Timing of Therapies: Chronomodulation and Metronomic Dosing
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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 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 November 4, 2021.
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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 may influence responses and drug schedule tolerability
Dr. Block and colleagues provide guidance on chronomodulating cancer treatment in their article Making Circadian Cancer Therapy Practical.
Improving Circadian Rhythms
Your treatment and wellness outcomes can benefit from achieving more normal circadian (sleep and rest) patterns. 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.
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. Their guidance on what and when to eat from Table 1 of that article:
General dietary guidelines:
- Eat a nutrient-dense, vegetable-rich diet.
- Maintain a low dietary fat intake; emphasize omega-3 fatty acids.
- Reduce your dietary glycemic load, especially in the morning.
- Optimize your potassium–sodium intake and ratio (lower salt intake).
- Eliminate chemicals that overstimulate neuron receptors (excitotoxins) including monosodium glutamate (MSG) and aspartame.
- Avoid depressants and stimulants such as alcohol, caffeine and nicotine.
- Do not overeat—consume the largest meal between noon and 6:00 pm when insulin is highest.
- Supplement with basic vitamins and minerals for stress reduction.
- Eat meals at the same time each day during normal waking hours.
Daylight dietary guidelines:
- Reduce or eliminate caffeine (optional) or stop early in the day.
- Emphasize protein earlier in the day (breakfast and lunch).
- Avoid foods containing tyramine after dinner, which increase norepinephrine release.
- Take adaptogens—such as Siberian ginseng (eleuthero), rhodiola, ginkgo or American ginseng—purported to aid in normalization of stress reactions and improve energy; take only in the morning if your sleep is disturbed.
Nighttime dietary guidelines:
- Emphasize complex carbohydrates.
- Avoid overly spiced foods or other foods that cause digestive problems during sleep.
- Avoid caffeinated beverages and other stimulant foods, such as chocolate.
- Reduce fluid consumption after 5 pm to reduce your need to urinate at night.
- Avoid adaptogens and other stimulant supplements including B vitamins, tyrosine, phenylalanine, glutamine, ginsengs, dehydroepiandrosteron (DHEA) and licorice in the evening.
- Consume herbal sedative teas or supplements—lemon balm, chamomile, valerian, hops, l-theanine, mimosa bark (Cortex albizziae), lavender, passionflower.
- Take melatonin or 5-HTP at bedtime.
More information is also listed in our Sleeping Well review in these sections:
- Balancing Sleep/Rest/Activity Biorhythms
- Activity and Sleep
- Preparing Your Mind for Sleep
- Food and Sleep
Treating the Cancer
Working against cancer growth or spread, improving survival, or working with other treatments or therapies to improve their anticancer action
For Health Professionals: Determining the Best Timing of Treatments
A group of researchers from Europe concluded that "optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor." They assert that "duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer cell cycle specific (CCS) drugs." They suggest how to individualize chronomodulated treatment schedules.
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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
- 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 RCT
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
- 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 conclusions
- 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.
Head, Neck and Oral Cancers
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- 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 study
See Head, Neck and Oral Cancers.
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
Read more
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 chemotherapy
Appetite-related Side Effects
Read more
- 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 conclusions
Blood-related Side Effects
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- 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)
- 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 conclusions
Gastrointestinal Side Effects Including Nausea and Vomiting
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- Reduced diarrhea (grade 2+) among people with primary pelvic cancers with evening delivery of radiotherapy compared with morning delivery in two randomized trials
- Reduced diarrhea in people with metastatic renal cell carcinoma
- Substantially reduced severe mucosal toxicity in people with colorectal cancer
- 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 study
- 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 conclusions
- 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 conclusions
Fatigue
Read more
- 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 conclusions
Hair Loss
Read more
- 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 study
Inflammation
Read more
- Reduced severe stomatitis (inflammation of the mouth and lips) in people with colorectal cancer
- 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 conclusions
Peripheral Neuropathy
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Lab and Animal Evidence
Read more
- 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.
Integrative Programs, Protocols and Medical Systems
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- 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.
- 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.
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- 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.
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- 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.
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- 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.
- Block KI, Block PB et al. Making circadian cancer therapy practical. Integrative Cancer Therapies. 2009 Dec;8(4):371-86.
- 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.
- 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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