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THE MOSS REPORTS Newsletter (05/30/03)

 

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Ralph W. Moss, Ph.D. Weekly CancerDecisions.com

Newsletter #85 05/30/03

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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.

 

 

 

Clinical Trials

 

 

 

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.

 

 

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The Denham Harmon Award

 

 

 

I recently returned from a 2,000 mile road trip, during

which I visited with many practitioners of

complementary and alternative medicine (CAM). In

Washington, DC, I had the pleasure of giving the Denham

Harmon Award lecture to the Spring Symposium of the

American College for Advancement of Medicine (ACAM).

(Prof. Denham Harmon is considered father of the free

radical theory of aging.) I received a plaque in

recognition of this honor and for my lifetime of work

in the CAM field. I last received an award from this

organization when Jimmy Carter was president. It was

with great pleasure that I recognized in this month's

audience some of those who were present when I received

that original award - Drs. Gary Gordon, MD, who signed

that original certificate, Michael Schachter, MD, and

Murray Susser, MD.

 

 

My profound thanks, this time around, to Jeanne Drisko,

MD, meeting chair, for inviting me to this symposium

and giving me this Denham Harmon Award. Dr. Drisko is

a rising star of CAM, as a full time faculty member of

the University of Kansas Medical School and developer

of their Program in Integrative Medicine. She is

currently doing a clinical trial on the use of

intravenous vitamin C in cancer, which may finally

provide us with reliable data on this persistent

treatment idea.

 

 

I thank all the other members of ASCO, including its

current president, Ronald Hoffman, MD, for including me

as a featured speaker at this event and giving me this

honor.

 

 

To see part of the ACAM audience at the Washington DC

Hilton,

click or visit:

http://www.cancerdecisions.com/images/ACAM1.jpg

 

 

To see a photo of the plaque, click or visit:

http://www.cancerdecisions.com/images/plaque1.jpg

 

To see a photo of Dr. Jeanne Drisko, click or visit:

http://www.cancerdecisions.com/images/drisko1.jpg

 

 

 

--Ralph W. Moss, Ph D

 

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References:

 

 

NCI Webcast:

http://videocast.nih.gov/ram/melatonin022803.ram

 

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.

 

Block Center:

http://www.blockmd.com/unique/Treatment.html

 

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IMPORTANT DISCLAIMER

 

 

The news and other items in this newsletter are

intended for informational purposes only. Nothing in

this newsletter is intended to be a substitute for

professional medical advice.

 

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