Management and prognosis of uterine sarcoma in elderly

Introduction

Background

Uterine sarcoma (US) belongs to a heterogeneous group of malignancies that represents less than 5% of uterine cancers (1,2) and is found as an incidental diagnosis in 26 per 10,000 hysterectomies for benign conditions such as uterine fibroids (3). The American College of Pathologists in 2018 made a classification of US dividing them into adenosarcoma (AS), endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), undifferentiated US (UUS) and other uncommon tumor types such as perivascular epithelioid cell tumor (PEComa) and rhabdomyosarcoma (4).

Rationale and knowledge gap

The median age at diagnosis depends largely on the histological subtype with ESS being reported in younger patients and AS being more commonly diagnosed in patients with a median age of 65 years (5,6). Despite the current context of an increasingly elderly population, clinical course and management of US in this population group remains uncertain.

Definitions of an elderly person ranged from 65 to 80 years and above. The age of elderly in developed countries today could be closer to 70 years, or even older, than the classic definitions of 70 years (7,8). Functional active age of our society has been increasing over the years, and frailty is increasingly implemented in therapeutic decision algorithms according to functional age rather than biological age (9,10). However, in the treatment of US, the age of the patient is a usual limitation to more radical surgical management, with the only evidence of a worse prognosis associated with postmenopausal status. Radical surgical treatment often is the only curative option, the gold standard being hysterectomy and double adnexectomy, given their low chemosensitivity and radiosensitivity, and the absence to date of molecular targets for pharmacological management (11). However, the reality is that surgical management of elderly cancer patients is often limited and there are no studies comparing variables associated with prognosis in this population subgroup.

Objective

We aimed to evaluate the impact of age on the management and oncological outcomes of patients with US focusing on the subgroup of patients older than 70 years of age. We present this article in accordance with the STROBE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-15/rc) (12).

Methods

Patients and procedures

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by CEIM La Paz institutional review board (IRB; No. #PI-1382) and individual consent for this retrospective analysis was waived. It is an international multicenter retrospective study of patients diagnosed with US (the SARCUT Study). The study collected cases of US patients treated between January 1^st, 2001, and December 31^st, 2007, including all histotypes but carcinosarcomas, among 46 European institutions. For cytoreduction nomenclature, we used the one reported by Zapardiel and Morrow (13).

Inclusion criteria were IRB approval from each collaborating center, pathological diagnosis of US, and primary treatment performed at the participating center. Exclusion criteria were carcinosarcoma histology or diagnosis of cancer other than sarcoma. Disease staging was based on the International Federation of Gynecology and Obstetrics (FIGO) 2009 classification system (14). Uniform criteria for surgical procedure nomenclature, pathologic variables, and sites of recurrence were established. If any of the previous conditions were not fulfilled, the cases were excluded from the analysis.

After surgical treatment, patient-appropriate follow-up consisted of clinical examination, blood sampling and computed tomography (CT)-scan/magnetic resonance imaging (MRI). Clinical visits were carried out every three to 6 months for the first year, every 6 months until the fifth year and annually until the end of follow-up. Local or distant recurrences were defined as the appearance of histologically proven malignant tissue. Cases where this follow-up was not performed were excluded from the database. Radiotherapy and chemotherapy were administered at the institution’s discretion based on local protocols.

Overall survival (OS) was defined as the duration from the date of surgery to death or last follow-up, with no restriction on the cause of death. Cancer-specific survival (CSS) was defined as the duration from the date of surgery until death due to oncological disease. Progression-free survival (PFS) was defined as the time from surgery to disease progression or death from any cause.

Data collection was performed via a web-based encrypted database.

Elderly patients were defined as patients aged equal to or over 70 years old, and non-elderly patients were defined as patients with less than 70 years (7,8).

Statistical analysis

Shapiro-Wilk and Kolmogorov-Smirnov tests have been applied to check if the criteria of normality are met and Levene test to check homogeneity of variances. Quantitative variables were presented as mean and standard deviation, and qualitative variables with absolute values and proportions. Differences in the distributions of clinicopathological characteristics among groups were analyzed by independent samples t-test for quantitative variables and with Chi-squared test or Fisher’s exact test for qualitative variables as needed. PFS and OS curves were estimated using the Kaplan-Meier method and were compared among groups using the log-rank test. Independent prognostic factors were assessed using multivariate Cox proportional hazards regression analyses. Hazard ratios (HRs) and their 95% confidence intervals (CIs) are presented to quantify association. A two-sided P value of 0.05 was considered statistically significant. All analyses were performed using Stata Statistical Software: Release 15. StataCorp LLC, 2017.

Results

A total of 688 patients were collected, 122 (17.7%) women ≥70 years old and 566 (82.3%) women <70 years old. The characteristics of both populations are reflected in Table 1.

There were no significative differences in the surgical route, adjuvant radiotherapy, pelvic and aortic lymphadenectomy, FIGO stage, complete cytoreduction, PFS and OS. But there was a significant difference in the chemotherapy received afterward (P=0.001) (Table 2). It is difficult to draw conclusions on the approach as most of the patients were operated by abdominal hysterectomy. Open approach is characterized by a longer recovery time, higher costs and a higher rate of complications. It is possible that where less invasive surgery is safely feasible, it may bring such clinical benefits to patients (15). Median PFS was 111 months, being lower in the non-elderly population (median not reached), although this difference was not statistically significant (log-rank: P=0.86) (Figure S1).

Median OS was 126 months (95% CI: 115–not reached), being higher in the non-elderly population than in the elderly (126 versus 115 months), and this difference was statistically not significant (log-rank: P=0.45) (Figure 1). A total of 161/547 patients (29.43%) in the non-elderly group died, with an incidence rate of 0.65% of patients per month (95% CI: 0.55–0.75%). Deaths were a total of 38/120 (31.66%) elderly patients, with an incidence rate of 0.77% per month (95% CI: 0.55–1.04%). OS data was available for 547 and 120 women of the total population.

Figure 1 Kaplan-Meier survival estimates. Overall survival: non-elderly vs. elderly. Log-rank: P=0.45. Cancer specific overall survival: non-elderly vs. elderly. Log-rank: P=0.47.

Median CSS was 136 and 115 months respectively, with an incidence rate in non-elderly of 0.63% per month (95% CI: 0.53–0.73%) and 0.73% per month (95% CI: 0.53–1.01%) in the elderly group and a log-rank of 0.4692 (Figure 1). Cumulative incidence is presented in Figure 2.

Figure 2 CI of deaths from cancer and other causes in both groups with their confidence limits. CI, cumulative incidence.

A Cox regression was performed with different predictors for OS finding significant univariate association with each increment of 1 year, margin involvement, persistent disease after treatment, extrauterine involvement, histology and chemotherapy (Table 3).

A stepwise backward model selection was performed for variables with P≤0.20 in univariable analysis with P<0.05 to be retained in the final model; only the age (HR: 1.05, 95% CI: 1.03–1.06, P<0.001), histology (AS: HR 0.30, 95% CI: 0.09–0.95, P=0.04 and ESS: HR 0.66, 95% CI: 0.45–0.96, P=0.03), persistent disease after treatment (HR: 2.24, 95% CI: 1.53–3.30, P<0.001), FIGO stage (HR: 1.27 95% CI: 1.08–1.50, P=0.004) and cytoreduction (HR: 1.51, 95% CI: 1.17–1.95, P=0.002) remain significant adjusted for other confounding factors. The same variables remained significant adjusting for the remaining confounding factors for non-elderly (except AS) and for elderly groups separately.

The most frequent histological group among both groups was LMS. Regarding OS only a significant difference was found in AS (log-rank, P=0.02) (Figure 3). In both groups, the two worst survival rates were obtained in undifferentiated groups.

Figure 3 Kaplan-Meier survival estimates. Overall survival by histology: non-elderly vs. elderly. ESS, endometrial stromal sarcoma; CI, confidence interval.

OS was associated with FIGO stage (log-rank, P<0.001) in overall and both groups, but there were no significant differences in each FIGO stage by group (Figure S2).

The cytoreduction performed is significantly associated with the CSS & OS of patients, both globally and by non-elderly and elderly groups (log-rank, all of them P<0.001). Median OS was 126, 61, and 12 months for complete cytoreduction, minimal residual, and gross residual. For the non-elderly, it was 126, 83 and 15 months respectively, and for the elderly group it was not reached for complete resection, for minimal residual it was 32 months, and for gross residual it was 6 months (Figure 4).

Figure 4 Kaplan-Meier survival estimates. Overall survival by FIGO surgical cytoreduction: non-elderly vs. elderly. Log-rank for Surgical cytoreduction (overall and by groups): P<0.0001. Log-rank for non-elderly vs. elderly: complete resection, P=0.51, minimal residual, P=0.85, gross residual P=0.42. FIGO, International Federation of Gynecology and Obstetrics.

Discussion

Key findings

Elderly population treated for US has a similar OS and CSS between the two, and it is the histological subtypes, FIGO stage and type of cytoreduction that determine survival.

In our analysis we have set the age limit for defining an elderly person at 70 years of age. The United Nations has established the age of 60 years as the age of an “elderly” person, although in various sociocultural environments other variables such as family status (grandparents), physical appearance or diseases typical of age are included in this definition; and it should be taken into account that certain traumatic experiences, together with malnutrition, exposure to diseases and living conditions of certain populations such as refugees can accelerate this aging process.

This is not the reality we live in our environment in the third world, where we consider patients with gynecological cancer aged 65 years to be young patients, and we place the upper limit, applying frailty scales above 70 years of age, in a similar way as other authors do (7,8).

Elderly woman management could be challenging due to associated pluripathology and lack of specific clinical guidelines. While elderly population demonstrated lower OS and CSS than those in non-elderly group, no differences were found. Previous research had reported age as an independent prognosis factor in OS and PFS but cut-off point between age groups varies among different research (16), which makes comparison challenging. Also, clinical behavior among the different histological subtypes could have an impact on results and affect the reliability of comparing published studies with each other.

In this study we demonstrate that age per se is not a factor that determines the prognosis of the disease, but that it is the histology, stage and cytoreduction performed that determine its prognosis; and the surgical effort to be made should be in accordance with the functional status of the patient and her vital state.

Strengths and limitations

The lack of a geriatric assessment is one of the main limitations of our study, as well as the shortage of literature on aged-specific studies to interpret obtained results. Of course, the retrospective nature of our study is an added limitation, although it would have been very difficult to obtain the number of cases we analyzed otherwise. The retrospective nature of the study may have had a greater influence on certain variables that were more susceptible to error in their collection and may explain results such as the similarity between overall and CSS. Since sarcoma is a very infrequent disease, evidence-based recommendations about management, especially in elders’ patients, might be challenging.

On the other side our study also has several strengths to highlight, it is one of the largest series published about US so far (17-19) and allows for analysis of the relevance of multiple variables, which is one of the main limitations in studies looking at US. Cases were collected in a multicentric database in which hospital participants comply with ESMO/EURACAN/GENTURIS guidelines for US management (20).

Comparison with similar research

Elderly patients appeared to behave to different histological subgroups the same way as non-elderly patients did. Contrasting survival results among the diverse subtypes highlights the aggressiveness of each one, especially in the case of undifferentiated sarcoma. US represents an increase in mortality compared to the most prevalent sarcoma, LMS, of an HR 2.13. This increase is up to an HR 5.84 in the group of patients aged over 70 years old.

When stratified by FIGO stage, prognosis did not differ between both groups. Even in FIGO stage III, where the biggest difference was found, it was not significant.

Regarding the analysis according to histology, LMS was the most common sarcoma subtype in non-elderly patients. Hensley et al. published a prospective series of 25 patients with LMS I–IV stage at diagnosis and described a median PFS of 13 months (21). Chantharasamee et al. described in retrospective research of 68 cases of LMS found a PFS of 23.1 months (22).

In most studies, tumor burden after cytoreductive surgery is not described, which could have impacted results, as it has been described as an independent prognosis factor (23). Other series described residual burden after surgery (>1 cm) in 24% of cases of uterine carcinosarcoma at III–IV stages (23,24). Our series showed complete cytoreduction in 84.3–84.9% of patients (in non-elderly group and elderly group respectively), and age did not impact in likelihood of complete surgery. Complete cytoreductive surgery was strongly associated in our study with improved survival with a median OS of 126 months and, meanwhile, non-elderly group showed better OS in tumor burden <1 and >1 cm than the elderly group (83 vs. 32 months and 15 vs. 6 months; respectively); there was no statistical association. However, the importance of complete cytoreduction in elderly group must be highlighted because of its ominous results.

It was observed that there was a lower likelihood for elderly patients to receive adjuvant chemotherapy which can be justified because of their fragile basal status. Nevertheless, the role of adjuvant chemotherapy has been largely discussed in previous reports yet there is still a lack of solid evidence available in its favor. An initial report showed slightly improved survival in the chemotherapy group, but it could not be demonstrated in statistical analysis (23). While others did not even find any improvement in survival in adjuvant chemotherapy treatment (25,26). Most studies used chemotherapy schemes based on doxorubicin or gemcitabine-docetaxel. Controversy continues nowadays, with studies supporting that chemotherapy can be beneficial for early-stage LMS showing prolonged PFS in comparison to historical reports (27) and others which did not find any differences in recurrence rate (28,29). Our study found a trend to improved CSS and OS in non-elderly patients who received adjuvant chemotherapy but not for patients over 70 years old. Further investigation must be carried out concerning this issue.

It must be considered that adjuvant treatment or surgery should not be denied to elderly patients just because of chronological age. The World Health Organization (WHO) 2015 report about aging and health, defends the right of the elderly population to receive quality healthcare without being discriminated (30). Each patient must be considered individually in terms of comorbidity, psychological and nutritional status, social support, and cognitive functionality, so the developing and implementation in clinical practice of geriatric assessment to identify risk factors have become more frequent (31-33).

Conclusions

Age alone should not be a contraindication for treatment with curative intention in patients with US. Patients aged ≥70 years do not have a different CSS compared to younger patients so maximal surgical effort should be carried out to achieve complete removal of the disease.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-15/rc

Data Sharing Statement: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-15/dss

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-15/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-15/coif). M.G. receives consulting fees from Medtronic, payment for lectures from Lumbeck, payment for lectures and training from Olympus, and support for attending meetings from Techdow Pharma Netherlands and Olympus. P.J.C. receives payment for lectures from Shiongi, payment for proctor in surgeries from Abex, and support for attending meeting and travel from Shiongi. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by CEIM La Paz institutional review board (No. #PI-1382) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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