Chronotherapy, also called a chronotherapeutic drug delivery system, basically means “time therapy.” It is the timing of chemo treatments and other medications.
Why would timing matter for chemo treatments for dog cancer?
As it turns out, the time of day that a drug is given can affect how well it works, and how many side effects it causes.
When a drug is given can affect how well it works and how many side effects it causes.
And this concept can apply to ALL medications and supplements that your dog takes, not just chemotherapy.
Your dog’s body has a daily routine – get up at a certain time, eat, sniff around, play, eat some more, go to sleep at the end of the day. You’ve probably heard this phenomenon described as a circadian rhythm or biological clock.
At different points in the day, your dog’s body (and yours!) is going through specific tasks. Some of these tasks include:
raising and lowering blood pressure
raising and lowering body temperature
adjusting hormone levels (including melatonin)
Certain processes occur in the morning, while others occur at night during sleep.
Does your dog seem to have psychic powers to know when it’s time for breakfast and dinner? That’s his biological clock at work.
These routines are controlled by clock genes that are turned on and off by the sun/dark cycle. Signals from the eye go to the brain and tell a part of the brain (the suprachiasmatic nucleus) which pathways to turn on or off. Day/night is the main control of the clock genes, but other things like eating have effects too.
Changing up your regular sleep schedule can knock these processes off-kilter. This is part of why you don’t feel so great when you make a dramatic change. And when you don’t feel good, your body isn’t working properly…
… and you are more susceptible to a variety of illnesses and problems.
There can also be issues with the clock genes themselves. Abnormalities in the clock genes not only mess up your dog’s schedule, but they can also increase cancer risk. Research has also shown that some cancers specifically turn off genes that control circadian rhythms. This allows them to grow and replicate whenever they want.
Back in 2017 researchers Jeffrey C. Hall, Michael Rosbash, and Michael W. Young won the Nobel Prize in Physiology or Medicine for their work on circadian rhythms. This stuff is pretty cool!
Chronotherapy for Dogs
Because your dog’s body is focused on different tasks at different times of the day, how he responds to a medication can vary!
Most dog owners have had to time a medication based on when their dog eats. Some meds have to be given on an empty stomach, while others need to be given as part of a meal.
This is basic chronotherapy, but it’s just the tip of the iceberg.
As well as timing medications to prevent stomach upset, in some cases it can also be possible to improve absorption, improve response to therapy, and decrease other side effects (such as low platelet counts and cancer cachexia).
Studies are also underway trying to develop drugs that can reset biological clocks and get them back on schedule. This would rob tumors of one unfair advantage!
Most of these studies are not in dogs, but cancer in dogs has many similarities to cancer in humans. Discoveries made in one species often apply to the other!
Minimize Side Effects for Dogs, Increase Chemo Effectiveness
If you are able to pin down when the best time to give a medication or have a treatment done is, the side effects go way down.
Your dog’s liver adjusts certain proteins throughout the day, which can change how well the liver metabolizes medications.
This means the dog will be able to handle a higher dose of the treatment, which is fantastic. Veterinary medicine has always focused on getting the maximum chemo and radiation doses without toxic effects to the rest of the body. Bigger doses mean more palliation (decrease in signs and symptoms). They also mean longer life expectancies.
And fewer side effects keep both you and your dog feeling better during treatment.
Best Time for Chemotherapy
A variety of studies have started looking at when different chemotherapy drugs are most effective.
Some of these results may seem to contradict each other. This could be due to how the studies were set up, other medications the subjects received, or the species being evaluated. For studies involving rats, remember that our morning is the start of their sleep time.
We still have lots to learn! But these are just a few of the completed studies looking at chronotherapy.
5-fluorouracil (5-FU) and Carboplatin:
Doxorubicin and Cisplatin:
A study in rats with plasmacytoma looked at both doxorubicin and cisplatin. The doxorubicin was found to be safest and most effective when given toward the end of the night, while cisplatin was best when given toward the end of daytime. Remember that rats are usually active at night and sleep during the day.
A study in humans with breast cancer found that doxorubicin was less likely to damage the heart if given mid-morning. This is when melatonin levels are at their lowest.
A study in humans found that doxorubicin was less likely to cause bone marrow suppression if given during the night.
A study in humans found that patients with brain cancer given temozolomide in the morning lived longer than those who took it in the evening.
Not Just Chemo
Chronotherapy concepts don’t just apply to chemo drugs!
In fact, the time of day can make a difference for a wide range of medications, and even supplements.
A review published in the Polish journal Medycyna Weterynaryjna in 2006 looked at a variety of medications commonly used in veterinary medicine.
Here are some of their findings:
Diazepam: Best absorbed in the morning
Gentamycin: Can be given any time
Hexobarbital: Better absorbed in the evening
Ketoprofen: Best absorbed in the morning
Midazolam: Can be given any time
Theophylline: Best absorbed in the morning
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) may provide the best pain relief and better bone healing when given during the day.
Steroids give the best relief for asthma patients in the morning, but provide more relief for rheumatoid arthritis patients when given in the middle of the night.
Apocaps: Best absorbed and most effective when given between 10 and 11 AM and PM. That doesn’t work with your sleep or work schedule? Give it one hour before or two hours after a meal instead.
Curcumin: Its ability to trigger cancer cell death is impacted by circadian rhythms, but more study is needed.
A study in mice showed that radiation therapy is also impacted by the time of day. Timing radiation with the patient’s circadian rhythm can increase survival times.
And a review of several radiation chronotherapy studies in humans found better outcomes when radiation was done in the morning.
Yes, we’re serious – the time of day that surgery is done might be important.
Researchers compared tissue damage after heart surgery in almost 600 people. What did they find out? Patients who had heart surgery in the afternoon were less likely to have heart damage than those who had surgery in the morning. This is wild!
Why Isn’t Chronotherapy Part of My Dog’s Treatment Plan?
Chronotherapy may or may not be factored into your dog’s current cancer treatment plan. There are a couple reasons for this:
One: There is still a lot to learn.
While all of the above is really interesting, chronotherapy is a complex issue. There are a lot of moving pieces. It’s going to take a while before we have definitive answers on when the best time to give each drug is.
Also, the “best time” may not only vary from drug to drug, but from disease to disease and species to species. Doxorubicin might be most effective against lymphoma at a different time of day than it is most effective for osteosarcoma.
Other medications that a patient is getting will also affect how well a drug works.
There are endless possibilities that can impact the ideal time to give any single drug, and it will take a while to sort all of those out.
Two: It can be difficult to implement chronotherapy.
Chronotherapy can be impractical, too – for both owners and veterinarians.
Veterinary hospitals can only see so many patients in a day and usually have limited business hours.
If they have twenty dogs all getting the same chemotherapy drug that is most effective when given at 9am… there may not be twenty teams of staff available to accommodate that demand at that time.
And drugs that are best if given in the middle of the night can be an issue too. Even 24/7 emergency hospitals don’t usually schedule non-emergency appointments at 2am.
Your work schedule or travel ability can also limit when you can take your dog in for treatments. Oral medications given at home are easier to accommodate, but even those might be difficult to squeeze into your workday.
Chronotherapy is a really exciting branch of medicine. We are learning that giving medications according to the patient’s biological clock can increase effectiveness and decrease side effects.
That said, there is still a long way to go. And even when we do know the “best” time to give a drug for a particular illness, that might not be a realistic option.
We expect chronotherapy will slowly work its way into veterinary medicine, but if it doesn’t fit with your dog’s treatment plan, don’t worry.
We live in an imperfect world, and are all doing the best we can for our pets with what we have. As we learn more about how circadian rhythms affect drug metabolism in dogs, we will be able to use it more to help our beloved pets.
Paws and wags,
Further Reading and References
A Chronopharmacological Study Related to Doxorubicin Based Bone Marrow Suppression
A Time for MYC: Metabolism and Therapy
DogCancer.TV: Cancer Cachexia and Dog Cancer- When Your Dog Won’t Eat
Chronotherapy in veterinary medicine
Chronotherapy with 5-fluorouracil, folinic acid and carboplatin for metastatic colorectal cancer; an interesting therapeutic index in a phase II trial
Chronotherapy of Non-Steroidal Anti-Inflammatory Drugs May Enhance Postoperative Recovery
Chronotolerance for cisplatin ototoxicity in the rat
Circadian chemotherapy for gynecological and genitourinary cancers
Abstract 1772: Circadian control of cell death in glioma cells treated with curcumin
Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis
Combined Systemic Chronotherapy and Hepatic Artery Infusion for the Treatment of Metastatic Colorectal Cancer Confined to the Liver
Control of a murine plasmacytoma with doxorubicin-cisplatin: dependence on circadian stage of treatment
Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study
Does the Time of Radiotherapy Affect Treatment Outcomes? A Review of the Literature
How to Ruin Cancer’s Day
Increasing doxorubicin activity against breast cancer cells using PPARγ-ligands and by exploiting circadian rhythms
Influence of dosing times on cisplatin-induced peripheral neuropathy in rats
Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules
Medicine’s secret ingredient — it’s in the timing
Nobel Prize Winning Research, Once Again, Can Help Your Dog
Sleep, Dog Cancer, and Melatonin
Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study
The Days and Nights of Cancer Cells
Time for chronotherapy? Clock genes dictate sensitivity to cyclophosphamide
Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer