufi C, Torsello A et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. British Journal of Cancer. 2010 Nov 9;103(10):1542-7; Garufi C, Torsello A et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. British Journal of Cancer. 2010 Nov 9;103(10):1542-7.
Improved survival (compared to other studies) with chronotherapy compared to continuous infusion in a small study of people with stage 3-4 colon cancer, although the numbers were too small to draw conclusions²³Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
Optimal chronomodulated schedules corresponded to peak delivery rates at 1am or 4am for 5-fluorouracil-leucovorin, at 1pm or 4pm for oxaliplatin, and at 4pm for carboplatin.²⁴Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035.

Head, Neck and Oral Cancers

Improved overall survival, objective response rate, although no improved progression-free survival among people with metastatic head and neck squamous cell carcinoma undergoing palliative treatments with paclitaxel, carboplatin, and 5-Fu in a small study²⁵Chen D, Cheng J, Yang K, Ma Y, Yang F. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. OncoTargets and Therapy. 2013 Oct 24;6:1507-14.

Kidney Cancer

Greater tolerance of chemotherapy in people with metastatic renal cell carcinoma as shown by greater dose escalation and less dose reduction²⁶Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.

Ovarian Cancer

Improved survival outcomes and lower toxicity for people with ovarian cancer²⁷Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.

Pancreatic Cancer

Better than expected survival and response rates among people with advanced pancreatic cancer (no control group)²⁸Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.

Lab and Animal Evidence

Click or tap to open.

Managing Side Effects and Promoting Wellness

Managing or relieving side effects or symptoms, reducing treatment toxicity, supporting quality of life or promoting general well-being

Clinical Evidence

Reduced rate and severity of adverse reactions while achieving higher rates of complete and partial remissions compared to those getting continuous infusion chemotherapy³¹Baker D. Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity? Advances in Pharmacy. 2004 Jul;2(3):222-228; Elliott WJ. Timing treatment to the rhythm of disease: a short course in chronotherapeutics. Postgraduate Medicine. 2001 Aug;110(2):119-22, 125-6, 129.

Appetite-related Side Effects

Reduced incidence of grade 3-4 loss of appetite (anorexia) with chronotherapy compared to continuous infusion in a small study of people with stage 3-4 colon cancer, although the numbers were too small to draw conclusions³²Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Blood-related Side Effects

Lower incidence of blood-related events (leukopenia, neutropenia) and of grade 3–4 incidents of leukopenia among people with metastatic head and neck squamous cell carcinoma undergoing palliative treatments with paclitaxel, carboplatin, and 5-Fu in a small study)³³Chen D, Cheng J, Yang K, Ma Y, Yang F. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. OncoTargets and Therapy. 2013 Oct 24;6:1507-14.
Reduced incidence of grade 3-4 neutropenia in a small study of people with stage 3-4 colon cancer, although the numbers were too small to draw conclusions³⁴Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Gastrointestinal Side Effects Including Nausea and Vomiting

Reduced diarrhea (grade 2+) among people with primary pelvic cancers with evening delivery of radiotherapy compared with morning delivery in two randomized trials³⁵Lawrie TA, Green JT at al. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database of Systematic Reviews. 2018 Jan 23;1(1):CD012529.
Reduced diarrhea in people with metastatic renal cell carcinoma³⁶Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.
Substantially reduced severe mucosal toxicity in people with colorectal cancer³⁷Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.
Lower incidence of nausea and vomiting and of grade 3–4 incidents among people with metastatic head and neck squamous cell carcinoma undergoing palliative treatments with paclitaxel, carboplatin, and 5-Fu in a small study³⁸Chen D, Cheng J, Yang K, Ma Y, Yang F. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. OncoTargets and Therapy. 2013 Oct 24;6:1507-14.
Reduced incidence of grade 3-4 neutropenia with chronotherapy compared to continuous infusion in a small study, although the numbers were too small to draw conclusions³⁹Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
Reduced incidence of grade 3-4 diarrhea, nausea and vomiting with chronotherapy compared to continuous infusion in a small study of people with stage 3-4 colon cancer, although the numbers were too small to draw conclusions⁴⁰Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Fatigue

Reduced incidence of grade 3-4 fatigue with chronotherapy compared to continuous infusion in a small study of people with stage 3-4 colon cancer, although the numbers were too small to draw conclusions⁴¹Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Hair Loss

Lower incidence of hair loss (alopecia) among people with metastatic head and neck squamous cell carcinoma undergoing palliative treatments with paclitaxel, carboplatin, and 5-Fu in a small study⁴²Chen D, Cheng J, Yang K, Ma Y, Yang F. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. OncoTargets and Therapy. 2013 Oct 24;6:1507-14.

Inflammation

Reduced severe stomatitis (inflammation of the mouth and lips) in people with colorectal cancer⁴³Lévi FA, Zidani R et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Journal of the National Cancer Institute. 1994 Nov 2;86(21):1608-17.
Reduced incidence of grade 3-4 mucositis with chronotherapy compared to continuous infusion in a small study of people with stage 3-4 colon cancer, although the numbers were too small to draw conclusions⁴⁴Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.

Peripheral Neuropathy

Reduced rate of functional impairment from peripheral sensitive neuropathy in people with colorectal cancer⁴⁵Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.

Lab and Animal Evidence

Click or tap to open.

Low-Dose Metronomic Chemotherapy

Early research as well experience in clinical practice is finding that metronomic chemotherapy—administering prolonged, repetitive and more frequent low doses of chemotherapy drugs—has these advantages:

Interferes with the ability of the cancer to create its essential blood supply
Reduces the cancer’s ability to become resistant

In a 2019 scientific review article the authors state: “The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment.”⁴⁷Simsek C, Esin E, Yalcin S. Metronomic chemotherapy: a systematic review of the literature and clinical experience. Journal of Oncology. 2019 Mar 20;2019:5483791. Other studies and reviews show benefit.⁴⁸Maiti R. Metronomic chemotherapy. Journal of Pharmacology and Pharmacotherapeutics. 2014 Jul;5(3):186-92.; Chen N. Advantages of Metronomic Chemotherapy in an Integrated Cancer Treatment Setting. March 21, 2015. Viewed August 27, 2019; Chue BM, La Course BD. Case report of long-term survival with metastatic triple-negative breast carcinoma: treatment possibilities for metastatic disease. Medicine (Baltimore). 2019 Apr;98(16):e15302.

Integrative Programs, Protocols and Medical Systems

For more information about programs and protocols, see our Integrative Programs and Protocols page.

Programs and protocols

Block program⁴⁹Block KI. Life over Cancer: The Block Center Program for Integrative Cancer Treatment. New York: Bantam Dell. 2009.
McKinney protocols⁵⁰McKinney N. Naturopathic Oncology, 3rd Edition. Victoria, BC, Canada: Liaison Press. 2016.

Helpful links

Block Center for Integrative Cancer Treatment:
- Chronomodulation
- When it comes to chemotherapy, timing’s everything
Chan S, Rowbottom L et al. Does the time of radiotherapy affect treatment outcomes? A review of the literature. Clinical Oncology (Royal College of Radiologists (Great Britain)). 2017 Apr;29(4):231-238.
Kobayashi M, Wood PA, Hrushesky WJ. Circadian chemotherapy for gynecological and genitourinary cancers. Chronobiology International. 2002 Jan;19(1):237-51.
Mormont MC, Lévi F. Circadian-system alterations during cancer processes: a review. International Journal of Cancer. 1997;70(2):241–247.
Medscape: 5 Things to Know about Chronotherapy
Cancer Causes & Control: Chronotherapeutics: the relevance of timing in cancer therapy
Gurdev Parmar and Tina Kaczor: Textbook of Naturopathic Oncology: A Desktop Guide of Integrative Cancer Care. 1st edition
Block KI, Block PB, Gyllenhaal C: Integrative Treatment for Colorectal Cancer
Danial E. Baker: Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity?
EmpowHER: Keith Block: My Activity
Henry Mayo Clinic: Keith Block: New Roads to Health: Life over Cancer
Keith I. Block, MD: Life over Cancer: The Block Center Program for Integrative Cancer Treatment

References[+]

1	Block KI. When it comes to chemotherapy, timing’s everything. Block Center for Integrative Cancer Therapy. June 29, 2012. Viewed August 22, 2018.
2, 11	Baker D. Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity? Advances in Pharmacy. 2004 Jul;2(3):222-228.
3	Block KI. Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States. Chronobiology International. 2002;19(1):275–287.
4	Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035; Ortiz-Tudela E, Mteyrek A, Ballesta A, Innominato PF, Lévi F. Cancer chronotherapeutics: experimental, theoretical, and clinical aspects. Handbook of Experimental Pharmacology. 2013;(217):261-88.
5, 6, 8, 23, 32, 34, 39, 40, 41, 44	Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
7	Innominato PF, Giacchetti S et al. Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer. Cancer. 2013 Jul 15;119(14):2564-73.
9	Elliott WJ. Timing treatment to the rhythm of disease: a short course in chronotherapeutics. Postgraduate Medicine. 2001 Aug;110(2):119-22, 125-6, 129.
10, 14, 18, 26, 27, 28, 36	Lis CG, Grutsch JF et al. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integrative Cancer Therapies. 2003 Jun;2(2):105-11.
12	Jacobs BA, Deenen MJ et al. Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers. British Journal of Clinical Pharmacology. 2016 Sep;82(3):706-16.
13	Lévi FA, Zidani R et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Journal of the National Cancer Institute. 1994 Nov 2;86(21):1608-17.
15, 43	Lévi FA, Zidani R et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Journal of the National Cancer Institute. 1994 Nov 2;86(21):1608-17.
16	Innominato PF, Roche VP et al. The circadian timing system in clinical oncology. Annals of Medicine. 2014 Jun;46(4):191-207; Giacchetti S, Dugué PA et al. Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis. Annals of Oncology. 2012 Dec;23(12):3110-6; Lévi F. Chronotherapeutics: the relevance of timing in cancer therapy. Cancer Causes & Control. 2006 May;17(4):611-21; Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035; Liao C, Li J, Bin Q, Cao Y, Gao F. Chronomodulated chemotherapy versus conventional chemotherapy for advanced colorectal cancer: a meta-analysis of five randomized controlled trials. International Journal of Colorectal Disease. 2010 Mar;25(3):343-50; Mormont MC, Waterhouse J et al. Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clinical Cancer Research. 2000;6(8):3038–3045.
17	Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.
19	Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997;350(9079):681–686.
20	Giacchetti S, Bjarnason G et al. First line infusion of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer: 4-day chronomodulated (FFL4–10) versus 2-day FOLFOX2. A multicenter randomized phase III trial of the Chronotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC 05963). Journal of Clinical Oncology. 2004 Jul 15;22(14_suppl):3526-3526.
21, 24	Lévi F, Focan C et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Advanced Drug Delivery Reviews. 2007;59(9-10):1015–1035.
22	Lévi F, Karaboué A et al. Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability. Cancer Chemother Pharmacol. 2011;67(2):339–348; Garufi C, Torsello A et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. British Journal of Cancer. 2010 Nov 9;103(10):1542-7; Garufi C, Torsello A et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. British Journal of Cancer. 2010 Nov 9;103(10):1542-7.
25, 33, 38, 42	Chen D, Cheng J, Yang K, Ma Y, Yang F. Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. OncoTargets and Therapy. 2013 Oct 24;6:1507-14.
29	Baker D. Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity? Advances in Pharmacy. 2004 Jul;2(3):222-228.
30	Bernard S, Cajavec Bernard B, Lévi F, Herzel H. Tumor growth rate determines the timing of optimal chronomodulated treatment schedules. PLoS Computational Biology. 2010 Mar 19;6(3):e1000712.
31	Baker D. Application of chronotherapy to the treatment of cancer: can changing the timing of drug administration influence efficacy and toxicity? Advances in Pharmacy. 2004 Jul;2(3):222-228; Elliott WJ. Timing treatment to the rhythm of disease: a short course in chronotherapeutics. Postgraduate Medicine. 2001 Aug;110(2):119-22, 125-6, 129.
35	Lawrie TA, Green JT at al. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database of Systematic Reviews. 2018 Jan 23;1(1):CD012529.
37, 45	Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.
46	Boughattas NA, Lévi F et al. Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice. Journal of Pharmacology and Experimental Therapeutics. 1990 Nov;255(2):672-9.
47	Simsek C, Esin E, Yalcin S. Metronomic chemotherapy: a systematic review of the literature and clinical experience. Journal of Oncology. 2019 Mar 20;2019:5483791.
48	Maiti R. Metronomic chemotherapy. Journal of Pharmacology and Pharmacotherapeutics. 2014 Jul;5(3):186-92.; Chen N. Advantages of Metronomic Chemotherapy in an Integrated Cancer Treatment Setting. March 21, 2015. Viewed August 27, 2019; Chue BM, La Course BD. Case report of long-term survival with metastatic triple-negative breast carcinoma: treatment possibilities for metastatic disease. Medicine (Baltimore). 2019 Apr;98(16):e15302.
49	Block KI. Life over Cancer: The Block Center Program for Integrative Cancer Treatment. New York: Bantam Dell. 2009.
50	McKinney N. Naturopathic Oncology, 3rd Edition. Victoria, BC, Canada: Liaison Press. 2016.