Over the past decade, targeted therapies have become an important tool for fighting a variety of cancers and patients are increasingly interested in receiving them. Not only has targeted therapy been shown to improve outcomes in certain cancers, [1][2] it also can avoid some of the harsh side effects of chemotherapy. Hair loss, for example, is a major concern for many patients undergoing chemotherapy and is often avoided with specific targeted therapies.[3] 

Targeted therapies are not without side effects, some of which can have similar or even more significant and unpredictable toxicities than chemotherapy, including fatigue, mouth sores and skin problems. Diarrhea, which also can occur with chemotherapy, is another common occurrence with targeted therapies such as tyrosine kinase inhibitors, EGFR, HER2 and PARP inhibitors and immunotherapy. As many as 50% to 100% of cancer patients experience diarrhea, depending on their treatment regimen.[3][4][5] Unlike chemotherapy, however, targeted therapies are often given for months or years without treatment breaks, meaning patients have no time to recover from the side effects.

Diarrhea can severely impact quality of life, including the ability to function well at work, care for children, travel, participate in outdoor activities and achieve good quality sleep. Even mild diarrhea over days and weeks can lead to weight loss, clinical deterioration, and mental stress. At its worse, it is a debilitating and potentially life-threatening toxicity that can cause dehydration, electrolyte imbalances, renal insufficiency, malnutrition and extreme dehydration, all of which can lead to cardiovascular compromise and death.[6] Frequent diarrhea also can limit reliable oral medication absorption, upon which clinicians rely to evaluate targeted therapy effectiveness.

Discontinuing Targeted Therapy Poses Problems
Life disruptions are a major reason why patients want to discontinue or lower the dosage of targeted therapy. For example, I have had patients who experienced an embarrassing diarrhea event and wanted to stop their treatment. Some clinicians may be reluctant to prescribe targeted therapy in the first place because of these potential side effects and because dose reductions or treatment breaks can compromise clinical outcomes.[7]

We, as oncologists, choose to use targeted therapy because we know it is the best treatment for a particular patient. When we must stop it due to diarrhea or other bothersome side effects, we have to use our treatment plans B, C or D, which are usually less optimal therapies. In essence, patients have lost one more rung on their treatment ladder. That scenario is particularly unfortunate and scary for metastatic or advanced cancer patients.

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Some HER2 tyrosine kinase inhibitors are a common cause of diarrhea I see in my practice. These therapies can be used for treating many different cancers, and they can cause diarrhea in the majority of patients. Another example is abemaciclib (Verzenio®; Eli Lilly and Company), a CDK 4/6 inhibitor, which causes diarrhea in about 80 percent of patients.[8]

As the use of targeted therapies increases, so too does the need to better control side effects like diarrhea.

In the past, targeted therapies were used primarily for treating metastatic disease, but they are increasingly being used in curable cancers. In curable cancer, patients don’t receive targeted therapy until after they have undergone chemotherapy and/or radiation. After up to a year of treatment, these patients finally feel like they are going to get their lives back. Unfortunately, when they go on targeted therapy, they may experience terrible diarrhea or other side effects, making it challenging to stay on treatment.

On the other hand, in the metastatic population, clinicians have already set the expectation among patients that they are going to be on treatment for life. In this case, the goal is to balance patients’ needs for good quality of life while also extending their lives. These patients are more willing to put up with side effects, and they know physicians will work with them to help alleviate these problems as much as possible.

Regardless of the individual circumstances while on treatment, it is imperative to control difficult side effects so patients can remain on treatment and have the best chance of fighting their cancer.

New Therapies Needed
Limited options are available for controlling diarrhea. Antidiarrheal use is challenging because patients typically use them after experiencing one or more diarrhea episodes. The available medications also cause constipation. While they may stop diarrhea for a few hours, patients often are constipated and uncomfortable the next day. This scenario begins to feel like a pendulum swinging from diarrhea to constipation and back again. As a result, patients may opt not to take antidiarrheals.

It’s clear that oncologists need new and better tools that target the underlying causes of diarrhea beyond decreasing motility of the gut. The OnTarget Study, for example, is investigating the drug, crofelemer (Mytesi®; Napo Pharmaceuticals), which is currently approved for HIV-related noninfectious diarrhea. Crofelemer targets the underlying mechanism of therapy-related diarrhea by regulating chloride ion channels that produce normal amounts of electrolytes and fluid in the gut and stool. If the OnTarget Study is successful, this drug could be available as a preventive treatment that avoids the rebound constipation associated with current antidiarrheals.

This type of study is an innovative approach to treating a supportive care problem in both early stage patients as well as those with metastatic disease. Supportive care and quality of life focused clinical trials may not at first glance seem as cutting-edge or exciting to oncologists as early phase therapeutics. These new medications do not necessarily hold the promise of extending survival or shrinking someone’s cancer. Still, if clinicians can more effectively control patients’ side effects, helping them to feel better and improve their nutritional status, they are more likely to remain on their cancer treatment and be in better shape to combat their disease. Supportive care studies can be extremely impactful and help us to improve both the quantity and quality of an individual’s life while fighting cancer.

Clinical trials
Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients (HALT-D) – NCT02910219
Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy (OnTARGET) – NCT04538625

Highlights of Prescribing information
Crofelemer (Mytesi®; Napo Pharmaceuticals)(Prescribing Information)
Abemaciclib (Verzenio®; Eli Lilly and Company)(Prescribing Information)

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[2] Eisenstein M. New lung-cancer drugs extend survival times. Nature. 2020 Nov;587(7834):S10-S12. doi: 10.1038/d41586-020-03154-y. PMID: 33208970. [Article].
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[5] Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, McCallum R, Mitchell EP, O’Dorisio TM, Vokes EE, Wadler S. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004 Jul 15;22(14):2918-26. doi: 10.1200/JCO.2004.04.132. PMID: 15254061. [Article]. 
[6] Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. doi: 10.1200/JCO.2017.75.6155. Epub 2017 Oct 2. PMID: 28968163. [Article]. J Clin Oncol. 2017;35(32):3638. Epub 2017 Oct 2.
[7] Van Sebille YZ, Gibson RJ, Wardill HR, Bowen JM. ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis. Cancer Treat Rev. 2015 Jul;41(7):646-52. doi: 10.1016/j.ctrv.2015.05.011. Epub 2015 Jun 6. PMID: 26073491. [Article].
[8] Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010 Jan;2(1):51-63. doi: 10.1177/1758834009355164. PMID: 21789126; PMCID: PMC3126005. [Article]. 

Featured image by Towfiqu Barbhuiya on Unsplash Used with permission.

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