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For oncologists, it is almost reflexive to order pre-medications for patients undergoing chemotherapy based on templates that often incorporate steroids like dexamethasone for chemotherapy-induced nausea and vomiting (CINV) prophylaxis, especially for highly emetogenic regimens. Indeed, dexamethasone was initially incorporated in treatment paradigms and clinical trials prior to the routine incorporation of modern antiemetics such as NK-1 antagonists, 5-HT3 antagonists, and olanzapine.

Dexamethasone can prevent CINV in both an acute and delayed manner when given before, during, and after chemotherapy. It also attenuates fluid retention in regimens incorporating docetaxel. However, cumulative doses over the course of a cancer journey can also lead to numerous side effects, including hyperglycemia, osteoporosis, immunosuppression and infection, poor wound healing, adrenal suppression, weight gain, insomnia, psychosis or anxiety, gastritis, skin changes, and high blood pressure amongst others.

It is also thought that high doses of dexamethasone could interfere with and annul the maximal effect of checkpoint inhibitors, which are often incorporated into chemotherapy regimens in modern cancer therapy.

Lastly, for patients with underlying medical issues such as hypertension, diabetes, or other conditions that compromise their immune system, the addition of dexamethasone can lead to significant morbidity leading up to hospitalization, which can interfere with the delivery of effective and tolerable chemotherapy and ultimately the optimal control of the underlying malignancy.

Systematic evaluation of removing routine dexamethasone prophylaxis had not been studied in a large trial until the Cancer Institute (WIA -- Women's Indian Association) group from Chennai, India, led by Venkatraman Radhakrishnan, recently reported the results of their in JCO Global Oncology.

In this randomized controlled, double-blinded clinical study, adult patients undergoing their first cycle of highly emetogenic chemotherapy were given either a non-dexamethasone antiemetic regimen incorporating olanzapine, palonosetron, and fosaprepitant (OPF) as compared with a dexamethasone-containing regimen with olanzapine and palonosetron (OPD). Powered for non-inferiority, the study's outcomes included the nausea and vomiting "complete response (CR) rate" from the onset of treatment until 5 days later, as well as certain patient-reported measures and toxicities.

Ultimately, 346 patients were evaluated in this trial and equally divided between the treatment arms. A vast majority of patients had breast cancer treated with doxorubicin and cyclophosphamide, followed by use of cisplatin, mainly in head and neck cancers, with a significant proportion receiving concurrent radiation.

Overall, there was a nearly 80% overall CR rate of the primary outcome, vomiting, with the OPF regimen compared with 48% with OPD. In the acute and delayed settings, it was 95% versus 85%, and 82% versus 51%, respectively.

Nausea as an outcome was better controlled in the overall and delayed periods in the OPF group, but not in the acute period compared with OPD. Rescue antiemetics were also required less frequently in the OPF group (8%) compared with the OPD group (24%).

Subgroup analysis favored OPF in numerous categories including sex, chemotherapy agent and setting, age, use of radiotherapy, smoking status, and ECOG 0-1 status. There was no difference in mortality, hospital stays, or febrile neutropenia between the groups.

As expected, patients in the OPD group had higher levels of insomnia and vomiting during days 1-4. However, fatigue and drowsiness were worse in the OPF group compared with the OPD group in the acute period. Global quality-of-life scores decreased in both arms from baseline, but was not statistically significant between them.

In summary, this trial met its non-inferiority endpoint and possibly even showed superiority of a non-dexamethasone antiemetic regimen (OPF) incorporating olanzapine, palonosetron, and fosaprepitant. This helped to demonstrate the modest effects at best of dexamethasone-based antiemetic regimens in this setting. It could be theorized that leveraging the combinatorial mechanism of action of NK-1, 5-HT3, and olanzapine effects could potentially contribute to this outcome.

In any case, there were several biases in this study, including the focus on the first cycle of treatment, exclusion of patients with immunotherapy, oncolytics, prior chemotherapy exposure or multi-day regimens, and enrichment of patients with breast cancers and head and neck cancers receiving concurrent radiation, along with specific regimens and toxicities exclusive to these settings.

Also, the trial was conducted at a single center in India with presumably a homogeneous racial background in patients mostly under age 60, making it difficult to apply the results globally. The outcomes related to questionnaires and patient-reported symptoms, such as nausea, could also have introduced some subjectivity.

Moreover, the study design allowed both groups to have olanzapine on days 2 to 4, at a relatively modest dose of 5 mg orally, which could confound the results. Though this study found no early complication rate between the groups, a significant divergence of mortality, hospital stays, or febrile neutropenia could potentially develop with further cycles, especially with longer durations of steroids in a dexamethasone-containing antiemetic regimen. However, it could also be argued that close monitoring can be commonly and easily accomplished in the modern era with the use of nurse navigators and primary care physician support, thereby ensuring that the most immediately noticeable effects of high-dose steroids such as hyperglycemia and hypertension could be recognized early and treated effectively with a team-based approach.

The fundamental design of the study, with chemotherapy-naïve patients being evaluated only for the first 5 days on the first cycle of treatment, makes it challenging to determine whether later patient adaptation, education, and experience alone could have potentially improved the symptoms of nausea and vomiting, as is common in clinical practice when patients become "used to" or even empowered with regards to their particular treatment plan, including not only the logistics and modifications, but also patients' own expectations, anxiety, and self-belief.

We also cannot be sure which of the antiemetic agents, or which ideal combination, provided the most "bang for the buck." Moreover, in the dexamethasone-containing regimen (OPD), not only was the dexamethasone given exclusively on day 1 of therapy, but it was also administered intravenously once at a fixed dose of 12 mg prior to chemotherapy.

In contrast, in clinical practice, we know that oral dexamethasone is one of the most common, available, and cost-effective strategies, especially in resource-limited settings, at doses up to 20 mg including regimens designed for BID dosing on day minus one through 3 days post-infusion of chemotherapy.

Nevertheless, despite the limitations above, this study provides important findings while appearing to be the first of its kind to evaluate non-dexamethasone based antiemetic regimens for CINV prophylaxis.

This topic certainly merits further investigation, including the evaluation of comparator arms consisting of standard oral dexamethasone strategies employed in routine clinical practice globally, pre- and post-chemotherapy, with and without other oral antiemetic agents including olanzapine, especially in resource-limited settings where next-generation oral and intravenous antiemetic agents could be lacking.

Future studies should also be conducted to evaluate dexamethasone-free strategies in a wide variety of malignancies, varying geographical and socioeconomic settings, and chemotherapy regimens including multi-day and combination therapies with oncolytics and immunotherapy.

, is a physician-scientist, educator, author, and speaker, who is involved with cancer care, personalized medicine, and innovation in healthcare. At Palomar Health Medical Group in San Diego, he is the Director of Oncology. He also serves as Alumni Specialty Director at the Cleveland Clinic Lerner College of Medicine and as Clinical Instructor at the University of California San Diego. You can also find him on and .

Read the study here and an interview about it here.