"The doctor of the future will give no medicine, but will interest his patients in the care of the human frame, in diet and in the cause and prevention of disease."
- Thomas Edison
Ralph W. Moss, Ph.D. Weekly CancerDecisions.com
Newsletter #85 05/30/03
Timing Is Everything
Imagine a treatment that could increase the effectiveness of chemotherapy threefold.that could turn a suspicious Pap test normal...or determine whether or not a breast cancer will spread or remain dormant. Such a "drug" would be worth a fortune to any pharmaceutical company. Sadly for Big Pharma, this treatment is not a patentable drug at all, but something we all have as part of our birthright: time.
The idea of using time, or rather proper timing, to treat illness is called by various names: circadian rhythm organization, chronobiology or chronotherapy. It is in fact more than just a treatment; it is a philosophical perspective that traverses all the realms of life. The ancient Greek poet Hesiod (c. 700 BC) once remarked, "The right timing is in all things the most important factor." In common English, "timing is everything." The right treatment given at the wrong time can be ineffective or create a crisis of escalating toxicity. Conversely, even a weak treatment, if given at the right moment, might prove surprisingly effective. The application of this principle to medical treatment constitutes the emerging field of chronotherapy.
There are over 50,000 articles in PubMed about chronobiology, nearly 2,000 of which are about cancer. There are 78 references to clinical trials. Favorable reviews of the topic have appeared in many of the top medical journals. Yet, incomprehensibly, the use of proper timing still remains peripheral to orthodox oncology. For example, there is no reference to chronobiology or circadian rhythms in the 164-page index of the DeVita cancer textbook, the so-called "Bible of Oncology."
In this brief newsletter I can only skim the surface of this intriguing subject. My interest in chronobiology dates back many years, but I was recently reminded of its importance by two events. The first was a Webcast of an important seminar on the topic by the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM). The second was a speech by Keith Block, MD, medical and scientific director of the Block Center for Integrative Cancer Care, in Evanston, Illinois. I had the pleasure of commenting on Dr. Block's presentation at the April, 2003 Comprehensive Cancer Care conference in Washington, DC. Dr. Block is one of the few American physicians who has incorporated chronotherapy into his own practice.
Although much of the discussion that follows focuses on cancer chemotherapy, I don't want to convey the impression that I am necessarily advocating that form of treatment for any particular kind of cancer. Each treatment must be taken on its own merits and all individuals are unique. My point is that the concept of chronobiology is much larger than any one modality. As several pioneers in the field recently said, "The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival." One could probably add that many CAM treatments would be enhanced by optimal timing, as well.
Chronotherapy in Colorectal Cancer
Francis Levi is one of the great pioneers of the chronotherapy concept. A French physician and researcher at the Hopital Paul Brousse, Villejuif, France, he has published nearly 150 articles on the topic, mostly in relation to cancer of the colon and rectum. In 1999, he and colleagues in Belgium carried out a randomized controlled trial (RCT) to compare two treatments for liver metastases from colon cancer. In each case, the treatment involved high-dose chemotherapy delivered via hepatic artery infusions (HAI) as well as the intravenous delivery of the standard drug 5-FU. The drugs were administered either at a constant rate (which is a common way that drugs are delivered) or else according to a chronotherapy schedule, which involved delivering the drugs at fixed, predetermined times of the day. Dosage timing was calculated to coincide with physiological rhythms in such a way as to maximize the efficacy of the drugs while minimizing their toxicity.
Ninety-two European patients with metastasized colorectal cancer were enrolled and randomly assigned to one or other of the treatments. In this trial, all treatment was delivered via a special programmable instrument called the Melodie pump. Drug delivery was kept constant over a five-day period for about half the patients, but it was "chronomodulated" for the other half. The standard drugs 5-FU, as well as an adjuvant drug, leucovorin, were given at 4 am, while the new European drug oxaliplatin was given at its optimal time, which is 4 pm.
Severe stomatitis (i.e., mouth sores, a typical side effect of 5-FU) occurred in five times as many patients on the traditional schedule compared to those who were chronomodulated (89% versus 18%). Yet the doses of 5-FU that were administered in the chronomodulated way were actually higher than those delivered to patients on the normal schedule.
Among the chronomodulated patients, 24 of 45 patients (53%) had an objective response compared with just 15 of 47 patients (32%) on the usual schedule. The median overall survival was 19 months for those who received chronomodulation compared to 14.9 months for those who received the usual schedule, a significant gain of four months. The European authors concluded that "this ambulatory treatment modality was both more effective and less toxic if drug delivery was chronomodulated rather than constant over time."
In a 1999 article in the journal Cancer, Dr. Levi stated that "the objective response rate appeared to be approximately three-fold as high as that achieved with current 5-FU-based regimens and translated into an approximately 50 percent increase in median survival."
Levi also observed that the survival rates of metastatic colorectal cancer patients were consistently the longest reported for this disease in multiple trials. "The chronotherapy concept has played an important part in the recognition of the activity of new drugs against colorectal cancer, and has given rise to a new... strategy with curative potential with patients with metastatic disease," he stated in a 2001 review in the journal Lancet Oncology.
Enter Dr. Hrushesky
In America, the field of chronobiology and circadian organization in medicine has been advanced by the work of many individuals. I wish to point out two of these. Prof. Franz Halberg, Director of the Halberg Chronobiology Center, University of Minnesota, Mayo Hospital, Minneapolis, was one of the original pioneers of this concept. He began his investigations of chronobiology in the 1950s, and has published nearly 500 articles on the topic, an extraordinary record of scientific achievement.
Bill Hrushesky (pronounced Ru-SHES-ki) was formerly a professor at the University of Minnesota and is now at the WJB Dorn VA Medical Center, and the School of Medicine and Norman J. Arnold School of Public Health of the University of South Carolina, Columbia. In the 1970s, Hrushesky was at the National Cancer Institute (NCI), and was involved in the search for new anticancer drugs. He was studying the use of high-dose chemotherapy for people who had lung cancer; he also worked on the first bone marrow transplants. "We were inducing a lot of damage to human beings with high-dose chemo," Hrushesky recently said on the NCI Webcast, "We were seeing deaths" from chemotherapy's toxicity.
At this point, he came across a scientific paper that changed the direction of his life. The paper had been published by Dr. Halberg in 1972 in the journal Science. This article concerned the use of a standard drug ARA-c, with which Dr. Hrushesky was already very familiar. Simply by changing the time of day at which the drug was given to leukemic mice, Prof. Halberg could increase their survival three-fold.
At that time, Dr. Hrushesky and his NCI colleagues were "kicking drugs up the decision network tree for a twenty percent increased life span." Yet here was a way of increasing survival by 300 percent! It didn't involve anything other than materials that lay at hand, just an existing drug combined with good timing. Hrushesky decided "I'd better pay attention to this," and has now spent nearly 30 years doing so. At times it has been a lonely quest but as he explained to the NCI conference, he was convinced that there was so little interest in the topic that if he didn't pay attention to it, no one else would.
He began to explore the many ways that timing influenced not just cancer treatment but human behavior in general. Rhythm (or high-frequency chronobiology, as it is called) is essential to life. The heartbeat is a rhythm (which, if it malfunctions, can cause illness or even death). The in-and-out of breathing; the seasonal drive toward sexual activity in nature; the menstrual cycle. Everywhere you look in life, even in plants, you find regularity, waxing and waning, circadian rhythms .
For instance, it is an odd fact that 60 percent of all heart attacks occur in the five-hour period of 6 am to 11 am. Hrushesky also uncovered research showing that cervical smears are more likely to be abnormal at some times of the year than at others. This could affect both the screening of whole populations and the treatment of individuals within that larger group. Similarly, the efficacy as well as the damaging effects of chemotherapy turned out to depend in part on the time of day that the treatment is given.
Hrushesky describes this by unfamiliar terms such as "chronobiotics," "synchronization" and "tuning", which introduce concepts quite foreign not just to most laypeople but to the established way that chemists, pharmacists and clinicians think about the activity of drugs. He also points to the central role of the hormone melatonin, calling it a "primary tuner." (Melatonin is produced by the pineal gland, a pea-sized structure that is located deep in the brain.)
The effectiveness of most anticancer drugs depends upon interfering with the synthesis of new DNA material. It is now well known that there are certain times of day in which DNA synthesis is either high or low. In order to maximize the effectiveness of these drugs it makes sense to administer them at a time when the synthesis of genetic material is at its height, since you will then catch most of the cancer cells with their DNA unzipped, as it were.
Chronomodulation of Radiation
Radiation therapy also works by disrupting DNA synthesis. The skin does much of its regeneration during the night. Yet the scheduling of radiation therapy for skin conditions is generally based on considerations of convenience to the staff and the patient, rather than timing for maximum effectiveness. "Treating somebody early in the morning for skin [disease, ed] will have little effect, positive or negative," says Hrushesky. "But if the same treatment were given in late afternoon one might have a tremendous effect on the tumor because a much larger proportion [of cancer cells, ed.] were in cell division." One wonders how many treatments that are only marginally effective might become far more worthwhile if delivered at the optimal time.
Time of day also influences the effectiveness of anti-pain medication. It has frequently been observed that some patients with skin damage have few symptoms in the morning but then progress to burning pain by late afternoon. At night the pain is even more severe. Yet, curiously, sleep "resets the clock, and the cycle starts all over again in morning. This pattern, says Dr. Hrushesky, is almost universal. The answer is to not administer maximum pain relief on a constant basis, as is frequently now done, but to base its administration around the time that the patient actually experiences the pain most severely, which is usually in the evening.
The notion of chronobiology is not just pie-in-the-sky theorizing. It has repeatedly been subjected to testing in patients, including a number of randomized controlled trials (RCTs), considered the gold standard of tests. One of the first such clinical studies in humans was done with NCI support at the University of Minnesota. The study, published in the journal Science in 1984, involved a group of women with advanced ovarian cancer, all of whom were given the standard drugs, Adriamycin (doxorubicin) and cisplatin. Half the patients received treatment at 6 am, the other half at 6 pm. The five-year survival rate was 44 percent in those who received a favorable timing schedule vs. just 11 percent in those who received a suboptimal schedule.
The results of this study were confirmed in a Phase II trial by the prestigious Gynecological Oncology Group (GOG). The GOG trial showed a higher response rate than expected in endometrial cancer when the treatment was given at the optimal time of day. Thus, patients with advanced endometrial cancer were given the drug Adriamycin at 6 am and their other drug, cisplatin, at 6 pm every 28 days. A review of 30 patients showed 6 (20%) complete responses, 12 (40%) partial responses, and 7 (23%) with stable disease. Thus there was clinical benefit in 83% of cases. There were no treatment-related deaths. The authors concluded that "circadian-timed delivery of doxorubicin-cisplatin chemotherapy was reasonably well tolerated and demonstrated notable response rates in patients with advanced or recurrent endometrial carcinoma."
In a recent review article, it was shown that chronotherapy could also be used in other forms of gynecological and genitourinary cancer as well. For example, the best time to give Adriamycin (doxorubicin) for ovarian cancer also seems to be 6 am, while for cisplatin it is 6 pm. This dosage schedule "enhanced the control of advanced ovarian cancer while minimizing side effects." (Kobayashi 2002). Similarly, the therapy of metastatic bladder cancer using these same two common drugs was made more tolerable by the circadian approach, and resulted in a 57 percent objective response rate.
In a study of patients with metastatic renal cell cancer, patients were given their drugs in either a traditional or a chronotherapy approach. "This study also confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group."
Overall, the use of timing in cancer therapy appears to be a logical approach that can greatly decrease the toxicity of standard treatments, while increasing effectiveness. Why then hasn't it been widely accepted?
The explanation offered by Dr. Block at the CCC meeting was that most doctors remain ignorant of this cutting-edge research, despite years of positive experiments. New knowledge enters medicine very slowly, especially when it is not promoted by a major pharmaceutical company. Chronomodulation also involves the use of special instruments. At this time Dr. Block is the only one in the US to utilize the Melodie pump from France. There also may be a perception that utilizing a predetermined treatment schedule (often early in the morning or in the evening) will crimp oncologists' ability to put considerations of convenience first in determining the schedule for their patients' treatment.
Chronomodulation also involves a somewhat higher initial outlay of funds, and thus may be resisted by insurance companies. However, this is shortsighted. True, the expense of the timed delivery of medications is often greater than with the standard approach, not least because it requires more frequent doctor visits. However, the outcome of this treatment is often more effective. As a recent Belgian study noted, "There was greater tumor response rate and longer time to progression with less treatment-associated toxicity."
Finally, it was shown that selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in "a further 18 percent reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life" (Focan 2002).
Chronotherapy seems like another in a long line of good treatment ideas that remains underdeveloped because it does not augment the short-term financial interests of those who provide, or reimburse for, cancer treatment.
--Ralph W. Moss, Ph D
Halberg's 1972 paper: Haus E., et al. Increased tolerance of leukemic mice to arabinosyl cytosine given on schedule adjusted to circadian system. Science 177: 80-82, 1972.
Levi FA, 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. J Natl Cancer Inst 1994 Nov 2;86(21):1608-17
Bertheault-Cvitkovic F, et al. Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer. Clin Oncol 1996 Nov;14(11):2950-8.
Levi F, et al. A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. International Organization for Cancer Chronotherapy. Cancer 1999 Jun 15;85(12):2532-40.
Levi F. Circadian chronotherapy for human cancers. Lancet Oncol. 2001 May;2(5):307-15.
Kobayashi M, et al. Circadian chemotherapy for gynecological and genitourinary cancers. Chronobiol Int 2002 Jan;19(1):237-51.
Barrett RJ, et al. Circadian-timed combination doxorubicin-cisplatin chemotherapy for advanced endometrial carcinoma. A phase II study of the Gynecologic Oncology Group. Am J Clin Oncol. 1993 Dec;16(6):494-6.
Focan C. Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer. Chronobiol Int. 2002 Jan;19(1):289-97.
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