Diarrhea Caused by Cancer Itself or Its Treatments – What Causes It and How Is It Treated?

Cancer and its treatments can cause diarrhea of varying severity. Careful assessment is needed to determine the most effective treatment for a patient. Both pharmacological (medication-based) and nonpharmacological steps are generally necessary to treat acute (sudden-onset) diarrhea, and some nonpharmacological measures are used in clinical practice to manage subacute (delayed-onset) diarrhea. Repeated or large-volume fluid losses are important in patients with diarrhea. Increasing clear fluid intake is generally sufficient to manage diarrhea, but some patients may need intermittent intravenous fluids and electrolytes or further investigations.

The table below describes the steps for assessing and treating patients with diarrhea:

Chemotherapy-induced diarrhea

Why does chemotherapy-induced diarrhea occur, and how common is it?

Chemotherapy can irritate the intestinal lining or damage the villous cells of the intestinal mucosa, causing diarrhea. Its frequency and severity depend on many factors, including the treatment regimen and drug doses. Among the chemotherapies that generally increase diarrhea risk, the best known is 5-FU. Diarrhea is also common with other chemotherapy drugs such as irinotecan and topotecan. After irinotecan, diarrhea may occur immediately or later develop into a severe, potentially life-threatening condition. High blood levels of SN38, a metabolite (breakdown product) of irinotecan, have been associated with delayed-onset diarrhea . Metastatic colon cancer patients’ frequency of diarrhea associated with these two drugs is shown in the table below .

However, patients who have previously received antibiotics or cisplatin -based chemotherapy may develop Clostridium difficile diarrhea, a particularly difficult condition, and patients with neutropenia are at risk of typhoid.

Targeted drug therapies and diarrhea

Diarrhea is a common side effect of most new-generation targeted drugs directed at genetic changes. EGFR-targeting small-molecule oral drugs erlotinib (Tarceva), gefitinib (Iressa) or afatinib (Gilotrif) have been associated with diarrhea in up to 90% of patients, but only 15% of cases are severe.

Two other EGFR-targeted drugs, cetuximab and panitumumab, which are intravenously administered monoclonal antibodies, have been associated with diarrhea in around 20% of patients, but severe diarrhea occurs in 3% or fewer.

By inhibiting the vascular endothelial growth factor (VEGF) pathway, drugs that prevent new blood vessel formation taken as tablets [sorafenib (Nexavar), sunitinib (Sutent), axitinib (Inlyta), regorafenib (Stivarga), pazopanib (Votrient), cabozantinib (Cometriq), lenvatinib (Lenvima), vandetanib (Caprelsa)], and the intravenously administered VEGF-targeted drug bevacizumab (Altuzan), have been associated with diarrhea rates of 30-80%. However, only 3-17% was reported as grade 3 or 4.

In breast cancer, drugs targeting HER2, lapatinib (Tykerb) and pertuzumab (Perjeta), are both known to cause diarrhea.

Both mTOR pathway inhibitors used in advanced kidney and breast cancer [everolimus (Afinitor) and temsirolimus (Torisel)] have been reported to cause diarrhea, although less often than other targeted drugs. BRAF mutation -positive patients receiving the MEK pathway inhibitors trametinib (Mekinist) and cobimetinib (Cotellic) develop severe diarrhea in fewer than 5% of cases.

The new-generation immunotherapies known as checkpoint inhibitors are an exciting group of drugs that activate the immune system against cancer. They are effective in some cancer types and have a markedly different side effect profile. Among these agents, diarrhea has been reported in 30% with ipilimumab (Yervoy), with 10% having severe diarrhea. PD-1-targeted immunotherapies have caused less diarrhea, at 1-3%.

Treatment of diarrhea associated with chemotherapy, targeted drugs and immunotherapy

To treat diarrhea, antimotility drugs (which slow bowel movements), such as loperamide, are generally used until symptoms lessen. The approach to immunotherapy-triggered diarrhea differs from that for other types of diarrhea, and corticosteroids (cortisone) are used in most cases. Drugs that slow bowel movements, such as loperamide (Lopermid), are not used for immunotherapy-associated diarrhea because they may mask the underlying cause. What needs to be treated here is the activity of immune cells directed against healthy intestinal cells: these cells must be calmed (suppressing the autoimmune reaction). In severe cases, intravenous high-dose corticosteroids are recommended; in resistant cases, the anti-TNF antibody infliximab is used.

As soon as your stools begin to soften after chemotherapy (such as irinotecan), you should take 2 Lopermid tablets and continue taking 2 after each episode of diarrhea. If, despite Lopermid, your diarrhea episodes in 24 hours exceed 4, inform your doctor or oncology nurse or go to the emergency department.

Atropine may be used to prevent or treat acute-onset irinotecan diarrhea. Antidiarrheal drugs should not be used for diarrhea caused by infection. Octreotide (Sandostatin) is also effective and generally well tolerated, but expensive.

A randomized, double-blind clinical trial was conducted in patients receiving cisplatin. All patients in the study had developed diarrhea as a result of cisplatin treatment; they were randomly divided into two groups to receive octreotide or placebo . Diarrhea was defined as more than two loose bowel movements per day. Diarrhea persisted in 75% of placebo recipients but in only 5% of octreotide recipients, and side effects were minimal. These findings suggest that octreotide is beneficial for cisplatin-induced diarrhea.

Chemotherapy-induced diarrhea can be managed using the following treatment algorithm:

Radiation-associated diarrhea

Diarrhea is the most common side effect of radiotherapy (radiation treatment) to the groin and lower abdomen. This treatment damages the mucosa (inner lining) of the small and large intestines and may cause diarrhea through excessive fluid movement into the intestinal lumen. Its frequency and severity increase when radiotherapy is supplemented with 5-FU.

Treatment of radiation-associated diarrhea

Octreotide can be used to treat diarrhea caused by pelvic (groin region) radiation therapy. Other agents tried—olsalazine, sulfasalazine, cholestyramine, sucralfate and glutamine—have not provided a significant benefit in treating radiotherapy-induced diarrhea.

Diarrhea caused by cancer itself

Sometimes cancer itself, rather than its treatment, can cause diarrhea. For example, in pancreatic cancer, insufficient production of digestive enzymes can lead to diarrhea. Patients whose stools become more foul-smelling may be given pancreatic enzymes as tablets. Various pancreatic enzyme medications contain lipase, protease and amylase.

Medullary thyroid cancer can cause diarrhea due to excessive production of calcitonin and prostaglandins. In this situation, octreotide is usually the best option to control diarrhea; cyproheptadine may also help.

Conclusion / Summary

• The chemotherapy drugs 5-FU, irinotecan and topotecan generally cause diarrhea. Irinotecan causes two types: early-onset and delayed-onset diarrhea. Delayed-onset irinotecan-induced diarrhea can sometimes become severe.
• Diarrhea is common with most targeted drugs.
• Although diarrhea is not common with checkpoint inhibitor immunotherapies, it can become severe and requires a different treatment approach.
• Radiotherapy to the lower abdomen may cause diarrhea in a substantial number of patients.
• Lopermid should be prescribed to all patients expected to develop chemotherapy-induced diarrhea. Octreotide (Sandostatin) may be useful for chemotherapy-associated diarrhea that Lopermid cannot control. Octreotide may also be useful for radiation-induced diarrhea.
• Pancreatic enzyme replacement may be beneficial for diarrhea associated with pancreatic insufficiency.