DNC NEWS: Chronobiology and Chemotherapy:
Subject: Administering cancer treatments according to circadian rhythms can increase chemotherapy effectiveness while decreasing toxicity.
In life, timing is everything.
There is a new buzzword in cancer therapy, Chronobiology.
Simply put, this means the study of clocklike stuff in living things. Or you can use the brainier definition, “Chronobiology is the quantitative study of rhythmic temporal relationships in biological phenomena.” Our bodies go through a day as if multiple clocks were hardwired into our brains, organs, and very cells telling us what to do and when to do it.
In recent years scientists have just begun to understand these multiple rhythms of activity and rest that different systems in the body go through on a daily basis. These daily, or circadian, cycles repeat themselves every 24 hours. Cells don't grow at a constant rate; rather there are bursts of frantic cell division followed by rest spells. Hormones are not generated at a steady flow rate but have high points when they are dumped into the blood and low points throughout the day. All animals have built in clocks in not just their bodies but in their individual cells that keep track of these scheduled activities. Some of the actual genes which are responsible for these clocks have been identified on the cellular level.
Circadian rhythms have been found in organisms ranging from photosynthetic algae to humans and everything in between.
Both animal and human evidence suggests that if these circadian rhythms are thrown off cancer risk increases. [i] In human studies, as I've written about before, night shift work which disrupts melatonin production and circadian rhythms, increases risk of disease, especially breast cancer. The events in the body do not occur at full throttle simultaneously at all times. There are regular patterns of cell growth and cell death. In cancer there is an imbalance between cell growth and cell death. What is a tumor but either too much cell growth or not enough cell death?
Our growing understanding of these cycles has produced various strategies to increase the effectiveness of cancer treatment. The toxicity of chemotherapy drugs varies considerably with the time of day administered. Clinical trials in which drugs were timed in a circadian manner taking this knowledge into account have consistently shown that drug toxicity can be reduced while the desired tumor kill can be increased and patient survival improved. In other words, it makes a big difference what time of day cancer patients are given their chemo drugs. [ii]
Different types of chemotherapy drugs kill cells at different stages of the cell cycle. Administering the specific drugs when the cancer cells are most sensitive and other cells are less sensitive makes them more effective. Some types of chemotherapy need to be activated in the body before they affect cancer cells; administering them at times when this will happen efficiently also improves effect.
Here are some examples.
In ovarian cancer, giving doxorubicin early in the morning is less toxic; the white blood cell levels recover faster returning to their starting level in 21 days. If the doxorubicin is given in the evening it takes 28 days to recover. If doxorubicin is given in the morning and cisplatin is given 12 hours later, there is a 44% five-year survival. If you shift the schedule and give doxorubicin in the evening and the cisplatin in the morning the survival rate drops to 11%. [iii]
This is a big deal. By simply paying attention to dosing schedules you can quadruple survival rates. Or on vice versa, by ignoring these findings you can get a quarter the survivors as you might.
Cisplatin and the other platinum drugs such as oxaliplatin are most effective when given in the evening. The same study reported that using doxorubicin in the morning and cisplatin in the evening was particularly effective in treating advanced metastatic bladder cancer.
Drugs referred to as antimetabolites, such as 5-FU and methotrexate work best when given in the evening or during the first few hours of sleep. This is when the cells in the bone marrow and cells in the gut make the least new DNA. Dosing these drugs during this slow period reduces the damage to these vulnerable areas and reduces the extreme diarrhea which often prevents patients from receiving effective doses of these drugs.
A recent trial on colorectal cancer which compared oxaliplatin, fluorouracil and folinic acid given either in a typical constant rate infusion or in a timed ‘circadian dose' is interesting as well. The attempt on the part of the researchers to divide the patients randomly between the experimental and control groups failed. Patients who were clearly worse off ended up in the experimental group to get the circadian doses. The experimental group started the study with higher rates of bone metastasis and other markers of poor prognosis. Nevertheless the tumors responded in 51% of the circadian dosed patients compared to only 29% of the standard dosed group. Only 14% of the circadian patients developed mucositis compared to 76% of the standard dosed control group. The same decrease was seen in neuropathy; 16% of the circadians developed neuropathy compared to 31% of the controls. [iv]
Animal studies of thirty different chemotherapy drugs, demonstrated that toxicity can be reduced by 50% by simply paying attention to the timing of the drugs during the day. [v]
By reducing drug toxicity higher and more effective doses of chemotherapy can be used. In another study of colorectal cancer that looked at 1000 patients with untreated and inoperable metastatic disease, the drugs were administered in circadian doses, increasing the amounts until toxic symptoms were seen. This high dosing produced a 41% tumor response rate and significantly longer survival times. [vi]
Corticosteroids and interferons are less toxic and work just as well if given either when a person first wakes up or just before sleep. It is starting to look like the timing of growth factors such as erythropoietin is more important than the timing of chemo. There is more than a 10-fold difference in effectiveness in these drugs depending on timing.
These studies go on and on. Let me see if I can simplify this. There are more studies on this than I can count. Here's one on pancreatic cancer. [vii] Here's one that says timing of radiation treatments also makes a difference. [viii] The thing is that current science is making it sound like timing is a big thing. I have not run into anything arguing otherwise.
This is basically good news. There is a lingering concern they also bring up. In searching for new cancer therapies, if a drug doesn't appear to work, it gets dropped from the running. How many drugs, herbs, or other treatments have been dropped from consideration because despite initial positive results they failed to work in a subsequent trial, the results of which may have been skewed simply by dose timing? There is no guarantee that all drugs will comply to the 8 am to 5 pm schedule worked by researchers. What if there was a miracle cure that only worked when given at 3 am ?
I know I'm going to get questions in response to this article about timing of supplements and vitamins. At this point I don't have any answers about when the best time of day will be to take various supplements, aside from taking melatonin at bedtime. Possibly the old idea of dividing them evenly over a day should be thrown out. I don't know what to say. Expect to see further updates on this topic over the coming months.
Here is what I think we know so far about chemo timing:
The bottom line:
The best review articleon this topic can be downloaded for free:
Integr Cancer Ther. 2003 Jun;2(2):105-11. Circadian timing in cancer treatment: the biological foundation for an integrative approach. Lis CG, Grutsch JF, Wood P, You M, Rich I, Hrushesky WJ.
[ii] Chronobiol Int. 2002 Jan;19(1):1-19.
From circadian rhythms to cancer chronotherapeutics.
[iii] Chronobiol Int. 2002 Jan;19(1):237-51.
Circadian chemotherapy for gynecological and genitourinary cancers.
Kobayashi M, Wood PA, Hrushesky WJ.
[iv] Lancet. 1997 Sep 6;350(9079):681-6
Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy.
Levi F, Zidani R, Misset JL.
[v] J Pharm Pharmacol. 1999 Aug;51(8):891-8.
[vi] Hepatogastroenterology. 2001 Mar-Apr;48(38):320-2.
Chronotherapy of colorectal cancer metastases.Levi F, Giacchetti S, Zidani R, Brezault-Bonnet C, Tigaud JM, Goldwasser F, Misset JL.
[vii] Ann Oncol. 2001 May;12(5):681-4.
A pilot study of chronomodulated infusional 5-fluorouracil chemoradiation for pancreatic cancer.
Penberthy DR , Rich TA, Shelton CH 3rd, Adams R, Minasi JS, Jones RS.
[viii] Chronobiol Int. 2002 Jan;19(1):77-100.
Chronobiology of the mammalian response to ionizing radiation. Potential applications in oncology.