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Abstract
Objective To explore the difference in chemotherapy completion and reasons for discontinuation between older (≥70 years) and younger (<70 years) patients.
Design Retrospective cohort study.
Setting Single tertiary centre in Thailand.
Participants The patients who received chemotherapy from 1 January 2009 to 30 June 2021 were included and followed up until 30 June 2022. Of the 757 patients with epithelial ovarian, fallopian tube and primary peritoneal cancer (EOC), 108 were in the older group and 649 were in the younger group.
Primary and secondary outcome measures The difference in chemotherapy completion, the association between younger and older patients and early discontinuation of chemotherapy.
Results The proportion of chemotherapy completion was significantly lower in older versus younger patients (84.3% versus 92.6%, p=0.007). Excluding discontinuation due to disease progression, the chemotherapy completion was comparable (93.5 versus 95.7%, p=0.456). Dose reduction and grade 3–4 hematotoxicity occurred more often in the older group. The univariable logistic regression model showed that older age (≥70 years) was significantly associated with early chemotherapy discontinuation (OR 2.39; 95% CI 1.29–4.24). However, after adjusting for potential confounders, age was not significantly associated with early discontinuation (OR 1.20; 95% CI 0.54–2.66). Multiple comorbidities and types of surgery were identified as independent risk factors for chemotherapy discontinuation.
Conclusion The completion of chemotherapy was observed in a majority of older adults with EOC. Age is not the only determinant of chemotherapy completion. Comorbidity and disease status are crucial for determining chemotherapy discontinuation.
- Epithelial Ovarian Cancer
- Elderly
- Older adults
- Frailty
- Chemotherapy Completion
Data availability statement
No data are available.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This retrospective design introduces the potential for information bias because of incompleteness in data collection.
The study was conducted at a single centre, which may limit its generalisability to other populations and settings.
The reporting of real-world experience (at the University Hospital in Thailand) in treating older people with epithelial ovarian, fallopian tube and primary peritoneal cancer and its long-term follow-up data were the strengths of the study.
Introduction
Epithelial ovarian, fallopian tube and primary peritoneal cancer (collectively referred to as EOC) are significant causes of morbidity and mortality in women worldwide. In Thailand, the age-standardised incidence rate of EOC is 7.9 per 100 000 women.1 Over one-third of these patients are aged 70 years or older at diagnosis. Given increased life expectancy and the ageing population, the number and proportion of older adult patients with EOC are rising.
The risk of developing ovarian cancer increases with age. For patients with ovarian cancer, increasing age is considered a poor prognostic factor for overall survival. Age may be a surrogate marker for poor performance status, compounded medical problems, more advanced disease, suboptimal treatment and increased treatment-related complications.
Most patients with ovarian cancer are diagnosed at an advanced stage of disease for which standard treatment includes cytoreductive surgery combined with chemotherapy. Platinum-based chemotherapy is a standard treatment for EOC but can be associated with significant toxicities, especially in older adults.2 In addition, studies have shown that older patients are often not offered definitive or potentially curative treatments to the same extent as younger patients, regardless of the type or stage of cancer diagnosed. This treatment disparity can result in reduced efficacy and worse oncological outcomes in older patients compared with their younger counterparts.3 4 Whereas intrinsic patient factors such as age contribute to poor outcomes, differences in patient treatment due to treatment biases may also play a role.
Multiple studies have demonstrated the safety and tolerability of combination platinum chemotherapy in older patients. However, this population is also more likely than younger patients to experience delays in chemotherapy administration and reduced doses.5–7 In addition, several studies have evaluated the appropriateness of current treatment strategies for older patients with EOC.8 9 Some studies have revealed that older patients have an improved likelihood of survival when recommended treatment is applied.10
Limited studies are available to date on the completion of chemotherapy in older adults with ovarian cancer in the Asian population and in Thai women in particular. Therefore, we conducted this retrospective study to evaluate the chemotherapy completion of older and younger patients with EOC, with a secondary objective of exploring reasons for chemotherapy discontinuation.
Methods
Study design and population
This retrospective cohort study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (Certificate of Expedited Review Approval No. 0034/2022). We reviewed the electronic medical records of 1637 women who were diagnosed with EOC (ICD-10 codes: C56, C570 and C482, respectively) confirmed by histopathology or cytology and received chemotherapy from 1 January 2009 to 30 June 2021 at King Chulalongkorn Memorial Hospital. We followed up with all the patients until 30 June 2022 and used this date as the cut-off point for observing outcomes in each patient. All patient data were deidentified to ensure patient confidentiality. In addition, patients with borderline or non-epithelial tumours, metastatic carcinoma and incomplete medical records were excluded. Finally, 757 patients were included for analysis (online supplemental figure 1). To confirm the accuracy of data entry, electronic medical records were reviewed by two investigators (NA and NP).
Supplemental material
Study setting
The treatment strategy for patients with EOC involved either primary surgery or neoadjuvant chemotherapy followed by interval debulking surgery, as determined by the treating physicians. Adjuvant chemotherapy was administered to all high-risk patients based on international guidelines,11 12 with the specific chemotherapy regimen chosen by the physician and patient. The standard chemotherapy regimen consisted of intravenous carboplatin area under the curve (AUC) 5 mg/mL/min plus paclitaxel 175 mg/m2 every 3 weeks, whereas single-agent carboplatin was given at AUC 5 mg/mL/min every 3 weeks. In addition, all patients received hydration and standard premedication, including antiallergic and antiemetic medications.
Treatment cycles were delayed when the patient’s absolute neutrophil count was <1.5 g/L or platelet count was <100 g/L before each cycle or because of medical comorbidities. The physician decided to reduce the dose to minimise toxicity or because of a lack of patient tolerance to side effects. The use of granulocyte-colony stimulating factor (G-CSF) in patients with a history of febrile neutropenia, multiple delays in chemotherapy cycles and prior radiation or chemotherapy was decided by physicians. Disease response or progression was assessed using clinical and imaging evaluations based on the Response Evaluation Criteria in Solid Tumours.13 Patients with a complete response underwent continuous surveillance, with follow-up appointments scheduled every 3 months for the first 2 years, every 6 months until 5 years and annually thereafter.
Outcomes
We stratified the study population into two groups according to age at diagnosis: an older cohort of patients aged ≥70 years and a younger cohort of patients aged <70 years. Data on patient demographics, cancer stage and grading of histology, chemotherapy regimen, dose reduction, treatment delay and proportion of chemotherapy completion were collected. The Charlson Comorbidity Index (CCI) was used to evaluate the presence of associated comorbidities at baseline (before cancer diagnosis).14 A higher CCI score indicates a greater comorbidity burden and is associated with worse survival outcomes. Chemotherapy completion was defined as the percentage of patients who completed the chemotherapy course determined by the physician or at least six cycles of neoadjuvant with adjuvant chemotherapy. Patients who did not receive a complete course of chemotherapy during the planning cycle were grouped into the early discontinuation group, and the reasons were collected. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events.15
Progression-free survival was defined as the time from the date of diagnosis by cytological or histological confirmation to the date of the first recurrence or last follow-up visit.16 Overall survival was defined as the time from the date of diagnosis to the date of death or last follow-up visit.16 We followed up with all patients until 30 June 2022, ensuring comprehensive data collection and analysis up to the specified cut-off date.
Statistical analysis
Categorical variables were reported by the number and percentage in each category. Continuous variables were characterised using mean values, SD, median and IQR. Comparisons between groups were performed using χ2 or Fisher’s exact tests for categorical variables and Student’s t-test or Mann-Whitney U tests for continuous variables. Multivariable logistic regression analysis assessed the association between demographic and clinical variables and chemotherapy early discontinuation. We initially included all variables that were statistically significant in the univariable analysis. Then, through a backward selection process, we refined the model by identifying and retaining only those potential confounders that contributed to the final model. Statistical analyses were performed using SPSS V.29 (IBM, Armonk, NY, USA). Two-sided p values of <0.05 were considered statistically significant.
Patient and public involvement
The data was collected using deidentified data and a retrospective chart review study, ensuring that patients were not burdened with additional requirements. There were no specific public involvement activities conducted for this study.
Results
Participants’ characteristics
As described in online supplemental figure 1, after reviewing a total of 1713 patients, we excluded 576 patients, leaving 1168 patients for further analysis. From this population, we excluded an additional 380 patients who did not meet the inclusion criteria, resulting in a final analysis of 757 (108 older and 649 younger) patients with EOC.
The baseline patient characteristics are shown in table 1. The mean age was 74.5 (SD: 4.0) years in the older group and 52.1 (SD: 9.6) years in the younger group. No differences were observed by race, body mass index or serum albumin levels in both groups. Older patients had more parity. Eastern Cooperative Oncology Group (ECOG) scores (indicating worse functional status) and the age-adjusted CCI (indicating more comorbidities) were higher in the older cohort (p<0.001) than in the younger group. Half of the older patients presented with clinical ascites, and the baseline serum creatinine in the older group was higher than in the younger group. However, no significant difference was observed in baseline serum CA125 levels.
Baseline characteristics (n=757)
The two groups differed significantly in the stage of disease, histology, type of surgery and residual disease. Half of the older patients presented with an advanced stage of disease, whereas more than 50% of the younger patients were in an early stage. The most common histologies observed were serous and clear cell carcinoma. However, serous (39.8%) and other (33.3%) histology subtypes were more common in older patients. In addition, the older patients underwent primary surgery less frequently than their younger counterparts (15.7% of older patients did not undergo surgery compared with 2.9% of the younger patients) and had a higher rate of residual disease.
The mean number of chemotherapy cycles administered was comparable, with 6.1 (SD: 1.7) cycles in the older patients and 6.3 (SD: 1.7) cycles in the younger. A significant difference was observed in the type of chemotherapy received (p<0.001). Adjuvant chemotherapy was more commonly administered in the younger (75.2%) patients compared with the older (56.5%) patients. In contrast, neoadjuvant chemotherapy with or without adjuvant chemotherapy was more commonly used in the older patients (43.5% versus 24.8%). Most of the patients received platinum-based chemotherapy. The use of single carboplatin was significantly higher in the older group than in the younger group (30.6% versus 8.8%).
Outcomes data
Chemotherapy completion and reasons for early chemotherapy discontinuation
Significant differences were observed in proportion of chemotherapy completion between older and younger patients, with proportion of 84.3% versus 92.6%, respectively (p=0.007). The older group had a higher rate of dose reduction (23.1% versus 11.8%, p=0.002), hematotoxicity grade 3–4 (32.4% versus 17.3%, p<0.001) and use of G-CSF (18.5% versus 10.4%, p=0.024). However, no significant difference was observed in cycle delay and neurotoxicity grade 3–4. The most common reasons for discontinuation in both groups were disease progression and toxicities. Excluding disease progression, the proportion of chemotherapy completion was comparable in both groups (93.5% versus 95.7%, p=0.456; table 2).
Chemotherapy completion, toxicity and reason for early discontinuation (n=757)
Factors associated with early chemotherapy discontinuation
Older age, higher baseline comorbidity index, more parity, poor performance status, anaemia, advanced stage of disease and use of neoadjuvant chemotherapy alone were risk factors for discontinuing chemotherapy early. Patients who did not undergo surgery had a significantly higher risk of discontinuing chemotherapy compared with those who had primary or interval debulking surgery (OR 22.48, p<0.001). In contrast, baseline CA125 level, residual disease and tumour grade were not significant predictors of chemotherapy discontinuation.
The multivariable analysis revealed that a higher comorbidity index and non-operative treatment were independent predictors of chemotherapy discontinuation in patients with EOC (table 3).
Logistic regression model of early discontinuation (n=757)
Survival outcome
The median follow-up time was 40 (IQR: 24–73) months. The older patients had significantly higher recurrent disease, shorter progression-free survival and overall survival compared with the younger patients. We observed trends towards higher cause-specific mortality because of cancer-related deaths in the younger group and higher medical comorbidities in the older patient group (table 4). Patients who discontinued chemotherapy early had a significantly higher hazard of cancer-related death. However, Dose reductions and delay in cycles did not show significant associations with cancer-related death (table 5).
Oncological outcomes (n=757)
Cox-proportional hazard model of cancer-related death (n=134)
Discussion
Summary of main results
This study explored the effect of age on chemotherapy completion in patients with EOC in a real-world setting (ie, a university hospital in Thailand). The definition of ‘older adult’ in the context of patients with EOC is unclear, with commonly used cut-offs typically set at 65 or 70 years of age.17 18 We analysed these two cut-off points in our study and observed comparable overall results. Therefore, we used a cut-off of 70 years. Older patients were more likely to have poorer ECOG performance status, higher prevalence of medical comorbidities, more advanced stage of disease, more aggressive histology and more suboptimal surgery than their younger counterparts. These findings were consistent with those of several studies.19 20
A significant difference was observed in the proportion of chemotherapy completion between older (84.3%) and younger (92.6%) patients. However, the chemotherapy completion was comparable in patients without disease progression (93.5% versus 95.7%, p=0.456). After adjusting for potential confounders, age was not independently significantly associated with early chemotherapy discontinuation. A high comorbidity index and not being a candidate for surgery significantly predicted chemotherapy discontinuation.
Notably, a single regimen of chemotherapy did not cause chemotherapy discontinuation. Older patients may require close monitoring, supportive care interventions and potential dose adjustments. Therefore, adjusting the dose of standard chemotherapy in frail older patients with cancer in accordance with the National Comprehensive Cancer Network (NCCN) guidelines11 is essential to minimise treatment-related adverse events.
Results in the context of published literature
These findings were consistent with previous studies by von Gruenigen et al 9 and Fairfield et al.21 We, therefore, suggest that older patients with EOC who are healthy enough to tolerate chemotherapy and can benefit from chemotherapy complete the course of planned chemotherapy.
Consistent with the findings of previous studies,9 22 23 the rates of grade 3–4 hematotoxicity (32%) and dose reduction (23%) were higher in the older versus the younger group. Our study demonstrated that chemotherapy’s toxicities and side effects are the reasons for therapy cessation and accounted for 20% of chemotherapy discontinuation. The Groupe d'Investigateurs Nationaux pour l'Étude des Cancers de l'Ovaire et du sein/Gynecologic Cancer Intergroup (GINECO/GCIG)23 reported that 15%–23% of patients discontinued treatment because of toxic effects.
Strengths and weaknesses
The major limitation of this study is that the retrospective design introduces the potential for information bias because of incompleteness in data collection. Additionally, the study was conducted at a single centre, which may limit its generalisability to other populations and settings. However, the strength of this study is its reporting of real-world experience (at the University Hospital in Thailand) in treating older people with EOC and its long-term follow-up data. Furthermore, the study integrates CCI with ECOG performance status to predict outcomes. The findings from this study provide valuable information for counselling older adult patients with EOC and their families and identifying opportunities to improve cancer treatment strategies.
Implications for practice and future research
A multidisciplinary approach involving gynaecological oncologists, geriatricians and other relevant specialists may be necessary to assess the risks and benefits of each treatment modality in older patients.24 To prospectively evaluate the impact of comprehensive geriatric vulnerability parameters, the Preoperative Assessment of Cancer in Elderly and the Geriatric Vulnerability Scale are needed in each step of the treatment plan to inform evidence-based decision-making and improve outcomes in this vulnerable population.25–27 We suggest incorporating these tools to stratify older women with EOC and predict the risks and benefits of different treatments. This approach may also help patients and families better participate in treatment decisions.
In conclusion, our study observed that the majority of older adults are able to complete a course of chemotherapy. However, a trend towards dose reduction and increased myelotoxicity was noted. A high comorbidity index and not being a candidate for surgery were significant predictors of chemotherapy discontinuation, whereas chronological age itself was not a predictor. The results highlight the importance of tailored treatment strategies that consider age-related factors—such as comorbidities, functional status and surgical interventions—to optimise chemotherapy completion and improve outcomes in this population. A geriatric assessment can guide treatment decisions. Finally, further research is warranted to inform evidence-based decision-making in this vulnerable population.
Supplemental material
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (Certificate of Expedited Review Approval No. 0034/2022).
Acknowledgments
We acknowledge the contribution and cooperation of all the staff at the Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University. We also thank Mr Wasan Panyasang, MSc, Biostatistics Excellence Center, the Research Affairs of the Faculty of Medicine, Chulalongkorn University, for statistical consultation and analysis. Finally, we thank Anahid Pinchis from Edanz (www.edanz.com/ac) for editing a draft of this manuscript.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @NichaAssa
Contributors Conceptualisation: NA and NP; data curation: NA, NP and SR; formal analysis: NA and SS; investigation: NA and SR; methodology: SS and RL; project administration: NA; resources: NA; software: SS; supervision: RL; validation: NA and NP; visualisation: NA; writing—original draft: NA and NP; writing—review and editing: SS, SR and RL. NA acted as guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.