Strategies for more complete relief of CINV in patients with ES-SCLC

Patients with ES-SCLC struggle with shortness of breath, fatigue, chest pain, and nausea and vomiting. The patient-perceived symptom burden of SCLC requires further study, including the impact of chemotherapy-induced nausea and vomiting (CINV).

Scope of CINV

This iatrogenic condition affects as many as 40% of patients. 

“Nausea and vomiting are the most feared, as well as the most common adverse effects among patients undergoing chemotherapy,” write authors in a review article in Cancer Treatment and Research Communications.^[] “Additionally, there are numerous unmet needs, such as optimizing control of non-acute forms of CINV, identifying and managing patients prone to CINV, and increasing adherence to guidelines.”

Prognostic value

A 2023 qualitative study found that nausea with or without vomiting was experienced by all participants with ES-SCLC. CINV was chiefly due to chemotherapy.^[] 

‘‘I had some nausea [when on chemotherapy]. The nausea was very uncomfortable. They gave me medicine for it, but the medicine made me sleepy, so it was a toss-up,” remarked one patient.

CINV bears relevance in terms of clinical outcomes. According to the results of the CASPIAN trial,^[] baseline patient reported outcomes (PROs) had prognostic value. That prognostic value could be associated with different outcomes depending on the symptoms scale. The PROs included five functioning scales, three symptom scales (one of which was N/V), five single-symptom scales, and one financial difficulties item. This study was extremely complex and explored relationships between multiple symptoms—including CINV—and OS/PFS.

Mechanisms

The review article in Cancer Treatment and Research Communications explains the mechanisms underlying CINV. Chemotherapy triggers neurotransmitter receptors in the area postrema of the brain and stimulates vagal afferents near the enterochromaffin cells in the intestine.

The peripheral pathway is stimulated within 24 hours of chemo initiation by the oxidation of free radicals produced by chemotherapeutic agents. These free radicals induce enterochromaffin cells in the GI tract to release serotonin.

Chemotherapy agents can also promote the release of substance P in the central and peripheral nervous systems, thus leading to NK1-mediated vomiting. Research has demonstrated that 5HT3 and NK1 receptor antagonists bolster central NK1 activation in delayed CINV.

Clinical presentation

CINV presents at different times during chemotherapy treatment, as discussed in the review article. Acute CINV occurs within 24 hours of initial administration and is mediated by 5-HT3. Delayed CINV occurs 24 hours to 5 days post-chemo and is mediated by substance P binding to NK1 receptors at the level of the central nervous system.

Anticipatory CINV entails nausea and vomiting occurring before chemo as a conditioned response related to CINV that occurs in previous cycles and is both physiologic and psychologic in nature. Refractory CINV occurs after the failure of prophylactic antiemetic agents during earlier cycles of chemotherapy.

Emetogenic drugs are classified into four levels, characterized by their risk of causing CINV: minimal (<10%); low (10%–30%); moderate (30%–90%); and high (>90%).

Management

CINV is treated with numerous antiemetic agents, with most given prophylactically. The most commonly used agents are 5-HT3 antagonists, corticosteroids, and NK1 receptor antagonists.

5-HT3 receptor antagonists

These drugs are commonly used in acute CINV and include ondansetron, granisetron, dolasetron, and palonosetron. The last agent is also used in delayed CINV. They block the serotonin receptors expressed both peripherally (in the intestine) and centrally (in the area postrema). 

Although usually well-tolerated, these drugs can cause mild adverse effects, including constipation, headache, higher liver enzymes, and QT prolongation.

Corticosteroids

Used for decades for CINV, corticosteroids are the principal treatment for acute and delayed episodes. These drugs are thought to act directly on the nucleus tractus solitarius, while interacting with serotonin and neurokinin receptors that potentiate the effects of other antiemetics.

Long-term use of corticosteroids can result in insomnia, epigastric discomfort, weight gain, hyperglycemia, and agitation.

NK1 receptor antagonists

These drugs act both peripherally and centrally by inhibiting substance P at the NK1 receptor. Examples include aprepitant, fosaprepitant, and rolapitant, which are usually given with a 5-HT3 antagonist and dexamethasone. For delayed CINV, aprepitant can be administered with or without dexamethasone. Common adverse effects include anorexia, fatigue, headache, diarrhea, hiccups, and increased liver enzymes.

Other agents used to treat CINV include olanzapine, dopamine receptor antagonists, benzodiazepines, and cannabinoids. Medications with specific anti-nausea effects include anticholinergics, antihistamines, and olanzapine.

Olanzapine is an atypical antipsychotic that inhibits dopaminergic and serotonergic neurotransmitters and is used for acute, delayed, and breakthrough CINV. This drug is linked to an increased risk of extrapyramidal symptoms, as well as dry mouth, headache, hyperglycemia, and diarrhea.

“Studies have shown it to be effective in treating acute and delayed CINV when combined with a 5-HT3 receptor antagonist and dexamethasone. Other studies have shown it to be comparable to arepitant in treating acute, delayed, and overall CINV. As a result, recent guidelines [eg, NCCN] suggest using olanzapine in combination with a 5-HT3 receptor antagonist and dexamethasone, with or without an NK receptor antagonist. Additionally, olanzapine is effective in treating breakthrough CINV,” state the authors in Cancer Treatment and Research Communications.

Current guidelines

MASCC/ESMO guidelines recommend a 3-drug regimen with NK1 receptor antagonists, 5HT3 RA, and dexamethasone, with olanzapine an option, although with a lower grade of evidence and recommendation.^[]

Results of a 2023 network meta-analysis suggested that four-drug regimens including olanzapine were most effective in terms of complete response. Alternatively, a three-drug regimen with olanzapine could be used if resources were limited.

Complementary treatments

Even after appropriate prophylaxis, many patients experience an incomplete response—here is where alternative or complementary treatments may provide more relief.

Results of a 2023 systematic review and meta-analysis including 38 RCTs (n=2,503) indicated that acupuncture along with the usual care increased the complete control of chemotherapy-induced acute vomiting and delayed vomiting compared with standard care only, "but the certainty of evidence was very low," the authors noted.^[]

Ginger can be used to treat nausea and vomiting without any adverse effects.^[] The active ingredients include gingerol and shogaol. These compounds possess antifever, antivomiting, anticoughing, antipressure, and anti-inflammatory effects. Ginger decreases prostaglandin levels and eases digestive symptoms.

Gingerol and shogaol reduce gastric contractions, while boosting digestive tract activity. These agents also have an antiserotonin effect.

The American Cancer Society provides comprehensive advice on diet modification to reduce nausea and vomiting.^[] Some of these tips include eating bland foods such as dry toast and crackers; avoiding fatty, spicy, fried, or very sweet foods; eating small quantities of high-calorie foods several times a day, such as ice cream, pudding, or yogurt; eating tart or sour foods (except with mouth sores); and increasing caloric intake with butters, oils, sauces, and so on.