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.

Author

Nancy Hepp, MS, BCCT Project Manager

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Reviewer

Laura Pole, RN, MSN, OCNS, BCCT Senior Researcher

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Last updated May 4, 2021.

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!1

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.2 US insurers may not reimburse for chronotherapy expenses.3

The patients' sex, genetic background, and lifestyle may influence  responses and drug schedule tolerability4

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.5  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.6

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:7

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.8

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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Bladder Cancer

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Colorectal Cancer

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Head, Neck and Oral Cancers

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Kidney Cancer

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Ovarian Cancer

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Pancreatic Cancer

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Lab and Animal Evidence

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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 chemotherapy29

Appetite-related Side Effects

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Blood-related Side Effects

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Gastrointestinal Side Effects Including Nausea and Vomiting

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Fatigue

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Hair Loss

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Inflammation

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Peripheral Neuropathy

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Lab and Animal Evidence

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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.”47 Other studies and reviews show benefit.48

Integrative Programs, Protocols and Medical Systems

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

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