Why does chemotherapy cause diarrhea?

Chemotherapy damages rapidly dividing cells. Cancer cells tend to divide rapidly and uncontrollably. However, some healthy cells also divide rapidly, such as those that line the interior of the digestive tract. Chemotherapy also damages these cells, leading to a disruption in the delicate fluid balance that they maintain. Specifically, absorption of fluid from the gastrointestinal (GI) tract back into the body is decreased and secretion of fluid and electrolytes in the stool is increased. This causes watery bowel movements, the definition of diarrhea.

Why is it important to manage diarrhea?

Diarrhea is not only an inconvenient side effect of cancer treatment, but also can be life-threatening if not adequately managed. It may lead to dehydration; electrolyte imbalance; low immune function; malnutrition due to reduced absorption of nutrients; and inflammation, pain and/or bleeding as a result of the increased frequency of bowel movements.

At its extreme, diarrhea can cause the critical electrolytes sodium and potassium to reach dangerously low levels, which are conditions known as hyponatremia and hypokalemia, respectively. The body continually regulates sodium in order to maintain levels within a narrow range. Diarrhea can disrupt this delicate balance by excreting too much sodium in the stool. Symptoms of mild low sodium levels include tiredness, disorientation, headache, muscle cramps and nausea. Severely low sodium levels can lead to seizures or coma. Severely low levels of potassium can cause abnormal heart function.

Diarrhea can be severe enough that you are unable to tolerate your prescribed chemotherapy treatments. Commonly, chemotherapy treatments are delayed if diarrhea persists. A disruption or delay in treatment may diminish the effect of treatment.

How is the severity of chemotherapy induced diarrhea rated?

The severity of diarrhea is determined by the number of bowel movements experienced per day above baseline (see table 1). Baseline is the number and quality of bowel movements that you have under normal circumstances. However, individual baseline activity may vary depending on your condition. For example, you may normally have multiple bowel movements per day if you have had abdominal or pelvic surgery, have cancer that has spread to the abdominal or pelvic area, or have other gastrointestinal conditions. And your movements may be soft, semiformed or even liquid. For this reason, an increase to six loose stools per day that is considered moderate in severity for one patient may be only mild for another.

Table 1 National Cancer Institute Common Toxicity Criteria for Diarrhea

Grade 1

Increase of less than 4 stools/day over baseline

Grade 2

Increase of 4-6 stools/day over baseline

Grade 3

Increase of greater than 7 stools/day over baseline, incontinence

Grade 4

Life-threatening consequences including extremely low blood pressure as a result of severe dehydration

Grade 5

Death

What makes diarrhea worse?

Some factors may make chemotherapy-related diarrhea worse. For example, damage to the intestines as a result of surgery or radiation may make the GI system more susceptible to irritation. Other medications, such as antibiotics, diabetes, irritable bowel syndrome, reduced pancreas function or other conditions, may also worsen diarrhea. If you have certain biochemical characteristics, you may be more sensitive to chemotherapy drugs.

Sensitivity to 5-FU: Some individuals are more sensitive to 5-FU because they have significantly less of the enzyme that breaks down this drug. These individuals experience more side effects from treatment with 5-FU including diarrhea, low white blood cell count and mouth sores.

Sensitivity to irinotecan: Some individuals are more sensitive to the drug irinotecan due to a genetic disorder called Gilbert’s Syndrome that limits their ability to remove the drug from their body. This syndrome is difficult to detect before administration of irinotecan. If you experience severe side effects after your first dose of irinotecan, Gilbert’s syndrome may be the cause. Irinotecan should be either discontinued or the doses should be substantially reduced if Gilbert’s syndrome is suspected.

Another cause of sensitivity to irinotecan is obstruction of the vessel that delivers bile from the gall bladder to the intestines, called biliary obstruction. As with Gilbert’s syndrome, biliary obstruction leads to a substantial increase in diarrhea and other side effects. Treatment with irinotecan is not recommended if you have this disorder.

How is diarrhea managed?

Diet: Several modifications to diet will help reduce the discomfort of diarrhea. Foods that irritate the GI system should be avoided, such as greasy, spicy or fried foods. You should also avoid milk and milk products because diarrhea may lead to a loss of the enzyme lactase which breaks down lactose, the sugar found in milk, resulting in temporary lactose-intolerance. Because of their high fiber content, vegetables tend to be difficult to digest and should be avoided during episodes of diarrhea. Cruciferous vegetables, such as cabbage, brussel sprouts and broccoli, can be particularly problematic.

Your diet should be limited to simple, easy to digest foods, then expanded as the diarrhea begins to subside. A diet consisting of bananas, rice, applesauce, toast (called the BRAT diet) and clear liquid is a good starting point. Eventually, pasta without sauce, white-meat chicken without skin, scrambled eggs and other easily digested foods can be added, as tolerated.

Fluid intake: Staying hydrated is very important in the management of diarrhea. You must consume enough clear liquids to make up for the volume of fluids lost due to the diarrhea. This amount is in addition to the usual daily intake. You may need to take in 3-4 liters or more of fluid per day. In addition to plain water, you should include fluids that contain some sugar and salt, such as broth or GatoradeÒ. Replacement of fluids with plain water alone can lead to low levels of salt or calcium in the blood. These can be life-threatening conditions.

Drug therapy: The first drug to be prescribed for chemotherapy-related diarrhea is usually loperamide (Imodium® or others). Loperamide slows the gastrointestinal system and reduced the amount of fluid lost in the stool. Loperamide is effective for managing mild to moderate diarrhea, though it may not work for severe diarrhea. It is an over-the-counter medication that is inexpensive and is available as a pill.

Which chemotherapy drugs cause diarrhea?

Some chemotherapy drugs are more prone to cause diarrhea. Diarrhea is particularly problematic for some drugs which are central to the management of colorectal cancer and cancers of the gastrointestinal tract, including the fluoropyrimidines (5-FU) and irinotecan (CPT-11, Camptosar®). Drugs used to treat other cancers may also cause diarrhea, although to a lesser degree.

The cancer treatments that have been reported to cause diarrhea in 30% or more of patients are:

  • Actinomycin (Cosmegen®)
  • Altretamine (Hexalen®)
  • Arsenic trioxide (Trisenox®)
  • Bortezomib (Velcade™)
  • Busulfan (Myleran®, Busulfex®)
  • Capecitabine (Xeloda®)
  • Docetaxel (Taxotere®)
  • Floxuridine (FUDR®)
  • Flutamide (Eulexin®)
  • Fulvestrant (Faslodex®)
  • Gefitinib (Iressa®)
  • Gemtuzumab ozogamicin (Mylotarg®)
  • Idarubicin (Idamycin®, Idamycin PFS®)
  • Imatinib mesylate (Gleevac®, Glivec®)
  • Interleukin-2 (Proleukin®)
  • Irinotecan (Camptosar®)
  • Liposomal daunorubicin (DaunoXome®)
  • Mitotane (Lysodren®)
  • Oprevelkin (Neumega®)
  • Paclitaxel (Taxol®, Onxal™)
  • Pemetrexed (Alimta®)
  • Plicamycin (Mithracin®)
  • Sagramostim (GM-CSF, Leukine®)
  • Teniposide (Vumon®)

The cancer treatments that have been reported to cause diarrhea in 10-29% of patients are:

  • Abarelix (Plenaxis®)
  • Carboplatin (Paraplatin®)
  • Celocoxib (Celebrex®)
  • Cyclophosphamide (Cytoxan®, Neosar®)
  • Darbepoetin alpha (Aranesp®)
  • Daunorubicin (Cerubidine®)
  • Denileukin diftitox (Ontak®)
  • Epirubicin (Ellence®)
  • Estramustine (Emcyt®)
  • Etoposide (VePesid®, Toposar®, Etopophos®)
  • Fludarabine (Fludara®)
  • Gemcitabine (Gemzar®)
  • Hydroxyurea (Hydrea®)
  • Ibritumomab (Zevalin®)
  • Interferon alpha (Intron®, Roferon-A®)
  • Liposomal doxorubicin (Doxil®)
  • Mechlorethamine (Mustargen®)
  • Melphalan (Alkeran®)
  • Methotrexate (Rheumatrex®, Trexall™)
  • Mitomycin (Mutamycin®)
  • Mitoxantrone (Novantrone®)
  • Oxaliplatin (Eloxatin®)
  • Pentostatin (Nipent®)
  • Procarbazine (Matulane®)
  • Rasburicase (Elitek®)
  • Streptozocin (Zanosar®)
  • Thalidomide (Thalomid®)
  • Topotecan (Hycamtin®)
  • Tositumomab and iodine 131 (Bexxar®)
  • Vinblastine (Velban®, Alkaban-AQ®)
  • Vincristine (Oncovin®, Vincasar PFS®)
  • Vinorelbine (Navelbine®)