Diarrhea is a frequently overlooked clinical issue that significantly affects the morbidity and mortality of cancer patients. Cancer patients experience diarrhea from a myriad of causes including the cancer itself, medications, antibiotics, infections such as Clostridioides difficile, radiation therapy, or gastrointestinal tract or other cancer surgery. However, the most common causes of diarrhea in cancer patients are due to cancer treatments such as targeted therapy, cytotoxic chemotherapy, and/or immunotherapy.

Cytotoxic therapies can cause epithelial cell damage resulting in loss of absorptive capacity and mucositis, such as in the conditioning regimens for hematopoietic stem cell transplantation. Certain targeted therapy agents such as tyrosine kinase inhibitors induce secretory diarrhea in part due to activation of chloride channels with resulting loss of fluid and electrolyte imbalance. Supportive care measures such as the use of enteral feeding can cause osmotic diarrhea.

Cancer itself, including hormone-producing tumors such as neuroendocrine tumors, will result in diarrhea. Agents targeting vascular endothelial growth factors can cause ischemia and manifest with diarrhea. Certain drugs such as irinotecan can stimulate intestinal motility and cause diarrhea.

Immunotherapy with checkpoint inhibitors, adoptive T cell treatments such as CAR-T or sequelae of hematopoietic stem cell transplantation including graft versus host can cause colitis and immune-mediated diarrhea. Neutropenia along with breaches in intestinal barrier function can facilitate colitis and favor bacterial translocation placing patients at risk for sepsis and/or septic shock.

Impact and Stigma of Diarrhea
In addition to causing dehydration and electrolyte imbalances that in some instances can be life-threatening, cancer therapy-associated diarrhea can affect quality of life, interfere with activities of daily living, and can impact the nutritional state of cancer patients.

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Cancer therapy-related diarrhea or CTD can interfere with cancer treatment and leads to alterations in cancer management in about 60 percent of patients exposed to agents that cause diarrhea. [1] CTD can result in reductions in dosing for 22 percent of patients, delays in dosing by 28 percent of patients and complete termination of treatment in 15 percent of patients, according to two studies. [2][3] Over 30 percent of sufferers say that CTD interferes with their daily activities, [4] as well as the mental and social health of cancer survivors.  Persistent and uncontrollable CID has been linked to anxiety, depression, social isolation, and low self-esteem. [5]

Persistent and severe CTD correlates with significant malnutrition and dehydration resulting in concomitant weight loss and even cachexia, fatigue, renal failure, hemorrhoids, and perianal skin breakdown.[6][7] CTD-related dehydration is linked to early death rates in roughly 5 percent of patients undergoing anti-cancer treatment.[8]

Diarrhea in cancer patients receiving chemotherapy may be underreported. Patients may choose not to report or minimize their diarrhea symptoms because of embarrassment or have to stop or adjust cancer therapy.

Sub-Optimal Agents
There have been no major modifications to our approach to managing diarrhea in cancer patients for decades. In the absence of other options, diarrhea has been accepted as “par for the course.”

Currently available agents, many of which are opioid-based, are sub-optimal in managing diarrhea and may force oncologists to pause cancer treatments or to reduce or discontinue cancer treatments which can compromise response to cancer therapies. In certain cases, diarrhea from CTD toxicity correlates with response to cancer therapy, and patients and their physicians are reluctant to dose adjustments trading cancer response at the expense of toxicities.

Currently, approaches for the management of diarrhea focus on assessing disease severity, co-morbidities, hydration status, presence of neutropenia, bleeding, fever, and abdominal pain. The first approach is to focus on rehydration and dietary modification. Sometimes, hospitalization for IV hydration and electrolyte replacement is required. The mainstay of treatment includes the use of antimotility agents such as loperamide, diphenoxylate-atropine, tincture of opium, or in some instances octreotide.

There have been no new agents approved to either prevent or symptomatically treat diarrhea in decades. Many of the antimotility agents are opiate agonists that act through reduction of gastric motility and cause stool hardening and constipation. Currently available agents have important drawbacks, including:

  • Severe constipation, abdominal distention.
  • In the case of opiates and opiate derivatives, CNS toxicity; and
  • Even after maximal doses, anti-motility agents cannot achieve complete diarrhea control.

Characteristics of Crofelemer
The first plant-based physiologically acting drug approved by the US Food & Drug Administration (FDA), crofelemer (Mytesi®; Napo Pharmaceuticals) is purified from sap of the South American tree Croton lechleri and is known to some as “dragon’s blood.”

Crofelemer reduces chloride secretion into the gut lumen and normalizes the electrolyte and fluid balance in the gut lumen to result in formed stools. A natural non-opioid anti-secretory product with minimal oral absorption, no antimotility activity with central nervous symptom effects, and no significant drug-drug interactions, crofelemer is the only FDA-approved oral botanical drug.

Ongoing Study Open to Patients with Cancer
Crofelemer is currently indicated for use in the U.S. for the symptomatic relief of diarrhea in HIV/AIDS patients receiving antiretroviral therapy (including protease inhibitors). In pre-clinical animal models, crofelemer showed significant efficacy in reducing neratinib-induced diarrhea in beagle dogs within a 4-week period. [9]

As principal investigator, I lead a randomized, double blind, placebo controlled, multicenter phase III study “Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy (OnTARGET)” to evaluate the safety and efficacy of crofelemer for the prevention of diarrhea in cancer patients receiving targeted therapies with and without concomitant standard chemotherapy.

The plan calls for enrolling 256 patients that are receiving targeted therapies associated with a high incidence of diarrhea including tyrosine kinase inhibitors and other kinase inhibitors such as mitogen-activated kinase inhibitors, EGFR inhibitors, and VEGFR inhibitors. Other targeted therapies such as CDK4 and CDK6 inhibitors are also permitted.

The study is designed to have two phases.  In Phase 1 which lasts 12-weeks, participants receive crofelemer or matching placebo; Phase 2 is an elective extension (per the patient choice) to continue on crofelemer or placebo for an additional 12 weeks. Patients will be randomized and started on crofelemer or placebo at the time targeted therapy is initiated. Patients will be assessed for the frequency and severity of diarrhea during study participation as measured by the average number of weekly loose/watery stools between the two treatment arms.

Physicians with patients interested in participating in the ongoing Phase III Study should contact the trial administrator

Choosing to participate in a study is an important personal decision.  Physicians should discuss the study with patients with CTD. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below.  To learn more about this study, you or your doctor may contact the study research staff Lauren Garufis, MA S or Gina B Franklin, RN MSN at (714) 210-6648 or Lauren.Garufis@Integrium.com.  Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04538625


Clinical trial
Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy (OnTARGET) – NCT04538625

Highlights of Prescribing Information
Crofelemer (Mytesi®; Napo Pharmaceuticals) [Prescribing Information]

[1] Verstappen, C. C., Heimans, J. J., Hoekman, K., and Postma, T. J. (2003). Neurotoxic complications of chemotherapy in patients with cancer. Drugs 63, 1549–1563. doi: 10.2165/00003495-200363150-00003
[2] Arbuckle, R., Huber, S., and Zacker, C. (2000). The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist 5, 250–259. doi: 10.1634/theoncologist.5-3-250
[3] Dranitsaris, G., Maroun, J., and Shah, A. (2005). Estimating the cost of illness in colorectal cancer patients who were hospitalized for severe chemotherapyinduced diarrhea. Can. J. Gastroenterol. 19, 83–87. doi: 10.1155/2005/618504
[4] Stein, A., Voigt, W., and Jordan, K. (2010). Review: chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv. Med. Oncol. 2, 51–63. doi: 10.1177/1758834009355164
[5] Viele, C. S. (2003). Overview of chemotherapy-induced diarrhea. Semin. Oncol. Nurs. 19, 2–5. doi: 10.1053/j.soncn.2003.09.007
[6] Mitchell, E. P. (2006). Gastrointestinal toxicity of chemotherapeutic agents. Semin. Oncol. 33, 106–120. doi: 10.1053/j.seminoncol.2005.12.001
[7] Shafi, M. A., and Bresalier, R. S. (2010). The gastrointestinal complications of oncologic therapy. Gastroenterol. Clin. North Am. 39, 629–647. doi: 10.1016/j.gtc.2010.08.004
[8] Rothenberg, M. L., Meropol, N. J., Poplin, E. A., Van Cutsem, E., and Wadler, S. (2001). Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J. Clin. Oncol. 19, 3801–3807.
[9] Michael K. Guy, A. T. (August 2020). Abstract 580: Effects of oral crofelemer on neratinib-induced diarrhea in beagle dogs. Philadelphia: AACR Journals.

Original title: Ongoing Multicenter Phase III Study Evaluating Safety and Efficacy of Crofelemer for the Prevention of Diarrhea Open to Patients with Cancer Receiving Targeted Therapies.

Featured image: Doctor and Patient. Photo courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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