Ovarian cancer is either epithelial cancer, i.e., originating from the surface of the ovary, or germ cell malignant neoplasm, i.e., originating from the egg cells (What is ovarian cancer?, 2022). According to the Globocan 2020 data, annual incidence and mortality from ovarian cancer worldwide were 3,13,959 cases and 2,07,252 deaths, respectively. South-Eastern Asia witnessed 31,169 new cases and 20,012 deaths yearly (Globocan, 2020: Ovary cancer, 2022). The incidence of ovarian cancer in India, one of the world’s most populated countries, was 45,701 in 2020. Ovarian cancer is the eighth most common cancer in females and the second most common gynaecological cancer in Asia (Globocan, 2020: Ovary cancer, 2022). Among Indian women, ovarian cancer is the third most common after breast and cervical cancer, and the second most common gynaecological cancer (Globocan, 2020: Ovary cancer, 2023). Apart from high incidence and prevalence, ovarian cancer was associated with 32,077 deaths in 2020, accounting for 3.8% mortality among Indian cancer patients (Globocan, 2020: Ovary cancer, 2023).

According to the cancer registry of India, the lifetime risk of Indian women getting ovarian cancer ranges from 0.9 to 8.84 per one lakh women. Although ovarian cancer has a poor prognosis and a high mortality rate, early diagnosis and judicious medical intervention show a better prognosis than in late and advanced stages (Consensus document for management of epithelial ovarian cancer, 2022). Ovarian cancer has a lower incidence but three times higher mortality than breast cancer and is the fifth most common cause of death in females (Momenimovahed et al., 2019; Key statistics for ovarian cancer, 2022). Approaches to managing ovarian cancer include surgery, radiation therapy, chemotherapy, hormonal, and targeted/immunological therapy (Treating ovarian cancer, 2023). However, the 5-year survival rate among ovarian cancer patients (revealed by SEER data) was reported to be 49.7% from 2014 to 2018 (National institute of cancer surveillance, 2022).

Despite significant advances in diagnosing and treating ovarian cancer, studying drug-related problems (DRPs) among ovarian cancer patients remains suboptimal in day-to-day clinical rotation. The risk of DRPs increases with polypharmacy, consequent to comorbidities and supportive therapy. More than 50% of elderly ovarian cancer patients experience polypharmacy because they receive a minimum of five medications (Oldak et al., 2019). DRPs are events or circumstances associated with drug therapy that potentially affect healthcare outcomes (Jayakumar et al., 2021). Complexity in cancer treatment extends beyond anticancer agents because comorbidities demand supportive therapy. A specialized pharmacist called an oncology pharmacist can initiate prescription audits, recommend deprescribing, minimize polypharmacy and reduce the potential harms due to therapy (Yokoyama et al., 2018).

The incidence of DRPs in ovarian cancer is unknown in India. Antineoplastic drugs produce serious DRPs, and their management is challenging because of their narrow therapeutic index (Sisay et al., 2015; Degu et al., 2017). In contrast to the therapeutic benefits of medicine, DRPs can increase morbidity and mortality (van Roozendaal and Krass, 2009). Unresolved and under-resolved DRPs can result in needless hospitalization, readmission, extended hospital stay, and extended care. DRPs will not only impact therapeutic efficacy, but also raise treatment costs.¹⁵ . Various studies have highlighted that patients’ safety is a crucial and continuous process (Oldak et al., 2019; Jayakumar et al., 2021), and one of the vital factors impacting patients’ safety is DRPs (Yokoyama et al., 2018; Jayakumar et al., 2021). A study focusing on DRPs in ovarian cancer is needed, which can give information regarding the incidence of DRPs in ovarian cancer and make the healthcare provider aware of the possible DRPs risk.

Reports suggest that 25% of hospital admissions of cancer patients possibly result from DRPs (Sisay et al., 2015), of which 50% were potentially preventable with timely intervention (Degu et al., 2017). DRPs may compromise patients’ physical health and health-related quality of life to a large extent, leading to a significant waste of healthcare expenditures (Ni et al., 2021). DRPs are critical, for saving on therapeutic costs, particularly in limited resource settings within low-middle income countries such as India (Dror et al., 2008; Sisay et al., 2015).

Indicators are clues that help detect DRPs within the healthcare organization and minimize overall harm from medications (van Roozendaal and Krass, 2009; Thiyagu et al., 2010). This approach is based on identifying and addressing the errors that are associated with adverse therapeutic outcomes. Indicators offer an approach to standardizing error identification that may provide more consistent and accurate information. Indicators enable healthcare professionals and patients to determine the future therapeutic course. Indicators enhance healthcare professionals to take a proactive stand, and stay informed and empowered to both prevent and manage DRPs (MacKinnon et al., 2008; van Roozendaal and Krass, 2009). With the help of developed indicators, the healthcare provider can identify DRPs and recommend to the prescriber what action plan could be implemented in the next steps to prevent or resolve potential DRPs. and timely identification of DRPs could prevent patients from possible harm. It is critical to optimize management by identifying and preventing DRPs (MacKinnon et al., 2008; Thiyagu et al., 2010).

The present study aimed to design and develop novel, evidence-based indicators for detecting DRPs among ovarian cancer patients to improve drug safety and promote positive clinical outcomes.

Indicators provide signals for the identification and management of DRPs by supporting quick detection, risk assessment, causative link determination, decision assistance, monitoring and evaluation, quality improvement, and fostering interdisciplinary communication and collaboration. By utilizing indicators, healthcare providers can improve patient safety, drug therapy, and outcomes. The Delphi approach was used in this study to validate the developed indicators. Through this Delphi approach, we may gather the most trustworthy consensus view on specific indicators from panel members in a multistage interactive session (Lecours, 2020; The Delphi method techniques and applications, 2022).

This study has developed a list of evidence-based indicators to identify DRPs in ovarian cancer patients and helped in detecting a significant number of DRPs. These DRPs were classified under four classes based on the PCNE classification of DRPs V9.1 (van Roozendaal and Krass, 2009; Classification for Drug related problems V9.1, 2022). The mean of DRPs per patient in our study was 8.7, which is significantly higher than the values reported in Kenya (2.65 ± 1.22 DRPs per cervical cancer patient) possibly because we evaluated all the treatment cycles of patients for one full year (Degu et al., 2017). Early detection and assessment of DRPs is a crucial step that may help mitigate the adverse effects of the DRPs and facilitate timely management (van Roozendaal and Krass, 2009; Yeoh et al., 2015). Collectively, patients undergoing antineoplastic therapy will have higher chances of DRPs because patients undergoing anticancer therapy are prescribed more than five drugs during admission and discharge (Sisay et al., 2015). For instance, our inpatient prescriptions had an average of 9.8 ± 1.8 drugs, and discharge prescriptions had an average of 5.3 ± 1.2 drugs.

Likewise, more than 60% and 80% of the gynecological cancer patients underwent polypharmacy in Kenya and in USA Odak S studies respectively (Degu et al., 2017; Oldak et al., 2019). As the number of drugs increases, the risk of DRPs also increases proportionately. Ovarian cancer patients are always at risk of polypharmacy, consistent with the study findings (Oldak et al., 2019).

We faced drug selection issues (the most frequently encountered issue) 62, comprising (7.7%) of the total DRPs. This is comparatively less than what was reported in cervical cancer 64 (29.8%) (Degu et al., 2017) and among cancers in general 92 (24.1%) (Sisay et al., 2015). Duplication of the active ingredients was the most common problem in drug selection 35 (38.1%), especially the duplication of vitamin B12 in multivitamins/other formulations. Absorption of vitamin B12 takes place through facilitated diffusion in the distal portion of the ileum, with the help of a transport protein called intrinsic factor. Overdose of vitamin B12 leads to saturation of intrinsic factors, simultaneously leading to the oligo absorption of vitamin B12, thus resulting in therapeutic failure and progression to megaloblastic anemia and peripheral neuropathy (Brahmkar and Jaishwal, 2015; Advantages and disadvantages of protein assisted transport, 2022).

Additionally, 7 patients were prescribed two proton pump inhibitors (pantoprazole and rabeprazole) and 5 patients were prescribed two antacid syrups containing the same active ingredients, namely, aluminium hydroxide and magnesium hydroxide. Using two drugs with the same mechanism concomitantly could lead to overdose, with increased adverse effects rather than therapeutic benefits. This, in turn, adds to the economic burden from unnecessary additional doses as well as the therapeutic burden from potential adverse effects of an overdose (Kumar and Rajasekhar, 2020).

Significant reasons for polypharmacy include the prescription of drugs without indication and the prescription of too many drugs for one indication. Both contribute to therapeutic complexity, DDIs, ADRs, and economic burden (Oldak et al., 2019; Kumar and Rajasekhar, 2020).

Under drug selection issues, the drug without indication was observed in 23 (25%) patients. On the other hand, 2 patients (2.2%) were prescribed 4 antihypertensives for a single indication, called multimodal therapy, potentially leading to severe hypotension (Taking multiple medicines safely, 2023).

In our study, 6 patients (6.3%) did not receive the second prescribed dose of aprepitant 80 mg, (24 h after the first dose of aprepitant 125 mg) to mitigate chemotherapy-induced nausea and vomiting (Ritchie and Kohli, 2022).

The most frequently observed ADRs were alopecia 75 (81.5%) and nausea and vomiting 65 (68.5%). Correspondingly, the results of an Indian study showed a similar predominance of alopecia and nausea and vomiting at 85.3% and 65%, respectively (Ingale et al., 2021). Likewise, reports from a Bangladesh study showed the incidence of alopecia (58%) and nausea and vomiting (52%) to be the most common (Poddar et al., 2010).

Most patients were prescribed highly emetogenic drugs like taxel, platinum derivatives, doxorubicin, and cyclophosphamide. Around 16 (17.4%) experienced itching or sensitivity issues with carboplatin therapy and blood transfusion. In our study, 15 (16.3%) patients experienced pain at the injection site and/or thrombophlebitis. Likewise, reports by the Korean study, advanced-stage cancer patients undergoing parenteral antineoplastic therapy were treated with topical local analgesics (Lee et al., 2019).

Following alopecia and nausea and vomiting, (12 patients (13%) had experienced diarrhea/constipation. A similar incidence of constipation was observed in 12.3% of patients in North East India study (Wahlang et al., 2017). Our results differ from the above study results in the Nepali population, wherein around 54% of patients had experienced constipation and diarrhea (Shrestha et al., 2017). The major reason for this could be the use of antineoplastics agents. Constipation could result from the concomitant use of antiemetics (5HT3 antagonist) and opioid analgesic. Diarrhea could be the result of laxatives.

The stress from chemotherapy could be the reason for the rise in blood pressure (BP) in our study (n = 37; 40.2%). Additionally, antineoplastic agents, steroids (dexamethasone) as antiemetic, etc., could also raise blood pressure. The temporary rise of BP was managed by psychosocial counseling and making the patients comfortable, whereas chronic BP was treated by antihypertensive as well as other palliative care. Hypertension was more prevalent in targeted therapy involving angiogenesis inhibitors (Mouhayar and Salahudeen, 2011).

Another frequently observed ADR was hematological disorders 39 (42.4%), dominantly anemia 13 (14.1%) followed by leucopenia 8 (8.7%), leukocytosis (7 (7.6%), eosinophilia 6 (6.52%) and thrombocytopenia (3 (3.3%) patients. Similar incidence of hematological disorder has been reported in 40.5% of the patients in Nepali populations (Mallik et al., 2007). Whereas, neutropenia was found only in two patients in our study, possibly due to the effective use of the granulocyte-colony stimulating factor (G-CSF) (Gupta et al., 2010).

Here, all listed drug-drug interactions in our study were potential interactions rather than actual ones. However, we need to be watchful so that we do not miss ADRs (van Leeuwen et al., 2015). Along with the anticancer agents, patients are also prescribed with supportive therapy to outweigh the risk of adverse effects of anticancer agents. As the number of drugs increase in the prescription, it makes the therapy more complex and increases the risk of interactions between drugs. Drug-drug interactions may result in negative outcomes either by suppressing the therapeutic effects of one drug by another drug or by promoting the toxic effects of another drug (Kannan et al., 2011; Riechelmann and Girardi, 2016).

In this study, we have observed 3.9 pDDIs per patient, which is similar to results from South India and Pakistan with 2.8 and 2.7 pDDIs per patient respectively (Kannan et al., 2011; Ismail et al., 2020). In the present study 75 pDDIs were observed among antineoplastic agents alone or with supportive therapy. Most commonly observed pDDIs were with paclitaxel and carboplatin, possibly due to frequent prescriptions. Platinum derivatives could cause pDDIs if administered before taxel, possibly because altered serum concentration can enhance myelosuppression by taxel. In case of supportive therapy, pDDIs were observed 279 times. Ondansetron and domperidone were the most common (n = 74) followed by domperidone and tramadol (n = 34) and tramadol and ondansetron (n = 27). Co-administration of ondansetron and domperidone may lead to QT-prolongation, necessitating frequent electrocardiograms (ECG) and monitoring of signs and symptoms for palpitations or arrhythmias. However, ondansetron and domperidone combination have a therapeutically superior antiemetic effect. Moreover, a combination of tramadol with domperidone or ondansetron may increase the risk of serotonin syndrome (Kamath et al., 2021).

Cancer treatment being highly complex, expensive, multidisciplinary, and extremely risky, therapy will benefit immensely from identifying DRPs which can potentially simplify preventive strategies by spotting real world problems at the point of care (Yokoyama et al., 2018; Oldak et al., 2019). Since most of the DRPs are preventable, an early detection can help to mitigate and treat them promptly and abort the incidence of adverse outcomes (Degu et al., 2017). Having adopted the Delphi approach towards identifying evidence-based indicators for DRPs, the study has incorporated multiple viewpoints and the cumulative experiences of a variety of interdisciplinary professionals in cancer therapy (Orkin et al., 2021). An extensive range of DRPs were identified from the indicator, namely, drug selection problems, drug use problems, ADRs, and DDIs. Data generated by our study may also be deployed as a training strategy for familiarizing healthcare professionals with the idea of task sharing and team work.