Diarrhoea, chemotherapy-induced

Various side effects can occur during chemotherapy. One of these is chemotherapy-induced diarrhea, which is treated with supportive measures (Guidelines Program Oncology 2020).

Chemotherapy-induced diarrhea (CID) is divided into different degrees of severity according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE):

- Grade 0: no diarrhea

- Grade 1: mild diarrhea < 4 stools/d above baseline

- Grade 2: moderate diarrhea 4 - 6 stools / d above baseline

- Grade 3: severe diarrhea ≥ 7 stools / d above baseline

- Grade 4: life-threatening diarrhea (Leithold 2016).

- Grade 5: death (any fatal complication from CID [Manski 2019]).

- Irinotecan

In treatment with the cytostatic drug irinotecan, one differentiates between 2 forms of diarrhea:

- Early diarrhea:

This occurs within the first 24 h after administration as a cholinergic syndrome.

- Late diarrhea:

The so-called late diarrhea occurs at the earliest > 24 h or later. Here, direct damage to the intestinal mucosa is found due to the toxic irinotecan metabolite 7- ethyl- 10- hydroxycamtothecin (SN-38) (Leithold 2016).

Chemotherapy-induced diarrhea is a common side effect of cytostatic drugs. The incidence depends on the type and dosage of the respective cytostatic drug and can be potentiated with combination drugs(Leithold 2016).

A CID grade 3 - 4 (see "Classification"), for example, occurs in 10 - 20% of patients (Ghidina 2021), under therapy with CapeIRI even in up to 47% (Guidelines Program Oncology 2020).

With target therapeutics, the incidence of all severity grades and especially severity grades 3 - 4 is even significantly higher (Leithold 2016).

Risk factors are:

- elderly patients (Schuler 2017)

- underweight patients with a body mass index < 18 kg / m³.

- 5% weight loss in the last 3 months

- simultaneous radiotherapy in the abdominal or pelvic area

- history of intestinal dysfunction such as irritable bowel syndrome, inflammatory bowel disease, lactose intolerance, bile acid malabsorption, celiac disease

- previous intestinal surgery with subsequent intestinal dysfunction

- stoma

- reduced performance status (Oncology 2020 guideline program)

Diarrhea occurs particularly after chemotherapeutic treatment with:

- Antimetabolites such as 5- fluorouracil, methotrexate.

- Anthracyclines such as doxorubicin

- Topoisomerase I inhibitors such as irinotecan (Retz 2010).

- Target therapeutics such as sunitinib, sorafenib, temsirolimus, and bevacizumab.

Severe diarrhea can result from treatment with 5FU infusions and/or irinotecan in particular (Kasper 2015).

The pathophysiology of CID has not been fully elucidated. Structural changes of the intestinal mucosa with inflammatory ulcerations and atrophy of the epithelium including vascular damage as well as functional restrictions of intestinal activity with increased intestinal mobility, reduced immune function, changes of the natural intestinal flora and an altered metabolism of bilirubin, cholesterol, fatty acids, bile acids, mucins, pancreatic enzymes and steroid hormones have been described (Leithold 2016).

The pathogenesis of acute-onset diarrhea with irinotecan is different. However, it is not well understood to date according to Keefe and Anthony 2008 (Guidelines Program Oncology 2020)

CIDs may occur immediately after infusion or may be delayed up to 48-72 h (Kasper 2015).

• Frequent discharge of thin stools with increased stool volume (> 500 g / d
• blood and / or mucus discharges
• colic in the abdominal region
• reduced quality of life
• fatigue (Leithold 2016)
• nocturnal diarrhea (see .a.)
• fever
• Nausea
• vomiting
• Cholinergic syndrome during irinotecan i. v. therapy occurs in 9% of patients and manifests as:
  • increased sweating
  • abdominal cramps
  • vomiting
  • watery diarrhea
  • bradycardia (Oncology 2020 Guideline Program)

Generally, in diarrhea - without previous chemotherapy - pathogens are found in only about 1.5 - 5 % of cases. Under chemotherapy, the number is probably even lower. Since there is some immune weakness under cytostasis, standard stool cultures should still be examined for:

- Campylobacter

- Salmonella

- shigella

- Yersinia

In particularly severe cases, testing should also be done for facultative enteropathogenic pathogens such as.

- Pseudomonas spp.

- Aeromonas spp.

- toxin-producing Clostridium perfringens, Staphylococcus aureus or Klebsiella oxytoca strains .

In the case of bloody diarrhea also for

- EHEC

- and in particular Clostridium difficile (culture plus toxin detection).

In severely immunosuppressed patients, the examination should also include the following viruses:

- Adenoviruses

- astroviruses

- noroviruses

- Rotaviruses (Guidelines Program Oncology 2020).

Abdominal sonography

Here, thickening of the intestinal wall, infectious foci, etc. may be detectable (Guidelines Program Oncology 2020).

Computed tomography

CT may be required for clinical signsof peritoneal irritation, such as guarding tension and release pain, to detect complications early (Oncology 2020 guideline program).

Endoscopy

Endoscopic examinations are recommended only when symptoms persist and increase (Guideline Program Oncology 2020).

Under CID, the following laboratory chemical changes may occur:

- electrolyte imbalance

- neutropenia

- hypovolemia

If fever occurs, blood cultures should also be examined (Oncology 2020 guideline program).

Differential diagnostic investigations are indicated only if the patient shows the following symptoms:

- particularly severe and persistent diarrhea

- steatorrhea

- fever

- blood inclusions

- neutropenia

- history of diarrhea of other origin

- additional occurrence of other symptoms that cannot be explained unconstrained by chemotherapy (Guideline Program Oncology 2020)

• paralytic ileus
• toxic deaths due to
  • Loss of bicarbonate
  • Dehydration
  • hypokalemia
  • metabolic acidosis
  • septic-related generalized metabolic derailment (Caspary 1999)
• perforation of the intestinal wall
• enterocolitis (guideline program oncology 2020)

Before the start of chemotherapy, the patient's bowel habits should be specifically queried to establish the baseline (Guidelines Program Oncology 2020).

Mild cases of chemotherapy-induced diarrhea can usually be treated as outpatients (Schuler 2017). Severe cases, on the other hand, should usually be treated as inpatients (Herold 2022). A balanced fluid and electrolyte supply is important, which may require i.v. infusions (Kasper 2015).

Medication can be used:

- Loperamide:

Loperamide represents the first therapeutic option for diarrhea of severity 1 - 2 (Leithold 2016).

Dosage recommendation: The patient should receive 4 mg after the first occurrence of diarrhea, and 2 mg every 2 h thereafter. However, the total daily dose of 16 mg should not be exceeded. When no loose stool has occurred for more than 12 h, loperamide can be discontinued (Kasper 2015). Patients should be advised that this dosage exceeds the dose according to the professional information (Guidelines Program Oncology 2020).

- Somatostatin analog:

If the patient does not respond to loperamide (Leithold 2016) or if a severe course of grade 3 or higher is present (Guidelines Program Oncology 2020), a somatostatin analogue such as octreotide should be given (alternatively). However, an evidence-based recommendation is not possible, as the study situation is inconsistent so far (Guideline Program Oncology 2020).

Dosage recommendation: The dose is 100 - 150 mcg (Kasper 2015).

- Tinctura opii:

Alternatively, preparations containing opiates can be used (Kasper 2015).

Dosage recommendation: Tinctura opii 0.6 - 1.2 ml orally up to 3 x / d (Guidelines Program Oncology 2020).

- Anticholinergic agents:

Cholinergic diarrhea occurring early during treatment with irinotecan responds best to anticholinergic agents such as atropine s. c. (Herold 2022). In the absence of randomized therapeutic trials, therapy with atropine is not recommended according to the Oncology Guidelines Program (2020).

- Antibiotics:

Antibiotics should be prescribed only if there is evidence of an appropriate pathogen (Oncology Guidelines Program 2020).

- Therapy of refractory CID:

To date, no randomized therapeutic intervention trials exist. Benson, Ajani et al. published a pragmatic algorithm in 2004, which is still the current expert consensus.

If the diarrhea does not resolve with the above treatment, salvage therapy should be used. In addition to electrolyte and fluid balance, this includes the following medications:

- Octreotide (off-label use):

Octreotide is an active substance from the group of somatostatin analogues (Wehling 2005).

Dosage recommendation: 3 x / d 100 - 150 mcg s. c.

Dosage escalation 3 x / d 500 mcg s. c. (Guideline Program Oncology 2020)

- Codeine (Off- Label- Use):

Dosage recommendation: Up to 4 x / d 15 - 60 mg (Guidelines Program Oncology 2020).

- Budesonide (Off- Label- Use):

This is a topical steroid (Vetter 2001).

Dosage recommendation: 1 x / d 9 mg (Guideline Program Oncology 2020).

- Racecadotril:

This is an enkephalinase inhibitor (WHO 2007).

Dosage recommendation: 3 x / d 100 mg (Guidelines Program Oncology 2020)

- Oral aminoglycoside (off-label use):

This includes paromomycin (Adam 2009).

Dosage recommendation: 500 mg p. o. 3 x / d (Caspary 2006).

- Tinctura opii:

Opiate-containing preparations can also be used (Kasper 2015).

Dosage recommendation: Tinctura opii 0.6 - 1.2 ml orally up to 3 x / d (Guidelines Program Oncology 2020).

CID can be severe or life-threatening in up to 50% of cases, particularly in patients with colorectal carcinoma and concurrent radiotherapy.

If left untreated, severe fluid and electrolyte loss with dehydration and malnutrition can occur, increasing overall morbidity and mortality in malignancies (Leithold 2016).

The patient should be advised of the possibility of chemotherapy-induced diarrhea before chemotherapy is started so that appropriate action can be taken early (Schuler 2017).

Prevention:

To date, no substance is known that can be unreservedly recommended as a preventive measure to avoid chemotherapy-induced diarrhea. Only in immunosuppressed patients the use of pro- or synbiotics has been shown to be beneficial (Leithold 2016 / (Guidelines Program Oncology 2020):

In a study from 2021 by Ghidini, a one-month treatment with probiotics is recommended before the start of chemotherapy, which should then be continued under chemotherapy. This showed a reduction in the incidence of severe grade 3 or 4 diarrhea (0% with probiotics vs. 17.4% with placebo, p = 0.11). There was also a reduction in the incidence of overall diarrhea (39.1% with probiotics versus 60.9% with placebo, p = 0.24). Additionally, there was likewise a reduction in the incidence of enterocolitis (0% with probiotics vs. 8.7% with placebo).

Nevertheless, the use of probiotics cannot be pronounced unequivocally, as studies were heterogeneous, used different bacterial strains and bacterial doses, and the incidence of diarrhea varied depending on the additional use of surgery, CT, RT, or a combination thereof (Ghidini 2021).

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