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Sarcopenia shortens overall survival of patients with platinum-resistant recurrent ovarian cancer: inverse probability of treatment-weighting analysis
  1. Masahiro Aichi1,
  2. Sho Hasegawa2,
  3. Satoru Shinoda3,
  4. Yukio Suzuki1,
  5. Natsuko Kamiya1,
  6. Yumi Ishidera1,
  7. Yuichi Imai1,
  8. Etsuko Miyagi1 and
  9. Taichi Mizushima1
    1. 1Department of Obstetrics and Gynecology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
    2. 2Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
    3. 3Department of Biostatistics, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
    1. Correspondence to Dr Sho Hasegawa, Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama 236-0004, Japan; t166064d{at}yokohama-cu.ac.jp

    Abstract

    Objective The association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian cancer.

    Methods A total of 52 patients diagnosed with platinum-resistant recurrent ovarian cancer who had undergone non-platinum chemotherapy at our institution formed our study population. Body composition and clinicopathological data of these patients were collected retrospectively. Abdominal computed tomography (CT) scans obtained at the time of platinum-resistant recurrent ovarian cancer diagnosis were used to measure the cross-sectional area of skeletal muscles at L3 level. These values were corrected for height to calculate the skeletal muscle index, and accordingly sarcopenia was defined. Overall survival was defined as the primary outcome of the study. The impact of sarcopenia on overall survival was assessed using Cox proportional hazards regression models with inverse probability weighting of treatment based on propensity scores and log-rank tests.

    Results The median patient age was 63 years (IQR: 53–71). The most common International Federation of Gynecology and Obstetrics (FIGO) 2018 stage was stage III (50%) and the most common histology was serous or adenocarcinoma (67.3%). The optimal cut-off value of skeletal muscle index was 35.6 cm2/m2, which was calculated using the data of 21 patients with sarcopenia and 31 without sarcopenia. Sarcopenia was significantly associated with shorter overall survival (HR 1.93; 95% CI 1.06–3.49; p=0.03). Subgroup analysis based on patient attributes and prognostic factors suggested a consistent prognostic impact of sarcopenia. Sarcopenia was identified as a significant risk factor, particularly in patients who had higher CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034) and a higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045).

    Conclusion Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.

    • Ovarian Cancer
    • Carcinoma, Ovarian Epithelial
    • Adnexal Diseases

    Data availability statement

    Data are available upon reasonable request.

    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi.org/10.1136/ijgc-2024-005323

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • Sarcopenia has been reported to be a prognostic factor in patients with ovarian cancer prior to initial treatment.

      WHAT THIS STUDY ADDS

      • We found that sarcopenia at the time of diagnosis of platinum-resistant recurrent ovarian cancer was also a prognostic factor in these patients. We also found that high neutrophil-lymphocyte ratio and high CA125 levels were associated with sarcopenia.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • Thus, sarcopenia is a useful prognostic predictor in patients with platinum-resistant recurrent ovarian cancer. Moreover, our findings underscore the necessity to take measures to prevent sarcopenia in patients with ovarian cancer during the early stages of treatment.

      Introduction

      Ovarian cancer has the highest mortality rate among all gynecological malignancies. In the year 2020, 314 000 people worldwide were diagnosed with ovarian cancer and 207 000 died due to the disease.1 Platinum-based drugs still remain pivotal for ovarian cancer therapeutic regimens, although treatment of ovarian cancer has made remarkable progress with the emergence of bevacizumab, poly-ADP ribose polymerase (PARP) inhibitors2 and antibody-drug conjugates.3 However, the options for treating platinum-resistant recurrent ovarian cancer that recurs within 6 months of platinum-based therapy are limited to monotherapy with non-platinum chemotherapeutic agents such as gemcitabine or liposomal doxorubicin, or combinations of these agents with bevacizumab. The response rate to these chemotherapies is only approximately 15% among patients with platinum-resistant ovarian cancer.4–6 The prognosis for platinum-resistant recurrent ovarian cancer is poor, with a median survival period of 9–12 months, and long-term survival in such patients is rarely expected.6

      A nomogram was developed to predict the prognosis of patients with platinum-resistant recurrent ovarian cancer.7 This nomogram assigned scores to the following parameters: (1) performance status, (2) ascites at the time of diagnosis, (3) platinum-free interval, (4) serum CA125 level, and (5) maximum tumor diameter. In the nomogram, the performance status score, particularly performance status 2, was found to be relatively high. However, no study has focused on the prognostic factors in patients with platinum-resistant recurrent ovarian cancer who demonstrate better performance status (performance status 0 or 1).

      Sarcopenia is characterized by reduction in skeletal muscle mass and decline in physical function.8 Studies on different types of cancers, including liver cancer and multiple malignancies, have reported sarcopenia as an independent prognostic factor.9 10 We previously reported that sarcopenia is an independent prognostic factor in patients with stage III cervical cancer.11 In the context of ovarian cancer as well, reports have indicated that sarcopenia at the time of initial diagnosis is an independent prognostic factor.12 13 Moreover, a meta-analysis focusing on ovarian cancer has demonstrated a significant association between sarcopenia and overall survival.14 Nevertheless, although reports exist proving the association between prognosis of recurrent pancreatic and colorectal cancers and sarcopenia, investigations specifically addressing recurrent gynecologic tumors have not been conducted yet.15 16

      Sarcopenia may also serve as a prognostic indicator in patients with platinum-resistant recurrent ovarian cancer. If sarcopenia acts as a prognostic factor in patients with platinum-resistant recurrent ovarian cancer, it would emphasize the importance of nutritional therapy after the diagnosis of ovarian cancer has been confirmed. Using treatment-related inverse probability weighting based on propensity scores, we aimed to examine the association of sarcopenia on the overall survival of patients with platinum-resistant recurrent ovarian cancer.

      Methods

      Patients

      Patients with histologically diagnosed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who were diagnosed with platinum-resistant recurrent ovarian cancer between April 2009 and March 2023 at our institution formed our study population, and their data were retrospectively collected. Patients who presented with progressive disease (based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) within 6 months of receiving platinum-based chemotherapy were defined as having platinum-resistant recurrent ovarian cancer. Additionally, patients who received chemotherapy and did not have secondary malignancies were included. Other selection criteria included an age of ≥20 years at the time of diagnosis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and no severe organ damage. The medical records of patients diagnosed with and treated for cervical cancer at Yokohama City University Hospital between April 2009 and March 2023 were analyzed. The observation period was defined as the number of days from the diagnosis of platinum-resistant recurrent ovarian cancer until the date of final survival confirmation or death. Information regarding factors that may affect survival, such as age at the time of diagnosis, pretreatment body mass index, histological type, blood investigation data (albumin, creatinine, hemoglobin (Hb), white blood cell (WBC), lymphocyte, and C-reactive protein (CRP)), and tumor markers (carbohydrate antigen (CA125)), were collected and analyzed. All the patients underwent abdominal computed tomography (CT) for the diagnosis of platinum-resistant recurrent ovarian cancer.

      Treatment for Platinum-resistant Recurrent Ovarian Cancer

      Patients were assessed for RECIST v1.1-based disease progression and response to chemotherapy. The chemotherapy regimen primarily consisted of liposomal doxorubicin and gemcitabine, with some patients receiving a combination with bevacizumab. Chemotherapy discontinuation or dose reductions were performed in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Dose reduction or temporary cessation was implemented for grade 3 or higher hematologic toxicities and grade 2 or higher non-hematologic toxicities. Chemotherapeutic efficacy was evaluated using CT every three cycles as a general rule. In the context of disease progression, the regimens were changed to non-platinum-based treatments. Additionally, chemotherapy discontinuation was considered based on declining performance status or patient preference.

      Image Analysis Method

      Cross-sectional enhanced CT (Aquilion 4/16/64, ONE; Toshiba, Tokyo, Japan; LightSpeed Qx/I, LightSpeed Ultra, LightSpeed VCT, Discovery CT 750 HD; GE Healthcare, Milwaukee, WI, USA) data were quantified as described below. Using 3D-CAV (Synapse Vincent; Fuji Film Medical, Tokyo, Japan), sectional CT images at L3 level were analyzed to calculate the skeletal muscle area, including the psoas major, erector spinae, transversus abdominis, quadratus lumborum, external abdominis, internal oblique abdominis, and rectus abdominis muscles (Online Supplemental Figure 1). The Hounsfield unit (HU) threshold of skeletal muscles ranged between −29–150 HU.17 These body composition variables were normalized for height in meters squared and expressed as cm2/m2. Two trained observers (MA and SH) measured the skeletal muscles to assess interobserver reproducibility.

      Supplemental material

      Nutritional Assessment

      This study was retrospective, and accurately assessing the nutritional status of patients at the time of recurrence based solely on clinical information had its limitations. We measured the prognostic nutritional index and conducted exploratory analysis to investigate whether the nutritional status at recurrence was associated with the skeletal muscle index. The prognostic nutritional index was calculated using the formula: prognostic nutritional index =10 × albumin (g/L) + 0.005 × total lymphocyte counts (/mm3). Patients with prognostic nutritional index <40 are considered to be in a state of malnutrition.18

      Endpoints

      The primary endpoint was overall survival, which was defined as the time from the diagnosis of platinum-resistant recurrent ovarian cancer based on abdominal CT to the date of death. As an exploratory analysis, the interaction terms were examined to detect the factors that interact with sarcopenia using a subgroup analysis.

      Statistical Analysis

      The cut-off value utilized for diagnosing sarcopenia was 35.6 cm2/m2, consistent with the thresholds employed in prior studies.11 Concurrently, a sensitivity analysis was conducted using the widely advocated cut-off value of 38.5 cm2/m2.14 19 20 To account for selection bias and confounding factors between the groups, weighted propensity score analysis was performed to correct for differences in baseline characteristics between sarcopenia and non-sarcopenia patients for outcome comparisons. Among the aforementioned prognostic factors, we focused on age at the time of recurrence, ascites at the time of diagnosis and maximum tumor diameter as factors associated with sarcopenia using causal inference. It is widely known that aging decreases muscle mass,21 22 and ascites in ovarian cancer patients can reportedly lead to skeletal muscle loss.23 Additionally, since large tumors are predominantly located in the abdominal cavity and are considered potential confounders for the development of ascites, tumor size was also included as a covariate. Propensity score was calculated as the probability of sarcopenia predicted by multivariate logistic regression, which included factors such as ascites and tumor size, which are both confounding factors for sarcopenia and have been previously reported as prognostic factors in patients with platinum-resistant recurrent ovarian cancer.7 We used the inverse probability weighting of treatment method to estimate the HR using a Cox proportional hazards model, intergroup differences in survival curves via log-rank tests, and Kaplan–Meier curves. Additionally, we used the distribution of propensity scores and love plot to confirm there were no significant issues when adjusting for background using propensity scores. All statistical analyses were performed using R software (version 4.2.0, R Core Team, Vienna, Austria).24 Statistical significance was set at p<0.05.

      Results

      Patient Characteristics

      A total of 664 patients were diagnosed with ovarian cancer, including borderline malignant tumors, at our institution between April 2009 and March 2023. Among them, 133 patients were diagnosed with platinum-resistant recurrent ovarian cancer on the basis of RECIST 1.1 criteria. Of these patients, the following were excluded: 70 who did not undergo chemotherapy (due to low performance status [n=61], declining chemotherapy [n=3], only radiation therapy [n=2], and other cases [n=4]), three who were categorized as performance status 2 (n=3), two with concurrent cancers, three who received CyberKnife treatment, two with cognitive impairment, and one with missing data. Therefore, 52 patients were included in this analysis (Figure 1). The median observation period was 276 days (range: 53–1338).

      Figure 1
      Figure 1

      Flow diagram of the overall study population.

      Information regarding patient age; body mass index; International Federation of Gynecology and Obstetrics (FIGO) classification at the time of initial diagnosis; histological type; prognostic factors of platinum-resistant recurrent ovarian cancer such as platinum-free interval, performance status, ascites, maximum tumor diameter, and CA125 levels; initial chemotherapy regimen after platinum-resistant recurrent ovarian cancer diagnosis; use of bevacizumab; and prior administration of PARP inhibitors before diagnosis were obtained retrospectively from the medical records of the patients. All these data are presented in Table 1 in the context of sarcopenia and non-sarcopenia groups.

      View this table:
      Table 1

      Patient and tumor characteristics

      Clinicopathological Factors Associated with Skeletal Muscle Index

      Table 2 shows the distribution of skeletal muscle index based on the clinical characteristics of patients with platinum-resistant recurrent ovarian cancer. Patients with sarcopenia tended to have lower body mass index. Patients were classified into sarcopenia (skeletal muscle index ≤35.6 cm2/m2, n=21) and non-sarcopenia (skeletal muscle index >35.6 cm2/m2, n=31) groups on the basis of the cut-off value of skeletal muscle index; 20 (95.2%) and 26 (83.9%) patients in the sarcopenia and non-sarcopenia groups died, respectively. The median survival period was significantly shorter in the sarcopenia group than in the non-sarcopenia group (218 vs 343 days; p=0.02). After adjusting for the covariates, the balance between the sarcopenia and non-sarcopenia groups improved through weighting, resulting in an absolute standardized mean difference of less than 0.1 (Online Supplemental Figure 2). Even after inverse probability weighting of treatment adjustment, sarcopenia continued to be significantly associated with worse overall survival (HR, 1.93; 95% CI), 1.06–3.49; p=0.03). In the sensitivity analysis, following inverse probability weighting of treatment adjustment, sarcopenia demonstrated a tendency toward worse overall survival (HR, 1.91; 95% CI, 0.99 to 3.69; p=0.06) (Figure 2).

      Supplemental material

      Figure 2
      Figure 2

      Inverse probability weighting of treatment adjusted Kaplan–Meier curves for 52 patients diagnosed with platinum-resistant recurrent ovarian cancer according to the presence or absence of sarcopenia. (A) In the case where the cut-off value is 35.6 cm2/m2 (B) In the case where the cut-off value is 38.5 cm2/m2.

      View this table:
      Table 2

      Skeletal muscle index with clinical factors of platinum-resistant recurrent ovarian cancer

      Subgroup Analysis

      The subgroup analysis results are presented in Figure 3, wherein patients were categorized into subgroups based on age, administration or no administration of bevacizumab, CA125 levels, neutrophil-to-lymphocyte ratio, platinum-free interval, performance status, and histological subtype to analyze the impact of sarcopenia on overall survival. The influence of sarcopenia on prognosis remained consistent across the subgroups. Particularly, elevated CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034), and higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045) showed strong interaction with sarcopenia.

      Figure 3
      Figure 3

      Forest plot of impact of sarcopenia on overall survival in subgroup populations. HR, hazard ratio; CI, confidence interval.

      The Correlation Between Prognostic Nutritional Index and Skeletal Muscle Index

      Illustrating the distribution of skeletal muscle index among patients with prognostic nutritional index <40 and prognostic nutritional index ≥40 (Online Supplemental Figure 3), the average skeletal muscle index value for patients with prognostic nutritional index <40 was 35.51±5.10 (n=11), while that for patients with a prognostic nutritional index ≥40 was 38.01±6.84 (n=41). No significant differences were observed.

      Supplemental material

      Discussion

      Summary of Main Results

      The primary outcome of this study clarified the negative effect of sarcopenia on the overall survival of patients with platinum-resistant recurrent ovarian cancer. Moreover, even after inverse probability weighting of treatment adjustment, sarcopenia remained a significant factor that shortened overall survival. Additionally, in the exploratory subgroup analysis, a consistent adverse effect of sarcopenia on prognosis was observed, particularly in patients who have elevated CA125 levels and a high neutrophil-to-lymphocyte ratio. These findings suggest the potential interactions among these factors.

      Results in the Context of Published Literature

      Based on the results obtained in this study, we cogitate that the reasons for exacerbation of overall survival due to sarcopenia should be approached from two perspectives. The first perspective suggests that malignancies themselves induce sarcopenia. Malignant tumor cells and surrounding tissues release inflammatory cytokines that inhibit muscle assimilation, which leads to skeletal muscle decline.25 In patients with colorectal cancer, it has been reported that the prognosis of patients with sarcopenia and high neutrophil-to-lymphocyte ratio is poor,26 and similar trends were observed in the subgroup analysis performed in this study. A high neutrophil-to-lymphocyte ratio, which is indicative of widespread inflammation, is considered a sign of advancing cachexia.27

      The second perspective is that sarcopenia affects the treatment outcomes of malignant tumors. Sarcopenia has been associated with dose-limiting toxicities during chemotherapy and increased risk of perioperative complications.28–30 However, evidence linking these increased risks to long-term prognosis has not yet been demonstrated. In this study, dose adjustments for patients with sarcopenia were not made, and dosages were determined based on body surface area. Patients with sarcopenia tended to undergo fewer total cycles of chemotherapy (Online Supplemental Figure 4), which we consider a potential contributing factor to dose-limiting toxicities. Overdosing of anticancer agents might lead to increased risk of side effects, early termination of treatment, and consequently contribute to shortened overall survival, especially in patients with progressive cachexia and relatively decreased skeletal muscle mass in comparison to patients with early-stage cancer. We believe that these mutual relationships between malignant tumors and sarcopenia may contribute to the prognosis.

      Supplemental material

      Next, we discuss the utility of preventing sarcopenia during the prediagnosis or initial treatment phase of platinum-resistant recurrent ovarian cancer. Currently, no interventional studies or investigations are being conducted in this regard. However, evidence suggests the potential of maintaining skeletal muscle mass through nutritional therapy, such as high nutritional diet, in reducing the prevalence of sarcopenia in cancer patients. This would support muscle assimilation and overcome the inhibition of muscle assimilation in malignant tumors.31 32 Although numerous reports have discussed the association between sarcopenia and prognosis of malignant tumors, there is a scarcity of specific clinical research addressing prevention of sarcopenia, including nutritional therapy. Due to the insufficient sample size and information regarding nutritional indices in this study, no significant difference was observed in the evaluation based on the prognostic nutritional index. However, our results suggest that the group with well-preserved skeletal muscle index (mainly ≥40) maintains a preserved prognostic nutritional index.

      Finally, regarding the cut-off value for skeletal muscle index, the value of 38.5 cm2/m2 was established in Caucasian patients with malignant tumors of the respiratory and gastrointestinal tracts. Determining a cut-off value without considering the cancer type and race poses challenges, with reports suggesting that Asians naturally exhibit lower cut-off values compared with Caucasians.33 Indeed, comparative studies utilizing dual-energy X-ray absorptiometry imaging to assess appendicular skeletal muscle mass by race have indicated differences between Caucasian and Asian populations.34 Furthermore, in this study, the mean skeletal muscle index measured from CT scans at the initial diagnosis was 39.46 cm2/m2, whereas at the time of platinum-resistant recurrent ovarian cancer diagnosis, it was 37.48 cm2/m2, indicating a decline in skeletal muscle mass during the course of ovarian cancer treatment. This underscores the dynamic nature of body composition changes between the initial diagnosis and recurrence. Hence, we advocate for the consideration of specific cut-off values when evaluating recurrent cancer in the context of sarcopenia.

      Strengths and Weaknesses

      This study investigated the association between platinum-resistant recurrent ovarian cancer and sarcopenia, and not the previously reported association between initial diagnosis of ovarian cancer and sarcopenia. Patients with platinum-resistant recurrent ovarian cancer form a heterogeneous group with significantly varying background factors, including the treatment process leading to diagnosis, feasibility of post-diagnosis chemotherapy, and activities of daily living at the time of diagnosis. Within this cohort, the study targeted patients with performance status of 0 or 1 who maintained relatively preserved activities of daily living and had aligned background factors to the maximum extent possible to more accurately evaluate whether sarcopenia directly served as a prognostic factor.

      However, this study had a few limitations that need consideration. First, since this was a single-center retrospective study, it was difficult to entirely eliminate biases and confounding factors. Second, the study population only comprised patients of Asian ethnic origin, limiting its focus to a single ethnic group. Third, there is a lack of clear diagnostic criteria for sarcopenia based on skeletal muscle index, and the definition of the European Working Group on Sarcopenia in Older People or the Asian Working Group for Sarcopenia that includes muscle weakness was used for accurate diagnosis.35 36 Finally, although the background factors were aligned, it resulted in a limited sample size.

      Implications for Practice and Future Research

      This study demonstrated an association between sarcopenia in patients with platinum-resistant recurrent ovarian cancer and prognosis. However, prospective investigations are needed to determine how prognosis changes after the diagnosis of platinum-resistant recurrent ovarian cancer when interventions such as nutritional or exercise therapy are implemented at the time of initial ovarian cancer diagnosis to maintain skeletal muscle mass.

      Conclusions

      Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.

      Data availability statement

      Data are available upon reasonable request.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This retrospective study was approved by the Ethics Committee of Yokohama City University Hospital (approval number: F231000026). Since this was a retrospective observational study, informed consent was obtained from the patients via the opt-out method.

      Acknowledgments

      We would like to thank Editage (www.editage.jp) for English language editing.

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      Supplementary materials

      Footnotes

      • Contributors Study design: MA, SH, YS, TM. Data collection: MA. Data analysis: MA, SS, YS, TM. Drafting of the manuscript: MA, SH, SS, YS, NK, YI, YI, TM, EM. SH is responsible for the overall content 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.

      • 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.