Objectives To evaluate differences in survival and recurrence patterns in stage I–IV uterine carcinosarcoma patients treated with surgery followed by adjuvant chemotherapy alone, radiation alone, or a combination of both chemotherapy and radiation therapy.
Methods A multicenter retrospective analysis of patients with surgically staged carcinosarcoma receiving adjuvant therapy from January 2000 to December 2019 was conducted. Inclusion criteria were patients with carcinosarcoma who had received primary surgical treatment, followed by adjuvant therapy with chemotherapy alone, radiation therapy alone, or a combination of chemoradiation. Patients were excluded for incomplete surgical staging data, adjuvant brachytherapy alone, adjuvant chemotherapy and brachytherapy without external beam radiation therapy, receipt of neoadjuvant chemotherapy and/or pre-operative pelvic radiation, and death due to non-cancer causes. Sites of recurrence were analyzed by adjuvant treatment modality using Pearson’s χ2 test. Progression-free and overall survival were calculated using Kaplan-Meier estimates. Multivariate analysis was performed using Cox proportional hazards model.
Results Of 176 evaluable patients, 27% (n=47) had stage I, 14% (n=24) stage II, 37% (n=66) stage III, and 22% (n=39) stage IV disease. Among them, 33% (n=59) received chemotherapy alone, 17% (n=29) received radiation therapy alone, and 50% (n=88) received chemoradiation. Patients with stage I disease recurred less frequently (64%) versus stage II (83%), stage III (85%), and stage IV (90%) (p<0.001). Stage I disease demonstrated improved progression-free and overall survival relative to all other stages (p<0.01). Across all stages, patients receiving chemoradiation experienced superior progression-free (p=0.01) and overall survival (p=0.05) versus single modality therapy. However, when analyzed in a stage-specific manor, stage III disease derived the greatest survival benefit from chemoradiation versus all other stages (p<0.01). On multivariant analysis, only stage and receipt of chemoradiation were independent predictors of survival.
Conclusion Stage I disease demonstrated improved survival compared with other stages regardless of adjuvant treatment modality. Chemoradiation was associated with improved survival and better distant and local disease control for all stages of disease. Patients with stage III disease derived the most benefit from chemoradiation.
Data availability statement
Data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The cornerstone of adjuvant therapy for all stages of uterine carcinosarcoma is chemotherapy. However, there is lack of prospective data to guide the addition of external beam radiation to chemotherapy in this patient population, therefore, studies are needed to identify the benefit of radiation and those patients who will benefit most from the addition of radiation therapy.
WHAT THIS STUDY ADDS
The present study demonstrates a benefit to the addition of radiation to chemotherapy in patients with stage III uterine carcinosarcoma.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The results of this study suggest the benefit of the addition to radiation therapy to chemotherapy may be limited to those patients with stage III disease. Further prospective research to confirm this benefit will help individualize adjuvant therapy and improve patient outcomes.
Carcinosarcoma is a rare, aggressive variant of endometrial carcinoma which poses a clinical management challenge due to its biologic behavior driven by both carcinomatous and sarcomatous components. Although it accounts for only 5% of all endometrial carcinomas, carcinosarcoma is responsible for a disproportionate amount of endometrial cancer related deaths due to its propensity for distant and local metastasis secondary to lymphatic, hematologic, and peritoneal spread.1 2 At the time of initial diagnosis, over 60% of patients will have metastatic disease to the upper abdomen, lung, or retroperitoneal lymph nodes.1 2 Although traditionally classified as a sarcoma, more recent data indicate a monoclonal cell origin and a metaplastic transition from epithelial to mesenchymal components.3 4 This is supported by genomic data from The Cancer Genome Atlas.5 Additionally, the majority of carcinosarcomas follow a clinical disease course most closely related to that of high-grade endometrial carcinomas, specifically, uterine serous carcinoma. As a result, carcinosarcoma is currently classified and managed as a high-grade endometrial carcinoma.5 6
Due to the overall rarity of this tumor, randomized trials are difficult and require many years of accrual to achieve statistical power. Consequently, the majority of literature specific to carcinosarcoma is retrospective in nature, and therefore limited by selection bias. Currently, the accepted management paradigm of carcinosarcoma is total hysterectomy, bilateral salpingo-oophorectomy, and surgical staging, followed by systemic chemotherapy, with or without pelvic radiation therapy.6 Due to the significant risk of distant and abdominal failure, chemotherapy has been well established as the cornerstone of adjuvant therapy. The recently published Gynecologic Oncology Group (GOG) 261 established carboplatin and paclitaxel as the preferred first-line chemotherapy regimen for all stages of carcinosarcoma, based on its non-inferiority and improved side effect profile compared with the previous standard of care regimen of paclitaxel and ifosfamide.7 By contrast, the role of radiotherapy remains controversial.8–10
At present, the only prospective data to guide the use of pelvic radiation therapy in carcinosarcoma is based on the results of the European Organisation for Research and Treatment of Cancer (EORTC) 55874, which evaluated adjuvant pelvic radiation therapy as a single modality in uterine confined disease. The authors observed an improvement in local control with radiation therapy versus observation; however, this did not translate into a survival benefit and excluded patients with stage III and IV disease.11 Currently, there are no prospective evaluations of the use of radiation therapy in combination with chemotherapy in the setting of advanced uterine carcinosarcoma. The GOG 258 trial evaluated the addition of radiation therapy to chemotherapy in advanced endometrial cancer. However, carcinosarcoma was excluded from this analysis.12 Multiple retrospective reviews have reported a benefit with combination chemoradiation, and this approach was recently endorsed by the American Radium Society multidisciplinary expert panel for the management of both early and advanced disease.13–15
Due to the paucity in prospective data, the utilization of radiation therapy has varied, as has the trend in the specific types in radiation therapy over time. Recently, Matsuzaki and colleagues published a contemporary clinical summary and review of the literature on uterine carcinosarcoma in which they included a review of adjuvant therapy practices and survival trends over the past 30 years. The authors reported an increase in the administration of chemotherapy and brachytherapy, with a recent decrease in the utilization of pelvic radiation therapy in an inverse relationship. Despite the alterations in the combinations of adjuvant therapy and a shift from ifosfamide-based to carboplatin-based systemic therapy, the overall survival remained stable over a 37-year period, with a disappointing 5-year overall survival rate of only 33.4%.16 Perhaps an additive approach to adjuvant therapy, rather than substitution of one modality for another, may lead to survival gains.
Previously, our group retrospectively evaluated the optimal adjuvant therapy strategy in a cohort of 148 patients with surgically staged, stage I–IV uterine carcinosarcoma. We observed a 6-month overall survival advantage with combination of chemotherapy and external beam radiation therapy with or without vaginal brachytherapy versus chemotherapy alone across all stages. These findings were not only statistically significant but represent a clinically significant survival gain in a disease with a dismal prognosis.17 Based on our prior findings, we now look to better guide individualized therapy by evaluating the optimal adjuvant therapy strategy for each specific stage of disease. In the current report, we present an updated and expanded stage-specific analysis of survival based on an adjuvant therapy regimen to determine if a specific subset of patients will receive a greater benefit with dual modality therapy.
From January 2000 to December 2019, a multicenter retrospective analysis of patients with uterine carcinosarcoma was conducted. Institutional review board approval was obtained at all participating sites. Tumor registries were reviewed to identify all patients with carcinosarcoma who received primary surgical treatment, followed by curative intent adjuvant therapy with chemotherapy alone, radiation therapy alone, or a combination of chemoradiation. Radiation therapy was defined as external beam radiation therapy with or without vaginal cuff brachytherapy. Chemoradiation was defined as receipt of at least three cycles of systemic chemotherapy prior to, after, or in sandwich sequence with external beam radiation therapy±vaginal brachytherapy. Chemotherapy alone was defined as receipt of at least three cycles of chemotherapy without external beam radiation therapy or vaginal brachytherapy. Patients receiving only cisplatin radiosensitization and no other systemic therapy were classified as radiation therapy only.
Primary surgical management was defined as hysterectomy with or without bilateral salpingo-oophorectomy and comprehensive surgical staging or cytoreductive surgery. Comprehensive surgical staging consisted of both pelvic and para-aortic lymph node dissection with or without omentectomy. Sandwich sequence was defined as the administration of three cycles of chemotherapy prior to radiation therapy followed by three additional cycles after the completion of radiotherapy. External beam radiation delivery strategies have varied over the 19-year course of this study, based on practice changes in radiation oncology, and include conventional four-field technique and intensity modulated radiation therapy. Patients with pathologically confirmed positive pelvic lymph nodes with or without positive para-aortic lymph nodes received extended field radiation therapy encompassing the para-aortic node basin based on institutional practices. It is standard practice at our institutions to perform pre-operative computed tomography imaging. Post-operative imaging was performed based on the discretion of the gynecologic oncologist and radiation oncologist and patient symptomatology. Exclusion criteria included histologic diagnosis other than carcinosarcoma, patients with incomplete surgical staging data or patients undergoing sentinel lymph node biopsy alone without subsequent full lymphadenectomy, adjuvant brachytherapy alone, adjuvant chemotherapy and brachytherapy without external beam radiation therapy, patients completing <50% of planned external beam radiation dose, patients in receipt of neoadjuvant chemotherapy and/or pre-operative pelvic radiation, and death due to non-cancer causes. Additionally, patients with a follow-up time of less than 6 months from completion of adjuvant therapy or those lost to follow-up were excluded from analysis. Lost to follow-up was defined as patients who failed to follow-up with either in-person or tele-visits for greater than a 12-month period.
Clinical and demographic data were obtained from a review of the tumor registry, operative notes, pathology reports, and both inpatient and outpatient medical records. Data regarding date of diagnosis, surgical procedures, types of adjuvant therapy, date and site of recurrence, chemotherapy regimen, number of chemotherapy cycles received, type of radiation therapy received, and date of death were extracted. A one-way analysis of variance (ANOVA) test was used to compare differences in mean age between treatment arms. Differences in the frequencies of treatment delays and sites of disease recurrence were identified using Pearson’s χ2 test. Progression-free survival was defined as the time of surgery to the time of first recurrence. Overall survival was defined as time of surgery to time of death. Patients who were alive at the date of the last follow-up were censored. Progression-free and overall survival rates were calculated using Kaplan-Meier estimates. Multivariate analysis was performed using Cox proportional hazards model. Statistical significance was defined as p<0.05. Analysis was performed using Statistical Package for the Social Sciences (SPSS) version 26.0 (International Business Machines Corp (IBM), Armonk, NY).
A review of our tumor registry identified 192 patients with uterine carcinosarcoma. Sixteen (8%) patients were excluded due to receipt of neoadjuvant therapy, incomplete surgical staging information, refusal of adjuvant therapy, or death due to non-cancer related cause. Final analysis included 176 patients with follow-up data available. The mean age was 66.5 years (range 49–87) and the majority of patients were African American (85%). Stage distribution included 26.7% (n=47) stage I, 13.6% (n=24) stage II, 37.5% (n=66) stage III, and 22.2% (n=39) stage IV. Eighty-eight patients (50.0%) received combination chemoradiation, 59 (33.5%) patients received chemotherapy alone, and 29 (16.5%) patients received radiotherapy alone. The chemoradiation cohort was comprised of 30.7% (n=27) sandwich sequence, 38.6% (n=34) chemotherapy-radiation sequence, and 30.7% (n=27) radiation-chemotherapy sequence. There was no difference in the age or race distribution between different stages or adjuvant therapy regimens (p>0.05). The stage distribution was well balanced across different adjuvant therapy regimens (p=0.15) and there was no difference in the use of specific chemotherapy regimens between chemotherapy-alone and chemoradiation cohorts (p=0.35) (Table 1).
The majority of patients in both arms received platinum-based chemotherapy (125/147; 85.0%). The most common regimen was carboplatin-paclitaxel (84/147; 57.2%). Other regimens included cisplatin-ifosfamide (35/147; 23.8%), paclitaxel-ifosfamide (14/147; 9.5%), ifosfamide single agent (6/147; 4.1%), carboplatin-paclitaxel-bevacizumab (4/147; 2.7%), pegylated liposomal doxorubicin (2/147; 1.4%), and pegylated liposomal doxorubicin-carboplatin (2/147; 1.4%). There was no significant difference in specific chemotherapy regimens between adjuvant therapy arms (p=0.35). The median number of cycles received in both cohorts was six (range 3–10). Of the patients receiving chemoradiation, the majority received external beam radiotherapy to the pelvis with or without extended field (68/88; 77.3%). The remaining received a combination of external beam radiotherapy±extended field plus vaginal brachytherapy (20/88; 22.7%). Sixty patients (40.5%) experienced a delay in treatment; 42.3% (n=37) of the chemoradiation cohort, 36.2% (n=21) of the chemotherapy-alone cohort, and 31.7% (n=9) of the radiotherapy-alone cohort (p=0.61). The most common reason for treatment delay in both arms was neutropenia. Other toxicities leading to treatment delay included thrombocytopenia, anemia, neurotoxicity, and nephrotoxicity.
Overall, 141 (80.1%) patients recurred during the study period with a total of 179 individual sites of disease recurrence. Patients with stage I disease were significantly less likely to recur versus all other stages. At a median follow-up of 34 months (range 6–60), 64% (n=30) of patients with stage I disease had recurred compared with 83% (n=20) of stage II, 85% (n=56) of stage III, and 90% (n=35) of stage IV disease (p=0.011). The most frequent location of disease recurrence was the abdomen (83/179; 46.4%), followed by the pelvis (51/179; 28.5%), lungs (40/179; 22.3%), and extra-peritoneal distant sites (4/179; 2.2%). Patients receiving chemotherapy alone were more likely to experience pelvic failure, but this difference was not statistically different (p=0.06). Additionally, we observed a trend for more abdominal recurrences in the radiotherapy alone group compared with chemotherapy alone or chemoradiation (p=0.07) (Online Supplemental Table 1).
The median follow-up was 34 months (range 6–60). The progression-free survival of the entire cohort was 13 months, and the median overall survival was 24 months. The median progression-free survival was higher in stage I (18 months) compared with stage II (11 months), stage III (14 months), and stage IV (10 months) (p<0.001). The median overall survival was also significantly longer in patients with stage I (30 months) versus stage II (23 months), stage III (24 months), and stage IV (16 months) disease (p=0.009) (Online Supplemental Figure 1). Across all stages, the median progression-free survival was improved with chemoradiation (15 months) compared with chemotherapy or radiation alone (11 months) (p=0.01). Additionally, there was a trend towards improved overall survival with the combination of chemoradiation (28 months) versus either modality alone (20 months) (p=0.054) (Table 2, Figure 1).
An exploratory analysis was conducted for each stage based on type of adjuvant therapy. Although, as an entire cohort, we observed improved progression-free and overall survival with the combination of chemoradiation, this improvement only reached statistical significance in stage III disease. In stage III disease, the combination of chemoradiation achieved a progression-free survival of 16 months compared with 11 months and 5 months with chemotherapy alone and radiation therapy alone, respectively (p<0.001). Similarly, the stage III patients experienced improved overall survival of 28 months versus 21 months and 13 months with chemotherapy alone and radiation therapy alone, respectively (p<0.001) (Table 2, Figure 2). On multivariate analysis, only stage and receipt of chemoradiation were independent predictors of survival (p<0.05). Age, race, and chemotherapy regimen did not independently alter survival outcomes (p>0.05) (Table 3).
Summary of Main Results
In the present study, we observed an improvement in both progression-free and overall survival across all stages of uterine carcinosarcoma with the combination of chemotherapy and radiation therapy compared with either modality alone. When analyzed in a stage-specific manner, the greatest benefit from dual modality therapy was observed in patients with stage III disease, suggesting that the addition of radiation to systemic chemotherapy is a critical component of adjuvant therapy in this aggressive disease.
Results in the Context of Published Literature
Our findings are consistent with those of the randomized, prospective PORTEC III which evaluated external beam radiation therapy alone or in combination with concurrent cisplatin followed by four additional cycles of carboplatin-paclitaxel.18 Although this trial excluded patients with carcinosarcoma, there are several key points relevant to the current report. First, pre-planned subanalysis demonstrated that patients with stage III disease received the greatest benefit to combination chemoradiation. Additionally, a post-hoc analysis, based on The Cancer Genome Atlas classification schema, demonstrated that only p53 mutant patients derived a significant benefit from the combination of chemoradiation.19 Data from The Cancer Genome Atlas suggest 90% of carcinosarcomas will harbor mutant p53, further supporting the use of multimodality adjuvant therapy in this histology.20 It is also worth noting that GOG 258, a prospective randomized trial which evaluated chemotherapy alone versus chemoradiation in advanced endometrial carcinoma, excluded patients with carcinosarcoma . This trial failed to demonstrate a survival advantage to the combination of chemoradiation over chemotherapy alone and is referenced by some as support for omission of radiation therapy in advanced endometrial carcinoma.12 However, these results are not generalizable to the carcinosarcoma population.
The majority of carcinosarcomas are composed primarily of carcinomatous elements. However, approximately 40% of all carcinosarcomas will be classified as sarcoma dominant, defined as >50% sarcoma elements. Recent literature suggests carcinosarcomas demonstrating sarcoma dominance carry a poor prognosis relative to their carcinoma dominant counterparts.21 22 Relative to the current report, a recent large scale retrospective review noted that patients with sarcoma dominant tumors experienced improved progression-free and cancer-specific survival when radiotherapy was added to chemotherapy compared with chemotherapy alone.21 In the present study, patients were not classified based on the proportion of carcinomatous versus sarcomatous components. However, based on the findings of Matsuo et al, the authors believe designation of carcinomatous or sarcomatous dominant could help guide treatment decisions in non-stage III patients, where the role of radiation therapy remains less certain.
The adoption of sentinel lymph node mapping to the standard surgical management of endometrial cancer has not only decreased the morbidity associated with full pelvic lymphadenectomy, it has led to an overall increase in the amount of nodal metastasis detected secondary to identification of small volume nodal disease.23 Because of this increase in small volume nodal disease at the time of initial surgery, we have observed a stage migration from uterine confined disease to stage IIIC disease. Simultaneously, this leads to an increase in the percentage of patients who will require more aggressive adjuvant therapy.23 24 Recently, both prospective and retrospective literature demonstrate the accuracy and reliability of sentinel lymph node biopsy in high-grade endometrial carcinomas, including carcinosarcoma. The recently published prospective SENTOR (Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging) trial, a validation trial evaluating the accuracy of sentinel lymph node biopsy in high-risk endometrial carcinomas, demonstrated that 78% of the lymph node positive patients would not have been identified by traditional pathologic evaluation of pelvic lymph nodes.25 These findings are extremely relevant to the current report. We observed the most significant survival improvement from combination chemoradiation in stage III disease, making it critical that we accurately identify those patients with nodal disease.
The present study did not include patients undergoing sentinel lymph node biopsy alone without completion lymphadenectomy. During the study period, the use of this modality for lymph node assessment in carcinosarcoma was primarily investigational and therefore no patients in our cohort underwent sentinel lymph node biopsy alone. Because of the limitations of traditional pathologic lymph node assessment, as demonstrated by the SENTOR trial, we cannot estimate the percentage of patients with presumed stage I/II disease who would have in fact been upstaged with sentinel lymph node assessment, and this could significantly alter survival outcomes. Future investigations of adjuvant therapy in this population are warranted.
Implications for Practice and Future Research
To address the predominant patterns of treatment failure, more effective systemic therapies are needed. As the future of oncology continues to evolve towards individualized therapy, it is important to recognize the potential role of targeted therapy in carcinosarcoma. Specifically, approximately 60% of carcinosarcomas express programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), 20% demonstrate microsatellite instability, and an additional 10% will be identified as polymerase epsilon (POLE) mutant.26 All of the aforementioned mutational aberrations have demonstrated sensitivity to immune-check point blockade with anti-PD-1/PD-L1 inhibition across a range of solid tumors, including endometrial carcinoma.27–29 The recently published KEYNOTE 775 trial demonstrated a significant survival advantage with the use of pembrolizumab combined with multi-tyrosine kinase inhibitor lenvatinib over traditional chemotherapy in the setting of recurrent endometrial carcinoma.30 Although this trial excluded carcinosarcoma, one third of patients in the study were classified as high-grade carcinomas. Notably, a single institution retrospective review of the lenvatinib-pembrolizumab combination demonstrated a 25% response rate and 58% clinical benefit rate in patients with carcinosarcoma.31 The relevance of these findings to the current study lies in the recent evidence suggesting radiation enhances the efficacy of immune checkpoint blockade in this patient population. Current trials investigating the role of immune checkpoint inhibitors in the frontline management of endometrial cancer are underway.32 The addition of radiation to this treatment cocktail is intriguing and the cumulative action of these different modalities demonstrate significant promise in in vitro models and other solid tumors.33 Unfortunately, our cohort has incomplete molecular profiling data based on the more recent adaptation of this as a routine practice. We are currently collecting molecular data on the present cohort with the goal of guiding adjuvant therapy decisions based on molecular data rather than pathologic data alone.
The impact of chemotherapy and brachytherapy without external beam radiation therapy was not evaluated in the present study. This was due to a small number of patients receiving chemotherapy and brachytherapy only, and concerns that this would cloud recurrence pattern data without adequate numbers to draw conclusions. Moreover, several different chemotherapy regimens were utilized in our cohort based on the large study period and trends in chemotherapy use overtime. Ideally, a future evaluation of carboplatin and paclitaxel plus brachytherapy versus carboplatin and paclitaxel plus external beam radiation therapy would clarify the benefit of each radiation mode and the impact on local recurrence with a standard systemic therapy regimen. Additionally, as discussed above, no patients in our cohort underwent sentinel lymph node mapping alone. As sentinel lymph node mapping moves into standard management algorithm for our high-risk uterine cancer patients, including carcinosarcoma, evaluation of adjuvant therapy in this population is an area of interest and future research.
Strengths and Weaknesses
The major limitation to the current report is its retrospective nature. Additionally, this study spans a 19-year time period, and there have been paradigm shifts in the specific chemotherapy regimens used throughout this time. However, the majority of patients received an ifosfamide-based or platinum-based chemotherapy regimen, and the use of specific cytotoxic agents was well balanced between treatment cohorts. Additionally, molecular data are lacking in the majority of this cohort, as it did not become common practice to molecularly profile all uterine carcinomas until the later part of the study period at our institutions. A key strength of the current report is the inclusion of only completely surgical staged patients with a minimum follow-up of 6 months. Despite these limitations, we observed an 8-month improvement in overall survival with combination chemoradiation across all stages of disease. When evaluating each stage individually, only patients with stage III disease achieved a statistically significant survival benefit from multimodal therapy. These hypothesis generating data are an important first step towards developing risk-adapted adjuvant treatment recommendations for carcinosarcoma. Additionally, in the era of individualized and targeted therapy, future investigations should not only focus on the combination of chemoradiation, but also on molecular tumor characterization to identify novel treatment pathways and targeted therapy options in combination with radiotherapy, with the goal of further improving outcomes for this high-risk patient population.
The combination of chemotherapy and external beam radiation was associated with improved survival as well as better distant and local disease control across stage I–IV disease when evaluated as a single cohort. However, when evaluated by stage, the survival benefit of chemoradiation was confined to patients with stage III disease, suggesting that individualizing adjuvant therapies based on stage and histology will contribute to improved patient outcomes.
Data availability statement
Data are available upon reasonable request.
Patient consent for publication
This study involves human participants and was approved by SUNY Downstate IRB 1138503-6. Retrospective review.
Contributors JM: conceptualization, methodology, formal analysis, writing – original draft, guarantor; YJC: data curation; NZ: data curation; JK: writing – review and editing; CG: writing – review and editing; MJK: conceptualization, writing – review and editing; YCL: methodology, writing – review and editing, supervision, project administration.
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.
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