Breast Cancer Chemotherapy and Respecting Biological Rhythms Breast Cancer Chemotherapy: Breast cancer will be diagnosed in more than 180,000 American women in 1994. One third of these women will be young otherwise healthy, premenopausal and at the peak of their social and economic productivity when their cancer's are diagnosed. Almost 50,000 women are destined ultimately to die from these breast cancers and almost half of these will still be young women at the time they die. Cytotoxic drugs are the centerpiece of breast cancer therapy. They are used to halt the progression of metastatic breast cancer and in many cases are useful for inducing complete or partial disappearance of widespread breast cancer. When this happens these drugs restore health and result in prolongation of excellent quality survival for many months and sometimes years. Very high doses of these agents given with growth factor support and/or bone marrow transplantation may result in longer episodes of disease control and longer spans of excellent quality survival. As importantly, cytotoxic chemotherapy used following local breast cancer treatment in the absence of clinically detectable cancer (adjuvant chemotherapy) is responsible for improving the 10 year disease free survival frequency (and perhaps cure) of patients at moderate to high risk for recurrence of breast cancer. Cytotoxics are not without Toxicities: Unfortunately the beneficial effects of cytotoxic chemotherapy for breast cancer do not come without significant cost. Each of the agents useful in the treatment of breast cancer has a profile of side effects which makes chemotherapy with that agent unpleasant and, to some extent, dangerous. While it is crystal clear that the danger of being made ill and dying from breast cancer far exceeds the danger of illness from cytotoxic chemotherapy; the side effects of these drugs are nonetheless vitally important to consider. It is reasonable to consider any strategy that offers promise for diminishing cytotoxic drug side effects. Since the real point of therapy is cancer cell kill, diminishment of side effects can be employed to increase dose intensity and increase cancer cell kill without increasing side effects or better yet decreasing them at the same time. Strategies for Improving Tolerance: There are pharmacologic strategies being developed to block specific toxicities of chemotherapy agents. Recent successes include the development of MESNA which when taken with Iphosphamide blocks the bladder damage which had prevented the delivery of high doses of this agent. Other agents are being developed which block the heart damaging effects of adriamycin. An alternative more natural approach that does not require the administration of a second drug entails administration of cytotoxic drugs at the optimal times within certain internal biological rhythms like the circadian cycle (time of day) or the menstrual cycle. A Natural Strategy: Biological rhythms are the way that living things organize their life processes over time. This organization in time confers essential stability to these living things. If an organism does not complete an essential task during one cycle it may accomplish that task during the next cycle. The ordering of important tasks within time also means that the living organism can do different essential tasks at different times increasing its efficiency and not wasting precious energy. In 1729 a French botanist noted that the mimosa plant continues to open its leaves in the "day time" and fold them up "at night" indefinitely regardless of whether lights were continuously on or off. This experiment can be duplicated in your kitchen. A tiger lily will open and close regularly each day regardless of whether or not you expose it to light available through your kitchen window. The clocks that time every internal aspect of our lives seem to be very similar across all categories of plant and animal life. Identical clocks are present in primitive organisms which have evolved without a nucleus, like blue green algae and even bacteria. The ability to keep time is one of the most fundamental properties of life. Medicine and Biologic Rhythms: It is mysterious to the few physicians who study biological clocks and the rhythms that are their footprints, why the medical applications of this organization in time have not been more thoroughly investigated in the last 250 years. The contrasting effects of timing cytotoxic cancer chemotherapy differently during the day, within the menstrual cycle and at different seasons is, however, one area which is being medically explored. Circadian Timing of Drugs Relevant to Breast Cancer Treatment. Adriamycin: Adriamycin is considered by many to be the most active single drug available for the treatment of breast cancer. It has many serious toxicities, some of which occur secondary to its interactions with DNA and others of which result because of its interactions with oxygen. Tissues that are dividing more rapidly and that are more likely to have their DNA damaged include gut, bone marrow and hair follicles. A tissue which does not divide but which has a very high oxygen concentration, the heart muscle, is most likely to be damaged by its oxygen interaction. It has been shown that both the gut and bone marrow of healthy individuals are more rapidly synthesizing DNA during certain specific spans within the day. Furthermore, the body's cellular defenses against damage from oxygen that has been activated following reaction with doxorubicin are also more robust in many cells including both bone marrow and heart in the hours between 6 and 10 each morning. Cancer patients given adriamycin in the early morning hours prior to usual daily awakening have been found to tolerate the drug better than those given identical doses in the early evening hours. Specifically the fall of the white blood count, the neutrophil count and the platelet count were far less severe when morning doxorubicin was given. The recovery of cellular blood counts was complete or had overshot pretreatment baseline values by 21 days after morning doxorubicin but had not recovered to baseline by day 28 after evening doxorubicin. Women with ovarian cancer randomized to receive morning doxorubicin got more drug more often and with lower incidences of bleeding, infection and half the blood transfusion requirement than women randomized to receive the drug in the early evening. There is no evidence that giving doxorubicin in the morning interferes with its anticancer efficacy. In fact, women with ovarian cancer who received morning doxorubicin and evening cisplatin were 4 times more likely to survive 5 years than women who received evening doxorubicin and morning cisplatin. Using a Brief Biological Rhythm to Prevent Adriamycin Heart Damage: The pulse quickens with breathing in and slows with breathing out. A portable computer based device that measures this high frequency heart rate rhythm very precisely, non invasively and automatically can be used to predict in 2-5 minutes how much subclinical heart damage has been caused by the adriamycin given to cancer patients. If the amount of heart rate swing diminishes to less than 50% of that expected for age, furthermore invasive testing may be indicated or alternatively, adriamycin might be replaced by a less heart damaging drug. This simple technology employing a high frequency biologic rhythm to predict and prevent drug toxicity could easily be made widely available. 5-FU: This agent has been commercially available for more than 30 years and has been given to more cancer patients than any other cytotoxic drug. It has good activity against breast cancer whether given alone; with the vitamin leucovorin; by intravenous push; or by continuous infusion. It serves as a cornerstone of virtually every commonly used first line combination chemotherapy program for breast cancer; whether in the advanced disease or in the adjuvant setting. A series of studies, mostly in patients with gastrointestinal cancers, have demonstrated that 5-FU is most safely given in the first half of the usual sleep span. This time seems to hold whether 5-FU is given by brief injection alone or with leucovorin and also when it is given over many days or weeks by infusion with or without concurrent leucovorin. In the case of continuous infusion, computerized pumps deliver the drug continuously but at pre-specified varying rates throughout each day. The mechanisms for the circadian coordination of the toxic side effects of 5-FU are among the most thoroughly understood in both experimental animals and men and women with cancer. 5-FU is an antimetabolite. An antimetabolite interrupts an important metabolic or biologic process. For 5-FU this process is DNA synthesis. The mechanisms responsible for the time of day differences in 5-FU toxicology relate to the cell division patterns in normal tissues; the patterns of enzyme activity responsible for activating 5-FU so that it can interfere with DNA synthesis; and the enzyme activities responsible for removing 5-FU from the body. The tissues damaged most prominently by 5-FU, the gut and bone marrow, do not undergo DNA synthesis randomly throughout the day. The highest levels of DNA synthesis each day occur during the 6 hours following daily awakening and the lowest daily levels of DNA synthesis in these tissues occur in the 3 hours prior to and following usual evening retiring. In human studies the activity of the enzyme primarily responsible for the removal of 5-FU from the body is not steady or constant throughout the day but peaks each day in the night and is at its lowest point in the middle of each day. This means that higher blood levels of 5-FU result if a fixed dose of the drug is injected during the day compared to if that same dose is given at night. The activity of the enzyme responsible for activating 5-FU to the state where it can interfere with DNA synthesis also varies throughout the day. Its levels are much higher at the time of day when the most daily DNA synthesis is ongoing in gut and bone marrow. The concatenation of these three rhythms results in much more activated 5-FU being present at precisely the wrong time of day if daytime 5-FU is given. Much higher doses of 5-FU are tolerated with much lower toxicity if the drug is given or mostly given in the hours around usual daily retiring. Cytoxan: This drug is an alkylating agent which cross links, among other things, important parts of the DNA molecule. It has a complex metabolism which requires a several step activation. There are also a variety of ways in which this molecule can be broken down. Unfortunately no human studies have been done testing whether there is an optimal time of day to give cytoxan. There are however some experimental animal studies which indicate that the therapeutic activity of this agent may be best when the drug is given shortly after usual daily awakening. Coincidentally, the time around daily arising is also the time of day when the highest doses of cytoxan are most well tolerated in mouse experiments. No clinical recommendations can be made about cytoxan timing, however, it certainly can be pointed out that animal studies indicate that there is likely to be a safer and less safe time to give this important agent. Clinical trials designed to discover the optimal time of day to give cytoxan must be supported so that we can confidently recommend an optimal time of day to administer this drug to women with breast cancer. Methotrexate: This antimetabolite works by inhibiting an enzyme which is essential to the process of DNA synthesis. It has been used in combination with other agents for breast cancer therapy for decades. There are no human data to guide its timing in breast cancer although there are some indications that its timing may be important in childhood leukemia and lymphoma treatment. Since this drug is more active against cells actively synthesizing DNA, the organization of human gut and bone marrow DNA synthesis within the day as outlined above is probably highly relevant. Experimental data in mice and rats indicate clearly that the way the drug is broken down by the body and gotten rid of; as well as its toxicity are different depending upon when in the day it is given. The rat studies indicate that the safest time for this drug may be in the afternoon and evening hours. This is the same time of day associated with higher cure rates of children with leukemia. There is however obvious need for clinical study which will pinpoint the best time of day for this drug to minimize its toxic effects and maximize its effects against breast cancer. Oncovin: This agent has been included in many breast cancer protocols. It has not been investigated whether there is an optimal time of day for vincristine in patients with breast cancer. Toxicity studies in mice indicate that it may be safest to deliver this agent in the morning hours of the day after daily arising. Obviously there is a great need for clinical data. Prednisone: Prednisone is a synthetic hormone modeled after the steroid produced in the adrenal gland. In very high doses it has proven useful in the treatment of several malignant diseases. It has been incorporated into a number of breast cancer combination regimens. The daily steroid rhythm was discovered by documenting the waxing and waning of cells in the blood which are destroyed by this hormone, several years before the actual steroid molecule was identified, isolated or purified. Natural steroid molecules are absolutely essential for survival and are always, in health, released with a typical daily pattern. They act through hormone receptors and have a myriad of biological effects. Most of the effects of these molecules are extremely dependent upon when in the day they are administered. When high doses of steroid are administered in an unnatural continuous daily pattern a great deal of toxicity ensues. Giving high doses of steroid every other day can obviate many of these side effects but does not appear to interfere with many of the therapeutic effects of these hormones. Administering all or most of each days low (physiologic) or high (pharmacologic) dose at the times of day normally associated with peak daily levels results in substantially less inhibition of the normal responsivity of the adrenal gland to stimulation by pituitary hormones, while giving high doses of steroid throughout each day severely diminishes the ability of the adrenal gland to respond to these normal control signals. While there have been no clinical trials in breast cancer comparing equally divided three times a day steroid doses to schedules mimicking the normal daily rhythm in circulating steroid, it may be a reasonable strategy to limit side effects by giving most or all of these high doses in the early morning hours until such data are available. Cytotoxic Drug Timing within the Female Fertility Cycle: Almost 60,000 of the women who develop breast cancer in 1993 will be young cycling premenopausal women. Outside the limited area of reproductive biology, the menstrual cycle has been all but ignored in medical practice and research. There is no more medical or scientific justification for not considering the potential importance of this biological rhythm than there is for ignoring circadian biology. While there are currently no data from patients, we have begun to ask questions in experimental animals about how the menstrual cycle might affect the woman-drug and woman-breast cancer-drug balance. 5-FU the most commonly used cell cycle active chemotherapy for breast cancer provides the backbone for breast cancer therapies. Each female fertility cycle represents a tight coordination of cell division events within the ovary. Ovarian follicular development (follicular phase) is totally dependent upon the division of cells tending the ripening ovum. In response to precisely timed surges of pituitary hormones the mature follicle ruptures and the egg becomes available for fertilization, supported hormonally by the quiescent non dividing follicle now called the corpus luteum (luteal phase). In mouse experiments we have repeatedly found that sexual dysfunction is several-fold more frequent, litter size is smaller, and live births are less numerous when 5-FU is given in the fertility cycle phase associated with follicular cell division. Surprisingly, bone marrow suppression and gut damage from 5-FU are also substantially worse when the drug is given in this same phase of the fertility cycle. This discovery, the mechanisms of which we don't yet understand, implies that a premenopausal woman's tolerance to cytotoxic chemotherapy may vary depending upon when in her fertility cycle it is administered. Based upon our mouse studies, 5-FU may be most well tolerated in the week following ovulation, 14-21 days after the first day of the last menstrual period, however, no clinical research has ever been done in this area. This research is surely needed. Season and Chemotherapy Toxicity: A single randomized clinical study has documented that the bone marrow toxicity of adriamycin differs substantially not only according to the time of day that it is given but also seasonally. Morning doxorubicin results in quicker and fuller recovery than evening doxorubicin in spring, summer and fall but both times of day are equally bad when this agent is given at fixed dose in the winter. Although far more clinical work is needed these results are totally consistent with a large experimental data base documenting seasonal variations in bone marrow function and bone marrow susceptibility to a wide range of cytotoxic agents prominently including adriamycin. While no firm therapeutic recommendations can be made it may be wise to be more vigilant for adriamycin associated side effects in winter months. Practical Aspects of Circadian Timed Chemotherapy: The usual "way of thinking" about cytotoxic chemotherapy is that the higher the dose the greater the toxicity and potential efficacy. Evidence summarized in this brief article demands a real modification of this "way of thinking" because it shows that the toxicity of a therapeutic regimen not only rests upon the dose given but also depends intimately upon when in the day and perhaps the menstrual cycle and season that it is given. This new way of thinking is fundamentally different. It should not, therefore, be surprising that these results have not been embraced by practicing physicians. In all fairness the data while provocative are very incomplete. For the 6 drugs reviewed here clinical studies of optimal circadian scheduling have only been done for two. It may not be reasonable to alter practice with these few data. It is, however, quite reasonable to expect physicians to keep an open mind about any possible methods of diminishing the toxicities and improving efficacy of cytotoxic breast cancer therapy. This is especially relevant in the adjuvant therapy situation where many women who are destined to have been cured by surgery alone are appropriately treated with many months of cytotoxic chemotherapy to increase their chances of having been cured. The woman with breast cancer should expect to be able to discuss the pro's and con's of a chronobiologic approach to her therapy with an informed and open minded physician. Patients and physicians should also be aware of the fact that a wide variety of wearable or portable ambulatory computerized multichannel delivery devices make stipulation of infusion timing in the home possible with even greater convenience for the patient than standard office based therapy. More Data Are Urgently Needed: During the last 4 decades the pharmaceutical world of cancer drug development and the medical world of cancer therapy development have focused both consciously and subconsciously upon finding the silver bullet that will cure cancer. Empirical successes have emerged just often enough to keep this dream alive. This notion has impeded a deeper understanding of the complex and beautiful balance between a woman and her breast cancer. Understanding this balance better, within the context of the biological rhythms that guide and coordinate it, has the promise to decrease the toxicity and increase the efficacy of all presently available cytotoxic therapy. This incremental step in the improvement of chemotherapy will not happen, however, without further investment in the basic and most importantly clinical research that will fill in the many blanks in our knowledge. Because this approach requires a fundamental rethinking of both the drug and therapy development process, money will not be made available for these sorts of studies unless the consumers of cytotoxic cancer chemotherapy demand that these investigations are expanded. Where to Read More About It: While it is not reasonable to expect practicing physicians to be aware of the many basic science studies unpinning the principles of circadian cancer therapy it is reasonable to expect your physician to have read summary reviews of this subject. Recent reviews of the effects of circadian chemotherapy timing can be found in "The application of circadian chronobiology to cancer chemotherapy" in Cancer: Principles and Practice of Oncology (4th Edition) pages 2666-2686 edited by V. T. DeVita, S. Hellman, and S. A. Rosenberg and published by J. B. Lippincott Co., 1992, and a review article in the Journal of Clinical Oncology, "Circadian Cancer Therapy", July 1, 1993. In addition to these reviews CRC press will publish a book Circadian Cancer Therapy within the next 6 months. Copies of this book may be ordered by contacting Ms. Suzanne Lassandro of CRC Press tel: (407) 994-0555 fax: (407) 994-3625. Table 1 Cytotoxic Agents Commonly Used for the Treatment of Breast Cancer Common Name- Adriamycin Generic Name- doxorubicin Utility- most active single agent Toxicities-total alopecia, bone marrow suppression, mucositis, moderate nausea & vomiting, heart damage Common Name-5-FU Generic Name -5-Fluorouracil Utility- most commonly used agent Toxicities-mild nausea & vomiting, bone marrow toxicity, diarrhea (esp. when used with leucovorin), hand/foot pain (esp. with long term continuous infusion), hyperpigmentation, mucositis Common Name Cytoxan Generic Name -Cyclophosphamide Utility- second most commonly used agent Toxicities-bone marrow suppression, moderate nausea & vomiting, alopecia, bladder irritation Common Name Methotrexate Generic Name -Methotrexate Utility- used in many combinations Toxicities-bone marrow suppression, mucositis, thinning hair, moderate nausea Common Name Oncovin Generic Name -Vincristine Utility- used in many combinations Toxicities-alopecia, peripheral nerve damage, constipation Common Name Prednisone Generic Name -Prednisone Utility- used in many combinations Toxicities-thinning hair, weight gain (fat and fluid), diabetes, suppression of adrenal gland, osteoporosis, immunosuppression, thinning of skin, poor healing This work was supported, in part, by NIH R01 CA 31635 "Clinical Applications of Chronobiology to Cancer Medicine," and NIH R01 CA 50749 "Chronobiological Investigation of TNF and IL-2," VA RAGS and VA Merit Review to William J.M. Hrushesky. William J. M. Hrushesky, M.D Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.