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Abstract
Objective To investigate the use and outcomes of adjuvant chemotherapy for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery.
Methods Patients diagnosed between 2010 and 2015 with International Federation of Gynecology and Obstetrics stage II–IV low-grade serous ovarian carcinoma who underwent primary debulking surgery with known residual disease status and had at least 1 month of follow-up were identified in the National Cancer Database. Adjuvant chemotherapy was defined as receipt of chemotherapy within 6 months of surgery. Overall survival was evaluated using the Kaplan-Meier method and compared with the log-rank test. A Cox model was constructed to control for a priori-selected confounders. A systematic review of the literature was also performed.
Results In total, 618 patients with stage II–IV low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery were identified; 501 (81.1%) patients received adjuvant chemotherapy, while 117 (18.9%) patients did not. The median follow-up of the present cohort was 47.97 months. There was no difference in overall survival between patients who did and did not receive adjuvant chemotherapy (p=0.78; 4-year overall survival rates were 77.5% and 76.1%, respectively). After controlling for patient age, medical co-morbidities, disease stage, and residual disease status, administration of adjuvant chemotherapy was not associated with better overall survival (HR=0.87, 95% CI 0.55 to 1.38). Based on data from three retrospective studies, omission of adjuvant chemotherapy following cytoreductive surgery was not associated with worse progression-free survival benefit (HR=1.25, 95% CI 0.80 to 1.95) for patients with stage III–V low-grade serous ovarian carcinoma.
Conclusions Adjuvant chemotherapy may not be associated with an overall survival benefit for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery.
- Ovarian Cancer
- Carcinoma, Ovarian Epithelial
Data availability statement
Data may be obtained from a third party and are not publicly available. Data obtained from American College of Surgeons and Commission on Cancer.
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HIGHLIGHTS
In the National Cancer Database, approximately 1 in 5 patients with advanced-stage low-grade serous ovarian carcinoma did not receive adjuvant chemotherapy.
In this study population, adjuvant chemotherapy was not associated with a survival benefit.
The presence of gross residual disease was associated with worse overall survival.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Low-grade serous ovarian carcinoma is relatively chemoresistant to standard-of-care platinum-based chemotherapy. The role of adjuvant chemotherapy for patients with advanced-stage disease is not well defined and has been extrapolated from managing patients with high-grade serous ovarian carcinoma.
WHAT THIS STUDY ADDS
Adjuvant chemotherapy following primary cytoreductive surgery may not be associated with a survival benefit for patients with low-grade serous ovarian carcinoma.
HOW THIS WORK MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Data support an ongoing phase III trial investigating the oncologic safety of adjuvant chemotherapy omission in this patient population.
Introduction
Low-grade serous ovarian carcinoma is a rare histologic subtype of ovarian cancer, representing approximately 5% of all epithelial ovarian tumors.1 Low-grade serous ovarian carcinoma is relatively chemoresistant to standard platinum-based chemotherapy, with response rates for advanced-stage disease of about 10–20%.1 2 On the other hand, these tumors consistently express hormone receptors and respond to hormonal treatment, demonstrating improvement in progression-free survival in the maintenance setting.2 Complete gross resection at the time of cytoreductive surgery has been identified as an important prognostic factor in patients with advanced-stage disease.3 Management of these patients has been extrapolated from those with high-grade serous ovarian carcinoma, typically using a platinum–taxane combination. Based on the European Society of Medical Oncology guidelines, adjuvant platinum-based chemotherapy is recommended following cytoreductive surgery.4
Similarly, the most recent National Comprehensive Cancer Network guidelines recommend systemic chemotherapy for patients with stage II–IV disease, although hormonal therapy alone can be considered (category 2B).5 However, the impact of adjuvant chemotherapy on patients with advanced-stage disease following cytoreductive surgery is not well established, as the available evidence consists of small inadequately powered retrospective studies, while inclusion of patients with low-grade serous ovarian carcinoma in major randomized trials was performed at a time when low-grade serous ovarian carcinoma was not appreciated as a molecularly distinct histologic subtype.6–8 The present study aimed to investigate patterns of use and outcomes of adjuvant chemotherapy for patients with advanced-stage low-grade serous ovarian carcinoma undergoing primary cytoreductive surgery using a large hospital-based database.
Methods
Patients diagnosed with pathologically confirmed ovarian carcinoma between 2010 and 2015 were identified in the National Cancer Database, a hospital-based database capturing approximately 70% of all malignancies diagnosed in the United States.9 The present study was deemed exempt from institutional board review from Penn Medicine (protocol #829268).
Based on ICD-O-3 histology codes and tumor grade collected from pathology reports, patients with grade 1 tumors and serous histology corresponding to low-grade serous ovarian carcinoma were identified. Those with stage II–IV disease who underwent primary cytoreductive surgery based on site-specific surgery codes and had at least 1 month of follow-up, known data on the administration of adjuvant chemotherapy, and known outcome of cytoreductive surgery (complete gross resection vs residual disease) were selected for further analysis. Patients who received neoadjuvant chemotherapy, those with no data on residual disease status following cytoreductive surgery, and patients who received chemotherapy more than 6 months after cytoreductive surgery were excluded from the present study.
Demographic, clinicopathological, and treatment variables were extracted from the de-identified dataset. Patient race was recoded into White, Black, and Other/Unknown, insurance status into private, government (including Medicaid and Medicare), and uninsured/unknown. The presence of co-morbidities was assessed from the Charlson-Deyo Comorbidity Index and classified as absent (score 0) or present (score ≥1). The type of treatment facility was categorized into academic/research and others, including community cancer program, comprehensive community cancer program, and integrated network cancer program.
The frequency of distribution of categorical variables was compared with the Χ2 test or Fisher’s exact test. After generation of Kaplan-Meier curves, overall survival was evaluated and compared with the log-rank test. A Cox multivariate model was constructed to control for a priori-selected confounders. Statistical analyses were performed with the Statistical Package for the Social Sciences, version 29 (International Business Machines Corporation. Armonk, New York, USA), and the α level of statistical significance was set at 0.05.
In addition, a review of the literature on the outcomes of patients with advanced-stage low-grade serous ovarian carcinoma receiving adjuvant chemotherapy was performed. The Pubmed/Medline, and Excerpta Medica Databases were searched between January 1, 2010 and January 1, 2023 using the keywords ‘ovarian’ and ‘carcinoma’ and ‘low grade’, and ‘serous’, while references of included articles were also hand searched. Studies in the English language that provided data on the progression-free survival of patients with advanced-stage II–IV low-grade serous ovarian carcinoma who did or did not receive adjuvant chemotherapy (with or without hormonal therapy) following primary or interval cytoreductive surgery were eligible for inclusion. Available data were extracted from the studies. Statistical analysis was performed with the Cochrane Review software (Review Manager, version 5.4).10 A random-effects model was used to compare progression-free survival between the two groups; HR and 95% confidence intervals were pooled using the generic inverse variance method provided by the RevMan software.10
RESULTS
In total, 618 patients with stage II–IV low-grade serous ovarian carcinoma who met the inclusion criteria were identified. Online supplemental figure 1 depicts the patient selection flowchart; the median patient age was 55 years (range 14–89 years) and most patients (76.2%) had stage III disease. A total of 501 (81.1%) patients received adjuvant chemotherapy while 117 (18.9%) did not. Median time from primary cytoreductive surgery to adjuvant chemotherapy initiation was 36 days, with 85% of patients initiating chemotherapy within 2 months and 95% initiating chemotherapy within 3 months from surgery. The rates of adjuvant chemotherapy use were 67.4% for patients with stage II disease compared with 83.2% and 86.5% for those with stage III and IV disease, respectively, p<0.001. Anti-estrogen hormonal therapy was rarely administered (n=22, 3.6%) in the present cohort (12 patients received hormone therapy alone while 10 patients received a combination of chemotherapy and hormone therapy). The rate of complete gross resection was 67.8%. Patients who did not receive adjuvant chemotherapy were less likely to be White than those who did receive adjuvant chemotherapy (81.2% vs 89.8%, p=0.017). There were no differences between patients who did and did not receive adjuvant chemotherapy in patient age, insurance status, co-morbidities, type of treatment facility and the presence of gross residual disease (Table 1). Patients who received hormonal treatment had a higher rate of gross residual disease (50% vs 31.5%, p=0.07).
Supplemental material
Demographic and clinicopathological characteristics of patients with advanced-stage low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery based on administration of adjuvant chemotherapy
The median follow-up of the present cohort was 47.97 months (95% CI 43.9 to 52.04). There was no difference in overall survival between patients who did and did not receive adjuvant chemotherapy, (p=0.78; 4-year overall survival rates were 77.5% and 76.1%, respectively) (Figure 1). After controlling for patient age, co-morbidities, disease stage, and residual disease status, administration of adjuvant chemotherapy was not associated with better overall survival (HR=0.87, 95% CI 0.55 to 1.38). In the present cohort, patients with gross residual disease had worse overall survival compared with those with complete gross resection (median overall survival 69.82 vs 90.32 months, p<0.001) (Figure 2). After controlling for other potential confounders, gross residual disease was associated with worse overall survival (HR=2.25, 95% CI 1.58 to 3.21). Following stratification by residual disease status, adjuvant chemotherapy was not associated with an overall survival benefit for patients with complete gross resection (p=0.60; 4-year overall survival rates 85.5% vs 79.5%) or for those with gross residual disease remaining after surgery (p=0.85; 4- year overall survival rates 63.1% vs 66.3%). In a sensitivity analysis, excluding patients who initiated adjuvant chemotherapy >2 months from cytoreductive surgery, again there was no difference in overall survival between patients who did (n=427) and did not (n=117) receive adjuvant chemotherapy (p=0.91; 4- year overall survival rates were 78.1% and 76.1% respectively).
Overall survival of patients with advanced-stage low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery based on administration of adjuvant chemotherapy.
Overall survival of patients with advanced-stage low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery based on residual disease status.
A systematic literature review identified three papers that met the inclusion criteria. All studies were retrospective and originated from the United States, Canada, and France (Table 2). After pooling available data, there was no difference in progression-free survival between patients who did (n=261) and did not (n=52) receive adjuvant chemotherapy (HR=1.25, 95% CI 0.80 to 1.95; I2 0%) (Figure 3).
Pooled progression-free survival of patients with advanced-stage low-grade serous ovarian carcinoma stratified by receipt of adjuvant chemotherapy.
Study characteristics examining role of adjuvant chemotherapy following cytoreductive surgery for advanced-stage low-grade serous ovarian cancer
Discussion
Summary of Main Results
We studied survival outcomes in patients with advanced-stage low-grade serous ovarian carcinoma using data from the National Cancer Database, a large hospital-based cancer registry. In this contemporary cohort of patients approximately 1 in 5 patients did not receive adjuvant chemotherapy. Administration of adjuvant chemotherapy following cytoreductive surgery was not associated with an overall survival benefit, even after controlling for confounders. Furthermore, we also conducted a systematic review of the literature and identified a small number of patients reported in retrospective studies. In this analysis of approximately 300 patients (approximately 50 untreated), we were unable to observe a detrimental impact on progression-free survival when adjuvant chemotherapy was omitted.
Results in the Context of Published Literature
Following cytoreductive surgery for ovarian cancer, microscopic disease most often remains even after achieving complete gross resection. In this setting, the administration of adjuvant chemotherapy aims to eliminate residual tumor cells. Based on the Norton-Simon tumor growth model, a greater log kill can be achieved during this rapid growth phase.11 However, low-grade serous ovarian cancer is a relatively chemoresistant tumor to first-line platinum-based chemotherapy. For chemo-naïve patients, reported response rates are <25%, far lower than those observed in patients with high-grade serous ovarian carcinoma, which is about 80%.12 13 An analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group metabase that included data from four randomized controlled trials, identified 39 patients with low-grade serous ovarian carcinoma and residual disease of >1 cm following cytoreductive surgery.12 In this cohort, following a median of six cycles of adjuvant chemotherapy, 6 (15.4%) patients had a partial response while only 3 (7.7%) patients achieved a complete response. Overall objective response rate was 23.1%, with 69.2% of patients having stable disease.12 Similarly, an analysis of the MITO Database reported an objective response rate of 23.7% to first-line chemotherapy.13 On the other hand, a retrospective study evaluating the role of neoadjuvant chemotherapy for patients with low-grade serous ovarian carcinoma (n=36) reported a much lower objective response rate of 11% (all partial responses) following a median of five cycles.14
Based on a recent survey study, although low-grade serous ovarian carcinoma is relatively chemoresistant, 83.5% of gynecologic oncologists recommend adjuvant chemotherapy for patients with stage IIIC who had an optimal cytoreduction secondary to paucity of data.15 Only a handful of retrospective studies have reported on the outcomes of patients with advanced-stage disease who did not receive adjuvant chemotherapy following cytoreductive surgery. Gershenson et al recently reported on the outcomes of a contemporary cohort of patients with stage II–IV low-grade serous ovarian carcinoma diagnosed between 2005 and 2019.7 Patients who received aromatase inhibitor maintenance alone (n=15) did not have worse progression-free survival than those who received adjuvant chemotherapy followed by maintenance anti-hormone therapy (n=84), with similar relapse rates (46.7% vs 50%).7 In another study, Scott et al analyzed the outcomes of 134 patients with stage II–IV disease managed between 2000 and 2016 in five Canadian referral institutions.6 Compared with patients who had surgery followed by adjuvant chemotherapy (n=75), those who had surgery alone (n=12, HR=1.25, 95% CI 0.56 to, 2.78) or surgery followed by hormonal therapy (n=6, HR=1.69, 95% CI 0.52 to 5.48) did not have worse progression-free survival.6 Similarly, the oncologic outcomes of a small cohort of stage II–IV patients (n=27) who did not receive adjuvant chemotherapy but were placed on hormonal maintenance therapy were encouraging, with 3-year progression-free and overall survival rates of 79% and 92.6%, respectively.16
Like prior studies,in our cohort the presence of residual disease following cytoreductive surgery was independently associated with worse overall survival. Prior studies have also underlined the importance of achieving complete gross resection at the time of cytoreductive surgery. In an ancillary analysis of the GOG-182 trial, which included 189 patients with advanced-stage grade 1 serous ovarian carcinoma, undergoing primary cytoreductive surgery, patients who had optimal (n=97, HR= 3.13, 95% CI 1.96 to 4.98) and suboptimal (n=45, HR=3.31, 95% CI 1.87 to 5.85) cytoreduction had worse progression-free or overall survival compared with those who achieved complete gross resection (n=47).17 An analysis of the AGO meta-base also revealed significant improvement in overall survival among patients with complete gross resection (n=75, HR=0.14, 95% CI 0.07 to 0.29) or optimal (n=31, HR=0.14, 95% CI 0.26 to 1.02) cytoreduction compared with those who had gross residual disease (n=39).12
Strengths and Weaknesses
A major strength of the present study is the large number of patients included, which permitted a meaningful survival analysis. Moreover, data originate from a hospital-based database reflecting real-world practice. Contrary to a prior analysis,18 we opted to include patients diagnosed from 2010 onwards, well after low-grade serous ovarian carcinoma had emerged as a distinct pathological entity19 while we focused on patients with known outcome of cytoreductive surgery. In addition, we performed a systematic review of the literature and pooled data from three studies examining the impact of adjuvant chemotherapy on progression-free survival.
However, several limitations should be mentioned. First, given the absence of central pathology review, the possibility of histology and staging misclassifications cannot be excluded. Molecular or immunohistochemistry data (eg, estrogen receptor expression, presence of MAPK pathway mutations) were not available. Moreover, data on tumor relapse or cause of death are not collected by the National Cancer Database, precluding analysis of differences in progression-free survival or cancer-specific survival. Overall survival may also be influenced from all lines of treatment received, including primary adjuvant treatment and salvage therapies. While we performed a multivariate survival analysis, patients who did not receive adjuvant chemotherapy had more favorable baseline pathologic characteristics (stage II and less likely to have gross residual disease). There was no information on the composition of the chemotherapy regimen administered (including use of bevacizumab maintenance) or data on the number of cycles, and given imbalances in some baseline characteristics selection bias might have been introduced. Similarly, there was no information on the specific anti-estrogen agents used in a subgroup of patients as maintenance treatment. Lastly, unmeasured factors, such as patient’s functional status, presence of specific co-morbidities, or patient’s preferences, might have influenced clinician’s decision to administer adjuvant chemotherapy.
Implications for Practice and Further Research
Results of the present study, as well as other retrospective data, question the usefulness of adjuvant chemotherapy in patients with advanced-stage low-grade serous ovarian cancer following cytoreductive surgery. Nevertheless, these results should be regarded as hypothesis generating since to date there are no prospective data to support omission of adjuvant chemotherapy in this patient group. On the other hand, strong data suggest a survival benefit in the use of hormonal maintenance treatment. It is unclear whether adjuvant chemotherapy can alter tumor biology and increase sensitivity to letrozole maintenance. This question is being evaluated by an ongoing phase III randomized trial. The NRG-GY019 non-inferiority trial is currently enrolling patients with stage II–IV low-grade serous ovarian or peritoneal carcinoma who underwent maximum primary cytoreductive surgery and randomizing them to maintenance letrozole alone or up to six cycles of adjuvant paclitaxel/carboplatin followed by letrozole maintenance. Primary outcome is progression-free survival, while secondary outcomes include objective response rates, quality of life, and overall survival. Participation of eligible patients in that trial is encouraged. Results of the trial are highly anticipated, before modifying current standard of care and omitting adjuvant chemotherapy from the management of these patients. Another multicenter phase III clinical trial (LEPRE; NCT05601700) is enrolling in Italy patients with stage III–IV low-grade serous ovarian carcinoma who underwent primary cytoreductive surgery and randomizes them to adjuvant letrozole (2.5 mg daily until disease progression or up to 60 months) or adjuvant chemotherapy with carboplatin/paclitaxel (6–8 cycles).
While low-grade serous ovarian carcinoma is relatively chemoresistant, as previously discussed, a proportion of patients do respond to chemotherapy. Identification of patients who may benefit from adjuvant chemotherapy also merits further investigation. In a small retrospective study that included 21 patients, high Ki67 expression was identified as predictor of response to chemotherapy.20 On the other hand, in the MITO 22 study, genomic alterations in the MAPK pathway (26.7%), homologous recombination repair DNA pathway (27.8%), and endocrine resistance pathway (23.1%) were not associated with different rates of response to first-line chemotherapy.13
While it is important to consider the use of molecular biomarkers to help select patients who benefit from targeted therapies, this study highlights the importance of measuring the impact of systemic therapies on overall survival outcomes. Low-grade serous ovarian cancer is often an indolent disease, and patients often receive many different types of treatment through their protracted disease course. As such, if treatment does not improve survival, then it may be best reserved for symptom control, or the prevention of complications such as bowel obstruction. This approach helps to protect quality of life and reduce the financial burden of treatment. These are also important considerations for future studies such that we broadly assess of the impact of new therapies on patient outcomes.
CONCLUSIONS
Adjuvant chemotherapy may not be associated with benefit for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery. Further research is highly warranted, and results of an ongoing phase III trial are highly anticipated.
Data availability statement
Data may be obtained from a third party and are not publicly available. Data obtained from American College of Surgeons and Commission on Cancer.
Ethics statements
Patient consent for publication
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
Twitter @amandanfader
Contributors DN conception, data acquisition, data management, statistical analysis, critical analysis, drafting/final editing, guarantor. XW, GD, NL, EMK, RLG, DG, AF, MC critical analysis, drafting/final editing. FS supervision, critical analysis, drafting/final editing.
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.
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.