Timing of Therapies: Chronomodulation and Metronomic Dosing
Author
 Nancy Hepp, MS, BCCT Project Manager
Read more Ms. Hepp is a science researcher and communicator who has been writing and editing educational content on varied health topics for more than 20 years. View profile. Reviewer
 Laura Pole, RN, MSN, OCNS, BCCT Senior Researcher
Read more Ms. Pole is an oncology clinical nurse specialist who has been providing integrative oncology clinical care, navigation, consultation and education services for more than 30 years. View profile. Last updated December 21, 2020.
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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.
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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 BCCT 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!
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. US insurers may not reimburse for chronotherapy expenses.
The patients' sex, genetic background, and lifestyle influenced responses and drug schedule tolerability
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.
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- Higher rates of complete and partial remissions compared to those getting continuous infusion chemotherapy
- Improved tumor response
- Improved outcomes and survival with metastasis
- Influenced all phenotype markers important for tolerability and efficacy of fluoropyrimidine drugs
Bladder Cancer
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Colorectal Cancer
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- 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 cancer
- Prolonged median overall survival in men, but not always in women
- Higher rates of complete and partial remissions compared to those getting continuous infusion chemotherapy.
- Improved tumor response (but also with greater bone metastases and and relapse from surgically treated metastases attributed to failed randomization)
- Longer median time to treatment failure compared to constant-rate infusion
- No difference in survival in four-day chronomodulated combination of 5-fluorouracil and oxaliplatin versus two-day FOLFOX2
- Improved tolerability and near doubling of anticancer activity with oxaliplatin and 5-FU-leucovorin given through chronomodulated vs. constant-rate administration
- Improved outcomes and survival with metastasis
- 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.
See Colorectal Cancer.
Kidney Cancer
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- Greater tolerance of chemotherapy in people with metastatic renal cell carcinoma as shown by greater dose escalation and less dose reduction
Ovarian Cancer
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- Improved survival outcomes and lower toxicity for people with ovarian cancer
Pancreatic Cancer
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- Better than expected survival and response rates among people with advanced pancreatic cancer (no control group)
Lab and Animal Evidence
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Findings of best times to administer specific chemotherapy drugs: oxaliplatin 1-4pm, 5-FU early morning before 6am, Irinotecan morning 6-9am
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 chemo
Gastrointestinal Side Effects
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Stomatitis
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- Reduced severe stomatitis (inflammation of the mouth and lips) in people with colorectal cancer
Lab and Animal Evidence
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- Reduced leukopenia (decrease of leukocytes), bone marrow lesions and cortical tubular necrosis in male mice receiving either cisplatin or carboplatin with injections timed hours after light onset compared to 8 hours after light onset
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.” Other studies and reviews show benefit.
BCCT plans to write a full summary on chronomodulated therapies. While our summary is in development, you can visit these sources:
- Block KI. When it comes to chemotherapy, timing’s everything. Block Center for Integrative Cancer Therapy. June 29, 2012. Viewed August 22, 2018.
- 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.
- Block KI. Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States. Chronobiology International. 2002;19(1):275–287.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Block KI. Life over Cancer: The Block Center Program for Integrative Cancer Treatment. New York: Bantam Dell. 2009.
- McKinney N. Naturopathic Oncology, 3rd Edition. Victoria, BC, Canada: Liaison Press. 2016.
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