About 50% of ovarian cancer cases are diagnosed in women >65 (1). Standard treatment of advanced ovarian cancer includes comprehensive cytoreductive surgery and six cycles of combination therapy with a platinum and taxane with, or without, maintenance bevacizumab and a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor. Neoadjuvant chemotherapy with interval debulking surgery is considered in patients with advanced-stage disease who are not good candidates for upfront primary debulking surgery (2). However, less than two-fifths of older women with advanced ovarian cancer received this modified treatment, usually due to poorer performance status or comorbidities (3, 4).

The outcomes of ovarian cancer worsen with age (5, 6). Cumulative analyses from 6 Gynecologic Oncology Group trials estimated that an interval increase of 10 years in age increases the risk for disease progression by 6% and for death by 12% (7). The EUROCARE study showed that relative survival among European women with ovarian cancer was much higher in middle-aged women than in older ones (8).

Several factors make the older population prone to a poorer prognosis, including delayed diagnosis, comorbidities, resistance to chemotherapy, poorer physical and cognitive performance, polypharmacy, depression and frailty (9, 10). Women >65 with advanced ovarian cancer are more likely to have incomplete surgery and more residual disease. These elements were prognostic factors for survival regardless of age (11). In the past, some clinical trials excluded older women, thus suboptimal oncological treatments provided to older patients were based on outcome data from a younger subsection (12).

In a previous analysis we have shown that weekly scheduling of paclitaxel 80 mg/m² and carboplatin area under the curve (AUC) 2, administered on days 1, 8, and 15 in a 28-day cycle (PC-1W) for first-line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m²) every 3 weeks (PC-3W) (13). To challenge the conventional assumption that older patients with advanced ovarian cancer do not tolerate standard therapy, we retrospectively analyzed and compared the effectiveness and tolerability of both regimens (PC-1W and PC-3W) in patients >70 years with advanced ovarian cancer.

This retrospective study showed that patients >70 treated with the modified PC-1W regimen had significantly longer median OS (57.17 versus 30.00 months) and PFS (19.09 versus 8.15 months) compared to patients >70 treated with the standard PC-3W regimen. The weekly protocol was more tolerable, as reflected by the higher rate of patients who completed ≥6 cycles of treatment compared to those treated with PC-3W, with similar rates of grade 3 toxicities, except for neutropenia. No statistically significant differences in median PFS and median OS were observed between septuagenarians and octogenarians. Toxicity rates were mostly similar between younger and older patients.

Patients >70 had significantly higher rates of comorbidities and advanced disease (stage IV) compared to younger patients, thus, neoadjuvant chemotherapy was more common in older patients. Neoadjuvant chemotherapy with interval debulking surgery is associated with higher rates of optimal cytoreduction, lower perioperative morbidity and mortality rates and similar outcomes, compared to primary debulking surgery (14, 15).

Although there was no difference in BRCA testing frequency in the younger and older groups, the rate of BRCA1/2 mutations was significantly lower in the older population. This may be explained by diagnosis of BRCA cancers at a younger age, or an active medical follow-up in patients carrying BRCA1/2 mutations.

Median PFS and median OS were 11.04 months and 41.26 months, respectively, among patients >70 treated with a platinum-taxane doublet. Liontos et al. (16) reported similar findings with a median PFS of 11.3 months and a median OS of 30.2 months among patients >70 years treated with a platinum-taxane doublet (84% of patients) or carboplatin monotherapy (16%). Although these values are significantly shorter than for younger patients, they suggested that older patients can still benefit from substantial lengthening of their lives.

In a previous study, we have found significantly longer median PFS and OS in patients with ovarian cancer (all stages) treated with PC-1W compared to PC-3W with a survival HR of 0.54 (95% CI, 0.43–0.67; p<0.001) (13). Our current analysis corroborates this finding in older patients. The MITO-7 study showed that carboplatin and paclitaxel given once a week versus every 3 weeks did not significantly prolong PFS in patients >70 years versus ≤70 years but it was associated with better quality of life and fewer toxic effects (17). The EWOC-1 trial provided evidence that the paclitaxel-carboplatin combination should remain the standard of care even for older and frailer patients with ovarian cancer because survival was significantly worse in the carboplatin monotherapy arm (18). In a pan-cancer meta-analysis of 19 randomized clinical trials that included 5 ovarian cancer trials, 6 breast cancer trials, 6 non-small cell lung cancer trials, 1 head and neck squamous cell carcinoma trial and 1 cervical cancer trial, the weekly paclitaxel regimen showed statistically significant better PFS than the 3-week paclitaxel regimen, with a HR of 0.90 (95% CI 0.82–0.99, p=0.02), but no significant difference in OS was found between the 2 paclitaxel regimens. Interestingly, PFS was affected by ethnicity with the weekly paclitaxel regimen showing improved PFS compared to the 3-weekly paclitaxel regimen in North American and Asia, but not in Europe (19).

In contrast to other reports (20), except for higher rates of asthenia in the older population, which is expected, no statistically significantly different rates of toxicities were observed in older patients (>70-80 and >80) compared to younger ones (≤70).

Patients >70 treated with PC-1W had statistically significantly higher hematological toxicities (neutropenia, thrombocytopenia and anemia) as well as asthenia; however, statistically significant difference in grade 3 toxicities was only observed for neutropenia. The higher rate of hematological malignancies in patients treated with PC-1W, may be due to the weekly complete blood count monitoring that these patients undergo prior to receiving weekly treatment, which may lead to the identification of hematological changes that would not have been detected with a longer interval between treatments. In contrast, a lower risk for grade 3/4 toxicities was reported for the weekly paclitaxel schedule compared to the 3-weekly one in the pan-cancer meta-analysis (19). In the current study, no difference in toxicity was observed when comparing septuagenarians to octogenarians, as had been suggested in prior studies (21).

The PC-1W protocol, which is administered over 28 days instead of 21-day cycles, includes a week without treatment, allowing older patients to recuperate. The fact that more patients treated with the PC-1W regimen were able to complete ≥6 cycles of therapy may also be attributed to the 6-week delay in course completion of this regimen (24 weeks instead of 18 weeks), allowing highly frail patients to recover between cycles and increasing the completion rate. Hence, the PC-1W regimen may offer advantages for older patients in terms of tolerance while retaining efficacy, perhaps by allowing more carboplatin to be given.

We further tried to evaluate differences in the characteristics and prognosis of older patients. Treatment guidelines for women >80 are undetermined; some research suggests that octogenarians may not tolerate combined surgery and chemotherapy (22). Octogenarians received more PC-1W in addition to carboplatin monotherapy compared to the septuagenarians. These subgroups had similar median OS and PFS, and no statistically significant differences in toxicities.

The strengths of this study include the assessment of a large patient population in a real-life clinical setting, in addition to a long ~20-year follow-up. The study findings are limited by its retrospective design. Our analysis only included a population of women diagnosed at stage III+IV. Surgical mortality and morbidity were not analyzed in our study. However, only 2 women died within 30 days of surgery in the entire cohort.

This study extends the literature describing treatment of older women with ovarian cancer, demonstrating that chemotherapy may be used with appropriate caution in this population with significantly improved survival rates and moderate toxicities. In recent years it has been suggested that patient frailty should be considered alongside their chronological age when making therapeutic decisions, as these are not synonymous and may allow a considerable number of women to benefit from an optimal treatment (23, 24). While we had no data on patient frailty, we emphasize the importance of increasing the use of a comprehensive geriatric assessment to formally assess the physiological, cognitive, functional and social support that older women receive during treatment planning. Frailer patients may benefit from the milder weekly paclitaxel carboplatin 28-day protocol.

Similar percentages of older patients underwent comprehensive genomic profile testing, but the numbers are too small to evaluate its prognostic contribution. Future studies should evaluate the use of this test in older patients, to improve tailored therapy, particularly in this population. The effects and toxicities of PARP inhibitors and bevacizumab in this population should also be further researched. As the use of PARP inhibitors was only approved for use in Israel for recurrent ovarian cancer in 2017, its use in our cohort was somewhat limited.

Older women, have substantial prognosis with conservative therapies with tolerable toxicity. Moreover, weekly intermittent therapy with carboplatin and paclitaxel seems less toxic and more effective in the older population and patients are more likely to complete the full chemotherapy course and survive longer. As we rapidly advance our understanding of the response to treatment in older patients, we urge care providers to carefully give them a complete treatment that would offer them an improved probability for longer survival.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Tel Aviv Sourasky Medical Center Ethics Committee. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because the study was a retrospective review of medical records.

MB: Data curation, Writing – review & editing. ES: Writing – review & editing. SP: Data curation, Writing – review & editing. IL: Data curation, Writing – review & editing. NM: Data curation, Writing – review & editing. BL: Data curation, Writing – review & editing. IW: Writing – review & editing. TS: Conceptualization, Data curation, Formal Analysis, Writing – original draft, Writing – review & editing.