INTRODUCTION:

Nausea and vomiting remain a significant challenge in the management of cancer patients undergoing radiotherapy¹. Despite advances in treatment modalities, nausea and vomiting persist as distressing side effects that can interrupt radiotherapy treatment schedules and also compromise adherence to therapy, quality of life, and overall treatment outcomes and enhance healthcare cost^2,3,4,5. The current standard of care for radiotherapy induced nausea and vomiting (RINV) typically involves serotonin 5-HT3 receptor antagonists, such as ondansetron, which effectively target nausea and vomiting triggered by radiotherapy-induced release of serotonin⁶. However, despite the efficacy of ondansetron, many patients continue to experience breakthrough symptoms, highlighting the need for alternative or adjunctive therapies or a personalised therapeutic approach^7,8,. Apart from nausea and vomiting induced by radiation therapy, cancer patients suffer from loss of appetite, lack of sleep, pain, disease and treatment related anxiety and depression, which can potentiate and bring down the quality of life and indirectly affects outcomes of the patients^9,10,11,12.

Olanzapine, an atypical antipsychotic medication with a broad receptor antagonist profile (including dopamine, serotonin, histamine, and muscarinic receptors), has emerged as a promising candidate for preventing the chemotherapy induced nausea and vomiting (CINV)¹³. Studies in the context of CINV have demonstrated olanzapine's ability to enhance the efficacy of standard antiemetic regimens, suggesting potential benefits in managing RINV as well¹⁴. The rationale for investigating olanzapine in RINV lies in its multifaceted receptor blockade, which may offer a broader spectrum of antiemetic activity compared to selective 5-HT3 antagonists alone¹⁵.By targeting multiple neurotransmitter systems involved in emesis, olanzapine has the potential to provide superior control of nausea and vomiting associated with radiotherapy, particularly when used in combination with standard care like ondansetron. This pilot trial aims to study the feasibility, safety profile and determine the appropriate sample size for a more extensive study employing a combination of olanzapine with standard of care.

Indications of pilot study in our scenario:

This pilot study, we believe, to execute a well-designed, realistic, and ethically viable randomized clinical trial on a larger scale besides helping us to determine the appropriate sample size. To guarantee that a clinical trial is substantially powered to identify significant variation in outcomes across treatment groups, accurate measurement of the sample size is essential and was well explained by Malmqvist et al¹⁶. Choosing the right sample size demands finding a balance between practical constraints including resource availability and recruitment feasibility and statistical challenges^17,18. Sample size computations for pilot studies are frequently guided by methods of statistical computation, such as effect size estimation based on preliminary information or simulations. This pilot study is intended to strengthen these estimations and promise that the major trial shall have the requisite power to detect clinically significant differences in outcomes.

The safety of olanzapine with ondansetron in the specific context of RINV must be examined, although both drugs are generally well tolerated and exhibit a well-established favourable safety record in other clinical contexts. The current pilot study attempts to figure out the sample size for the main investigation, and additionally analyse the safety of using olanzapine when used along with ondansetron and thereby we can assess the feasibility of continuing our investigation. The purpose of these evaluations is to guarantee the security of all research subjects and carry out any necessary modifications to the dosage or monitoring regimen for the main experiment¹⁹.

This pilot study is one of the cardinal steps towards assessing the potential of olanzapine as an adjunctive therapy to ondansetron for managing RINV in patients undergoing radiotherapy. By assessing proper sample size, feasibility, and preliminary safety study will provide information on optimal design and implementation for a future main randomized clinical trial. Optimizing sample size and other logistic issues will add to the robustness and validity of the subsequent efficacy and safety evaluations.

MATERIALS AND METHODS:

Design of the study:

This is a randomized parallel placebo-controlled pilot study to determine the appropriate sample size and to assess the feasibility and safety aspects of olanzapine in cancer patients receiving radiation therapy. Participants were randomized to one of the following two treatment conditions with 1:1 ratio.

1. Test Group: Participants received olanzapine along with the standard care ondansetron.

2. Control Group: Participants received placebo in addition to standard care ondansetron.

The present internal pilot study complies with the Consolidated Standards of Reporting Trials (CONSORT) guidelines extended for pilot and feasibility trials.

Participants:

Patients undergoing radiation therapy in radiation oncology department of study centre were included in the research population. At the time of randomization, all patients who were receiving radiation therapy to the abdomen and pelvic area, were 18 years of age or older, and had never had radiation therapy before had to meet the inclusion criteria. Any patients or caregivers who agree to sign an informed consent form were also included.

Patients who underwent radiation therapy with fewer than fifteen fractions were excluded from the study. Individuals who have experienced brain metastases and seizures in the past, individuals who started antipsychotic medication within 30 days after starting radiation therapy, individuals with previous history of nausea, elderly individuals experiencing psychosis due to dementia, individuals with drug addiction, uncontrolled diabetic mellitus (HbA1c>8%), intolerance to any of the research drugs, vomiting during the previous day, before to radiation therapy

Study Site:

This prospective double-blind randomized controlled trial (approved by the Institutional Ethics Committee Ref:no: IEC.AIM5-2021-PHARM.O41) is currently underway in the radiation oncology department of a tertiary care teaching hospital in South India. Patients were allocated to different study groups by simple randomization method with the help of computer-generated random assignment schedule using Graph Pad Prism software with the help of statistician. Patients and health care team were blinded to the treatment plan.

Methods and Treatment:

The eligible patients were randomized into the control and test arms. Test arm received olanzapine 5mg daily oral (Brand name: Oleanz ® Sun Pharma product) in addition to standard care. All recruited individuals received ondansetron 4mg twice daily (Brand name: Vomikind ® Mankind Pharma, India). Control group received placebo along with ondansetron. Olanzapine was given 30 minutes prior to radiation on all days of radiotherapy. Placebo was manufactured and supplied by Lisie Pharmaceuticals along with analysis certificate. Dose of ondansetron was based on worldwide guidelines for the prevention and management of RINV. Likewise, we chose the dose of olanzapine based on past clinical experience^20,21,22. The patient allocation into each group of 12 participants was done by employing the Thumb rule of statistics¹⁷.

Assessment and Evaluation:

Data were collected from health records and through direct consultation with patients and recorded in a specially developed structured data collection form. (Data captured include Patient characteristics; information about the category of cancer, its staging, anatomic site of radiation, type of radiation therapy, total radiation dose and fractions received, chemotherapy details, and surgery details.) Patients recorded the duration and frequency of nausea and vomiting incidents from day one until the end of radiation therapy in a specially prepared diary. Adverse reactions adverse events, vital signs, and laboratory parameters (including nausea and vomiting) during treatment were also noted and grading was done using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0²³.

Outcome Measures:

Complete control of nausea (no nausea and no rescue therapy during radiotherapy) was the primary goal of our pilot trial. We also tested the statistical significance of the difference in the occurrence of nausea between control and test groups.

Statistical Analysis:

Microsoft Excel was deployed to compile the data and Statistical Package for the Social Sciences software version 20 (SPSS Inc, Chicago, USA) was employed for analysis. This pilot study used descriptive statistics to summarize the preliminary data including mean, standard deviations, and proportions. The results are expressed in mean±SD for all continuous variables and in frequency (percentage) for categorical variables. Pearson chi-square test was applied to compare the incidence of nausea and the adverse drug reactions between two groups. p value of <0.05 was considered statistically significant. All test of statistical significance were two tailed. The results from the main study will be analysed to estimate the effect size variability of primary and secondary outcomes which will guide the determination of the sample size for the main randomized clinical trial.

RESULTS:

The pilot study we conducted involved a total of 24 patients. The patients were sorted into two groups of 12 in each arm of the experiment according to the inclusion and exclusion criteria shown in our trial's consort diagram (Figure 1).

Figure 1: Consort diagram for pilot and feasibility study in patient receiving abdomen/ pelvic radiation therapy

For our pilot study, participants were enrolled starting on February 1st, 2022, and their nausea was monitored daily until the end of radiation treatment. Baseline demographic parameters were similar in both the study groups (Table1). Mean age of the study patients was found to be 65.33±13.957 in control group and 64±13.957 in test group. Rectal carcinoma was the most common type of cancer in both groups (58.33% control group vs 50% test group), followed by cancer of the prostate. There is no difference in the mean duration of radiotherapy given in both groups (25.58±4.010 days control group vs test group 24.42±2.778 days). The mean dose of radiation therapy received in both groups were similar (control group 220.83±33.428 vs test group 226.25±33.38). Pelvic area was the most common site of radiation and image guided radiation therapy (IGRT) technique was the commonly employed technique in both groups. Diabetes Mellitus was the most common type of comorbidity found in both groups. Control and test groups did not differ significantly in age, sex, family history, chemotherapy received, hormone therapy received, mean dose and duration of radiation etc.

Table 1: Baseline characteristics of the study patients

Parameter	Control Group(n=12)	Test Group(n=12)	p value
Mean age (years) ±SD	65.33±13.957	64±13.957	0.766
% of males/females	83.3/16.7	58.3/41.7	0.371
Smoking (% of patients)	2(16.7%)	0(0%)	0.478
Alcohol (% of patients)	3(25%)	0(0%)	0.217
Family History	4(33.3%)	4(33.3%)	1
Comorbidities (% of patients) Diabetes Mellitus Hypertension Hyperlipidaemia Hypothyroidism	9(75%) 6(50 %) 6(50 %) 6(50 %) 0(0%)	8 (66.7%) 5(41.7%) 6(50 %) 5(41.7%) 2(16.7%)	1 1 1 1 0.478
Baseline Weight	61.92±11.540	61.25±12.527	0.893
% of patients receiving concurrent chemotherapy	7(58.3%)	7(58.3%)	1
% of patients receiving hormone therapy	4(33.3%)	4(33.3%)	1
Type of cancer (% of patients) Rectum Cancer Prostate cancer Endometrial Cancer Anal Canal	7(58.33%) 5(41.7%) 0(0%) 0(0%)	6(50%) 4(33.3%) 1(8.3%) 1(8.3%)	0.534
Type of Radiotherapy (% of patients) IGRT 3DCRT	11(91.7%) 1(8.3%)	9(7.5%) 3(25%)	0.590
Site of radiotherapy (% of patients) Pelvic area	12(100%)	12(100%)	-
Distant Metastasis	-	-	-
Mean dose of radiotherapy (cGy)	220.83±33.428	226.25±33.38	0.695
Mean duration of radiotherapy (days)	25.58±4.010	24.42±2.778	0.416

IGRT: Image Guided Radiation Therapy, 3DCRT:Three Dimensional Conformal Radiation Therapy, cGy: CentiGray

Sample Size Estimation:

Sample size for the main trial was determined by comparing the proportion of patients with occurrence of nausea in two groups. In our study proportion of patients with occurrence of nausea was found to be higher in control group when compared with experimental group 41.7% vs 16.7% (p=0.371) and was represented in Table 2.

Table 2 : Proportion of Patients with Nausea

Nausea	Control Group (n=12)	Test Group (n=12)	p value
No	7 (58.3%)	10(83.3%)	0.371
Yes	5(41.7%)	2(16.7%)	0.371

Based on the magnitude of the effect size found in our pilot study, 80% power and 99% confidence interval, we calculated the sample size for the main study. The estimated proportion shows there is high percentage of variations in the occurrence of nausea between two groups. It was found to be clinically significant, even though statistically insignificant. The formula based on the proportion of patients with occurrence of nausea in both groups was used for the estimation of the sample size and was given below. According to this formula the minimum sample size required for our future trial was found to be 152 patients in total.

– Proportion in the control group (41.7%=0.417)

- Proportion in the test group (16.7%=0.167)

- 0.84

Significance Level - 2.58 ,

= 152 total sample size

Safety Assessment:

The frequency and grading of adverse drug reactions (ADR) encountered during radiation therapy is displayed in Table 3. Constipation was among the major adverse drug reactions in both groups with 83.3% in the control group and 75% in the experimental group. There were a few ADRs experienced exclusively by the test group such as orthostatic hypotension 1(8.3%), drowsiness 1(8.3%), hypertriglyceridemia 1(8.3%) and hyponatremia 1(8.3%). There was no grade 4 and grade 5 toxicities encountered in our study. Drowsiness, and orthostatic hypotension comes under grade1 category.

Table 3: Grading of ADR during radiation therapy

ADR	Control Group1 (n=12)			Test Group2 (n=12)
ADR	Grade1	Grade2	Grade3	Grade1	Grade2	Grade3
Constipation	-	10(8.3%)	-	-	9(75%)	-
Nausea	1(8.3%)	4(33.3%)	-	2(16.7%)	-	-
Vomiting	2(16.7%)	-	-	-	-	-
Cystitis	-	2(16.7%)	-	-	4(33.3%)	-
Anal Mucositis	-	6(50%)	-	-	2(16.7%)	-
Diarrhea	-	2(16.7%)	-	-	2(16.7%)	-
Black Discoloration of skin	1(8.3%)	1(8.3%)	-	1(8.3%)	-	-
Haematological Abnormalities	-	-	1(8.3%)	-	-	2(16.7%)
Gastritis	-	2(16.7%)	-	-	-	-
Fatigue	3(25%)	-	-	7(58.3%)	-	-
Dysgeusia	1(8.3%)	3(25%)	-	-	-	-
Orthostatic hypotension	-	-	-	1(8.3%)	-	-
Hypertriglyceridemia	-	-	-	-	2(16.6%)	-
Hyponatremia	-	-	-	-	1(8.3%)	-
Drowsiness	-	-	-	1(8.3%)	-	-

Feasibility Assessment:

Recruiting patients, meeting sample size requirements, obtaining Informed consent, adherence levels, drop outs etc remained within acceptable feasibility limits. Being a large tertiary care teaching hospital in South India, with advanced facility in radiation oncology, employing qualified doctors with clinical research experience and good publication history, we did not face any problems in recruiting adequate number of patients in this pilot trial. Out of about 70 patients seeking radiotherapy per month, about 16 undergo abdominal/pelvic radiation therapy, ensuring ample patients for the future trials. Since this study was funded by the Indian Council of Medical Research, Govt of India, there was no shortage of funds.

DISCUSSION:

This pilot study was aimed to estimate the appropriate sample size required for a more extensive randomised control trial and to analyse the feasibility and safety aspects comparing standard care Ondansetron with Olanzapine 5 mg for preventing RINV. The main reasons for conducting this pilot study are, as there is no published literature available for assessing the safety and efficacy aspects of olanzapine in radiotherapy settings. Also, to determine the correct sample size needed for the main study, to know more about the safety and feasibility aspects of olanzapine in the present scenario, and to identify any challenges in our research scenario. An adequately sized sample improves the generalizability of the study findings to the broader population also keeps the credibility and applicability of the research findings, ultimately contributing to better decision-making in clinical practice. There are different methods or approaches for estimating the sample size. In our study variability in patient responses with respect to nausea were considered for determining the sample size. Since we used complete control of nausea as the primary end point of our future trial. The incidence of nausea (16.7% in the Olanzapine group Vs 41.7% in the control group, p=0.371).), the effect size 0.25 obtained from this pilot study and by using other factors like 80 % power, 99% confidence interval has helped us to arrive at the right sample size. The outcome was deemed clinically significant even though, statistically not. We need to investigate with a wide number of sample sizes whether the clinical effects of olanzapine in reducing nausea would be statistically significant in a bigger sample size.

Power analysis is important in determining precisely what number of participants are required to validate findings and make sure the study has adequate power to find significant differences between the treatment groups. The uncertainty regarding feasibility was whether the observed clinical benefits of Olanzapine in reducing nausea would be statistically significant in larger sample.

The reduction in nausea rates observed in our pilot study suggests that Olanzapine is potentially an effective adjunct therapy for RINV. These findings are consistent with previous studies²⁴ which have demonstrated Olanzapine's efficacy in reducing nausea and vomiting associated with chemotherapy. In radiation therapy delayed nausea and vomiting is common. According to a study by Tagoore^25, individuals receiving chemotherapy concurrently and those receiving radiation therapy alone have higher incidences of adverse drug reactions.Another study by Rojas et al ²⁶ reported that Olanzapine was effective in reducing both acute and delayed nausea in patients undergoing chemotherapy, and similar benefits may extend to radiotherapy-induced nausea and vomiting. The absence of severe toxicity—that is, grade 4 or 5—related to olanzapine in this pilot study further reiterates its safety profile, which is very critical when one considers adjunctive therapies to patient management in oncology settings²⁷.These findings are consistent with other studies that have reported a favourable safety profile for Olanzapine, reinforcing the potential for its broader application in managing nausea and vomiting across various clinical settings.

CONCLUSION:

The pilot trial has shown promising results regarding the use of Olanzapine in conjunction with Ondansetron for managing RINV, highlighting a potential area for further investigation. The absence of severe toxicity and the feasibility of sample collection support the continuation of this research to better define the role of Olanzapine in enhancing patient care during radiotherapy. For our upcoming experiment, a minimum sample size of 152 patients is required.

ABBREVIATIONS:

RINV - Radiotherapy-induced nausea and vomiting

CINV - Chemotherapy-induced nausea and vomiting

CTCAE- Common Terminology Criteria for Adverse Events

ADR- Adverse Drug Reactions

SPSS- Statistical Package for the Social Sciences software

IGRT-Image guided Radiation Therapy

cGy – Centigray

ACKNOWLEDGEMENT:

The authors are thankful to Amrita Vishwa Vidyapeetham for providing opportunity to work on this project. We are grateful to Professor Emmanuel James for his insightful suggestion regarding the topic of our study and significant contributions to this research.

ETHICAL APPROVAL AND INFORMED CONSENT STATEMENTS:

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and Good Clinical Practice guidelines. Institutional Review Board (IRB) approval (Ref:no: IEC.AIM5-2021-PHARM.O41) was obtained before the commencement of the study. Written informed consent was be obtained from all participants prior to enrolment, ensuring voluntary participation and confidentiality of personal health information.

FUNDING DETAILS:

The work is supported by the Govt. of India under the grant of Indian Council of Medical Research (ICMR) Extramural Ad-hoc scheme and sanctioned to Dr. Deb Narayan Dutta –Research Associate fellowship to Ms. Meenu Vijayan (IRIS ID: 2020-9414, File number: 58/22/2020/PHA/BMS).

CONFLICT OF INTEREST:

The authors declare that they have no known competing financial interest or personal relationship that could have appeared to influence the work reported in this paper.

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Received on 11.11.2024 Revised on 10.03.2025

Accepted on 20.05.2025 Published on 01.10.2025

Available online from October 04, 2025

Research J. Pharmacy and Technology. 2025;18(10):4902-4908.

DOI: 10.52711/0974-360X.2025.00707

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.