Many of the chemotherapy agents introduced in recent years come in the form of a tablet, capsule, or liquid. This is particularly true of the metabolic inhibitor drugs, such as kinase inhibitors. Indeed, of the 63 new drugs approved by the FDA for cancer treatment from 2019 through 2023, 33 are designated for oral administration. Cancer patients have long taken pills as chemoprotectants or to address side effects, but it is only in recent years that antineoplastic medications have come in pill form. While all patients should follow doctors’ orders in taking medicine of all sorts all the time, special attention should be given to chemotherapy medicine. It truly must be taken on time and the correct dose to fit in the prescribed regimen.

Patients often (perhaps subconsciously) think IV chemotherapy is the real deal, while oral preparations are less serious and/or effective. However, oral chemotherapy is a real treatment, given by doctors for good reasons.  These drugs are sometimes called oral anticancer agents (OACs).

When taking oral chemotherapy at home, patients usually get special instructions from the medical team and there are many precautions to be followed.

Sometimes the care team prefers that the patient take the oral chemotherapy in the office or clinic in the presence of a nurse. There are good reasons for this

• The high cost of oral chemo agents (many are expensive because they are patent-protected) means some patients decline to get their prescription filled and do not follow doctors’ orders.
• Even if the patient has the medicine in his or her home, he or she may fail to take the medicine or take it at the wrong time or at the wrong dose. This might be due to forgetfulness or other reasons.
• OACs can be hazardous, and technicians in the office/clinic are more likely to follow safe handing procedures than patients and their family members in the home.
• The medical team does not want the patient to have an inventory of the drug, but instead receive it right as it is ingested.
• The other part of the combination regimen may include medicine that must be delivered at the clinic (e.g. intravenously)

Cytotoxic and transduction inhibitor drugs

Hormone agonists or antagonists used in treatment of cancer

Abiraterone

Apalutamide

Bicalutamide

Darolutamide

Degarelix

Estramustine

Enzalutamide

Flutamide

Goserelin

Mitotane

Nilutamide

Megestrol

Tamoxifen

Toremifene

Aromatase inhibitors

All aromatase inhibitors given in adjuvant cancer therapy are oral:

Anastrozole

Aminoglutethimide

Letrozole

Exemestane

Taking the Drugs with Food

Should oral chemotherapy drugs be taken on an empty stomach or with food? As with any medicine, it is best for the patient to follow the instructions that come with the medicine and whatever the cancer care team (nurses and doctors) say. It is interesting, however, that different drugs have different instructions. Food with high fat content often helps medicines become more bioavailable – a greater percentage of absorbed in the digestive system – but often the medicine should be taken first thing in the morning, before breakfast. This kind of thing is determined in clinical trials and the manufacturer knows how to advise patients and doctors. 

A review found that early stage trials usually give the patient the drug on an empty stomach and claimed many drugs got to approval without the right food studies to determine how they should be taken.

Some kinase inhibitors are recommended to be taken with a meal and some while fasting.  Some labels say nothing about the question. Researchers at the University of Chicago compared the labels of oncology drugs and other drugs and concluded that the instructions for “oncology drugs are in contradiction with fundamental pharmacologic principles.”

They found cases where it was known that food-drug interactions increased bioavailability of the active medicine but the label nevertheless told patients to take the pills after fasting.  An article in the science magazine Undark mentioned that some oncologists have noted that a lower dose is needed when the pill is taken with food, and that changing recommendations so that patients take the pills with food may have benefits.

Worries about Interactions

There are also concerns about interactions between the oral cancer medicines  and other medicines the patient may take, although interactions are a potential hazard no matter what method of delivery is used.  Antacids, proton pump inhibitors, and H2 blockers lower the solubility of kinase inhibitors, and special instructions are often given to patients who need to use these medications while they are under cancer treatment.

The liver enzyme CYP3A4 is important in the metabolic breakdown of many drugs – it is estimated that about half of drugs are catabolized with the assistance of this enzyme.  If a kinase inhibitor patient takes a drug classified as a CYP inhibitor at the same time, the concentration of the kinase inhibitor in the blood increases.  If the co-administered drug is a CYP inducer, the blood plasma concentration of the kinase inhibitor can increase. 

Likewise, the plasma concentration of cholesterol medication statins can be affected by co-administration of kinase inhibitors.  Oncologists must take these interactions into consideration when advising patients.

Chemotherapy Without Side Effects?

All drugs produce side effects, at least in some patients – even over-the-counter ones.   Cancer chemotherapy is notorious for the severity of side effects – it’s the first thing that comes to mind to many people when they hear “chemotherapy”.  As with other drugs, the nature and severity of side effects from chemo is highly individualized.  But old-style cytotoxic chemotherapy drugs tend to give people anemia and make their hair fall out.  The anthracycline doxorubicin is even called “red devil” because the side effects are so severe.

Oral chemotherapy medicines are, in general, less toxic and produce milder side effects than the cytotoxic medicines.  A treatment regimen consisting of only targeted medicines would be relatively low in side effects, all other things being equal.  Ask your medical team for specifics.  Although the targeted medicines have found widespread use, oncologists tend to include them as part of combinations with cytotoxic medicines, so not many chemo patients are getting only targeted medicines.  Consult your oncologist for questions on this.

Rule of Thumb

Medical chemist Christopher A Lipinski proposed a heuristic as to what makes a drug likely to be effective in oral administration. Called the “rule of 5”, the rule has a few tenets that apply numbers with multiples of 5. These tenets relate to the drug’s pharmacodynamics.

• No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)
• No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms)
• A molecular weight of less than 500 daltons
• An octanol-water partition coefficient log10 of the partition coefficient of five or less

These are not hard-and-fast rules.

Adherence Questions

Intravenous medicines are delivered under medical care, but oral medicines are often taken by the patient at home.  Medical pros worry about whether patients take their medicines as directed. This issue used to be called “compliance” but it’s now called “adherence”.  Studies show that patient adherence can be low for all sorts of medicines. The oncology world largely sidestepped this problem because cancer drugs were given intravenously and hence by professionals in a clinic or doctor’s office.  However, now that so many cancer drugs are pills and taken by the patient at home, adherence has become an issue. Patients must be instructed closely as to when to take their medicine and that the pills should not be doubled-up.

Chemo Parity

A common policy of insurers was to cover IV chemotherapy costs with only a nominal co-pay expected of patients, but not to cover pills in the same way. Prescription oral medication drugs were either not covered at all or were in a separate tiered structure that called for the patient’s share to increase with increase cost. While this was not a burden for patients when pill costs were low, many of the new oral chemotherapy drugs can cost tens of thousands of dollars per month. Also, the high cost of oral chemotherapy agents means some insurers won’t pay for them because conventional IV drugs are available and approved for the same indications. Some states have adopted “chemo parity” laws which require equal treatment of drugs regardless of how they are administered.

The federal government does not have such a law. The Cancer Drug Coverage Parity Act was introduced in 2015 and another Cancer Drug Parity Act was introduced in 2017 but neither passed Congress. It would have required insurance companies to “not, for anticancer medications: (1) change or replace benefits to increase out-of-pocket costs; (2) reclassify benefits to increase costs; or (3) apply more restrictive limitations to orally administered medications than to intravenously administered or injected medications.”

Spanish: Quimioterapia Oral