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Next steps in treating CINV in patients with ES-SCLC

MDlinx Mar 27, 2024

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.

Gupta K, Walton R, Kataria SP. Chemotherapy-induced nausea and vomiting: pathogenesis, recommendations, and new trends. Cancer Treat Res Commun. 2021;26:100278.

“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.”



Oncologists should preemptively target the symptoms of CINV and adhere to guidelines when addressing the condition. But even with appropriate prophylaxis, more needs to be done. Complementary therapies may play an important role in eliciting a (more) complete response.


Complementary treatments


A look at alternative and complementary treatments for CINV in patients with ES-SCLC, its mechanisms, and a review of conventional management may benefit oncologists and pulmonologists treating patients and provide a robust picture of this debilitating adverse effect.

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.

Yan Y, López-Alcalde J, Zhang L, et al. Acupuncture for the prevention of chemotherapy-induced nausea and vomiting in cancer patients: A systematic review and meta-analysis. Cancer Med. 2023 Jun;12(11):12504-12517. doi: 10.1002/cam4.5962.



Well‐designed RCTs with larger sample sizes, standardized treatment regimens, and core outcome measures are needed.

Ginger can be used to treat nausea and vomiting without any adverse effects.

Sheikhi MA, Ebadi A, Talaeizadeh A, et al. Alternative methods to treat nausea and vomiting from cancer chemotherapy. Chemother Res Pract. 2015;2015:818759.

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.

They also demonstrate major effects on free radicals that trigger nausea. Research findings from one study indicated that ginger may be more effective at reducing CINV than metoclopramide. Ginger may also be effective at reducing CINV during the delayed phase.

The American Cancer Society provides comprehensive advice on diet modification to reduce nausea and vomiting.

Managing nausea and vomiting at home. American Cancer Society. September 10, 2020.

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.



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.

Bebb DG, Murray C, Giannopoulou A, et al. Symptoms and experiences with small cell lung cancer: a mixed methods study of patients and caregivers. Pulm Ther. 2023;9(3):435–450.



‘‘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,

Ganti AK, Johal S, Jackson D, et al. The prognostic value of patient reported outcomes (PROs) and clinical/demographic variables in the CASPIAN study [Abstract 8516]. J Clin Oncol. 2023;41(16 suppl).

baseline 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.





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.

Serotonin stimulates abdominal afferent vagal fibers that constitute the peripheral emesis pathway and stimulates the emetic response by means of the vomiting center. Acute CINV is related to the activation of the peripheral pathway. 

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%).

For instance, traditional therapy for SCLC, to which more than 50% of patients respond,

Oronsky B, Abrouk N, Caroen S, et al. A 2022 update on extensive stage small-cell lung cancer (SCLC). J Cancer. 2022;13(9):2945–2953.

involves etoposide, which is a low-level emetogenic drug, and cisplatin or carboplatin, which are both highly emetogenic. 





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.


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.


Importantly, aprepitant can interfere with drugs metabolized by CYP3A4 or CYP2C9, including chemo agents like cyclophosphamide, etoposide, paclitaxel, and tamoxifen, as well as dexamethasone. Thus, dose adjustments may be necessary.

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


NCCN/ASCO guidance overlap in the recommendation for a 3-drug regimen (ie, NK1 receptor antagonists, 5HT3 RA, and dexamethasone regimen with or without olanzapine) for managing highly emetogenic CINV.

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.

Filetti M, Lombardi P, Giusti R, et al. Efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: a systematic review and network meta-analysis. Cancer Treat Rev. 2023;115:102512.


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.


What this means for you

The management of CINV in the context of ES-SCLC and other advanced cancers is challenging. Complete response likely requires multiple agents, including olanzapine, according to research and guidelines, as well as the incorporation of complementary treatments. Effective treatment of CINV should not be underestimated, as it has a significant impact on quality of life and clinical outcomes.


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