Abstract
Background/Aim: The prognosis of metastatic and inoperable sarcomas is extremely poor, and intensive chemotherapy-based treatment is typically administered to prolong survival. Currently, pazopanib, eribulin, and trabectedin are key drugs used in patients with these sarcomas. The aim of the study was to identify prognostic factors for metastatic and inoperable bone and soft tissue sarcomas. Patients and Methods: Clinicopathological data of 46 patients with metastatic and inoperable sarcomas treated with pazopanib, eribulin, and trabectedin between January 2013 and February 2022 at our institution were retrospectively analyzed. Age, sex, primary tumor location, adverse effects, history of doxorubicin and radiation therapy, performance status scores, maximum tumor response, and survival duration were evaluated. The significant prognostic factors were identified using Cox proportional hazards models. Moreover, the 5-year survival rate was evaluated using the Kaplan-Meier method. Results: The median survival duration after treatment was 13.3 months, where the 5-year overall survival rate was estimated to be 9.85%. Both univariate and multivariate analyses revealed significant relationships among patient prognosis, performance status, and tumor response. Conclusion: Performance status scores and tumor response were significantly associated with patient prognosis. Therefore, regardless of age, sex, primary tumor location, adverse effects, and history of doxorubicin and radiation therapy, use of cutting-edge drugs, such as pazopanib, eribulin, and trabectedin, may be advantageous in patients with advanced sarcomas, if their drug response and performance status scores are good.
Soft tissue sarcomas do not occur frequently, accounting for 1% of all malignant tumors (1). Approximately 50% of patients with soft tissue sarcomas develop distal metastasis despite adequate treatment, such as wide resection based on treatment guidelines (1). The standard treatment for metastatic sarcomas includes systemic chemotherapy aimed at prolonging survival or extending palliative care for comfort measures (2). However, the prognosis of metastatic and inoperable sarcomas is still extremely poor, with an overall patient survival of less than 1 year without treatment (3).
Doxorubicin, the only approved first-line chemotherapy for patients with metastatic and inoperable sarcomas, has been used for more than 40 years (4). Prior to 2012, chemotherapy with doxorubicin and ifosfamide was approved only for patients with soft tissue sarcomas in Japan. However, the inherent heterogeneity of soft tissue sarcomas makes the development of new anticancer drugs extremely difficult, owing to the abundance of histological subtypes (5).
In the last decade, three new anticancer drugs (pazopanib, eribulin, and trabectedin) were introduced for patients with metastatic and inoperable sarcomas who had been previously treated with doxorubicin (6-8). Notably, these cutting-edge drugs can now be administered to patients without a history of systemic doxorubicin-based chemotherapy for various types of sarcomas in Japan, based on the findings of various clinical trials (9).
Previous studies have focused on metastatic and inoperable sarcomas to analyze clinical outcomes, with respect to the use of three new drugs (pazopanib, eribulin, and trabectedin), and patient prognoses. However, only a few reports have indicated the optimal prognostic factors with the intent to elucidate the clinical efficacy of these cutting-edge drugs. Therefore, the aim of this study was to identify prognostic factors for advanced sarcomas following treatment with these drugs.
Patients and Methods
Data aggregation. We retrospectively investigated the clinical characteristics of 46 patients (33 men and 13 women; median age at initial consultation: 58.5 [range 15-85] years) treated with new drugs (pazopanib, eribulin, and trabectedin) for metastatic and inoperable sarcomas at the Department of Orthopaedic Surgery (Osaka Metropolitan University Hospital) between December 2012 and February 2022. This study was approved by the Institutional Review Board of the Osaka Metropolitan University Graduate School of Medicine and was conducted based on the ethical standards outlined in the Declaration of Helsinki (no. 4394).
Patient diagnoses. All patients underwent radiological examinations, such as X-ray examination, local computed tomography (CT), and magnetic resonance imaging (MRI) with or without gadolinium enhancement. Fluorodeoxyglucose positron emission tomography (FDG-PET) coupled with CT and chest CT was performed to evaluate distant metastases before treatment. All specimens after biopsy were evaluated by three pathologists specializing in sarcoma pathology, based on the standard diagnostic criterion for soft tissue sarcoma (1).
Parameters. The following pre-chemotherapy parameters were assessed: age, sex, primary tumor location, adverse effects, history of doxorubicin and radiation therapy, performance status, tumor response, and survival duration. Primary tumors and metastatic lesions at the time of initial diagnosis were estimated using MRI or CT. Performance status was scored as follows: 0, asymptomatic; 1, ambulatory, only able to perform light work; 2, recumbent for less than 50% of the day; 3, recumbent for more than 50% of the day; 4, completely disabled (10).
Patient follow-up and drug treatment. Pazopanib was administered orally once every day at doses of 800 (n=9), 600 (n=6), or 400 mg (n=5), based on patient’s overall status. Eribulin was intravenouslyadministered at a dose of 1.4 (n=13) or 1.1 mg/m2 (n=6) (approximately 5 min) on days 1 and 8 of each 3-week treatment cycle. Trabectedin was administered at a standard starting dose of 1.2 mg/m2 (approximately 24 h) as a continuous intravenous infusion via a central vein on day 1. Dosage adjustment was allowed at the discretion of oncologists per the prescription label information (8, 11, 12).
After chemotherapy, patients were regularly followed up at 3-month intervals under the Revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) methodology (13). During each visit, the patients underwent clinical assessment of blood cell count, renal and hepatic functions, and evaluation of treatment-related toxicities. Local examination, chest radiography, and/or CT were performed every 2 or 3 months for the first 2 years after the commencement of chemotherapy. From 3 to 5 years after chemotherapy, the patients were followed up every 3 or 6 months, based on the oncologist’s assessment. Additionally, MRI examinations were performed every 3 months for the first 3 years. The follow-up time was defined as the duration from the first treatment to the last follow-up.
Chemotherapy treatment was discontinued in the event of rapid disease progression, severe toxicity, or patient-initiated cessation. The clinical outcomes were measured by assessing the maximum drug response (MDR) and survival duration. MDR was determined by the sum of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), which is assessed at the best response of all target lesions 2 or 3 months after starting treatment. Survival duration was defined as the time from the start of chemotherapy until death. Adverse effects were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Statistical analysis. Data were plotted to create post-treatment survival curves for patients, using the Kaplan-Meier method (14). Univariate analysis was performed using a log-rank test to compare survival periods between groups (15). Multivariate analysis was performed using the Cox proportional hazards models (16), which covered two factors (each presenting with p<0.05 in the univariate analysis). Fisher’s exact probability test was also used to compare the two variables. All statistical analyses were performed using a statistical software package (Excel - Toukei 2015; Social Survey Research Information Co., Ltd., Tokyo, Japan). Results with p<0.05 were considered statistically significant.
Results
Clinical information. The sarcomas retrospectively investigated in this study were located in the lower limbs, trunk, and upper limbs of 18, 19, and 9 patients, respectively. Regarding the treatment, 21 patients were treated with doxorubicin. Of the three new drugs, pazopanib (20 patients) was the most frequently administered drug, followed by eribulin (19 patients) and trabectedin (7 patients). In addition, 23 patients underwent radiation therapy before treatment. A total of 13 patients had a performance status score of 1, and the remaining 33 patients had a score of 2, as shown in Table I.
Descriptive patient demographic data.
Histological diagnoses. All 46 sarcomas subtypes are listed by histological classification in Table II. The most common sarcoma subtypes identified in this study were undifferentiated pleomorphic sarcomas (12 cases, 26%) and malignant peripheral nerve sheath tumors (5 cases, 11%).
Relationship between histological classification and drug response.
We identified 2 patients with undifferentiated pleomorphic sarcoma, 1 with myxoid liposarcoma, 1 with extraskeletal myxoid chondrosarcoma, 1 with epithelioid sarcoma, and 1 with malignant giant cell tumor of soft tissue who exhibited PR (Table II).
Drug response. PR was observed in six patients, and the histological classifications of tumor in these six patients were undifferentiated pleomorphic sarcoma (n=2), myxoid liposarcoma (n=1), extraskeletal myxoid chondrosarcoma (n=1), and epithelioid sarcoma (n=1). Of the 46 patients, 15 maintained SD for over 3 months. However, 25 patients exhibited signs of PD (Table I).
None of the patients dropped out from this study owing to toxicity, and there were no deaths attributable to drug therapy. The information on adverse effects is shown in Table I. The representative clinical course of metastatic undifferentiated pleomorphic sarcoma treated with eribulin is shown in Figure 1.
Representative clinical course of eribulin treatment. Images of the pelvic musculature of a 73-year-old male patient: (a) axial MRI T1-weighted sequence; (b) axial MRI T2-weighted sequence (the tumor (arrow) appears as a heterogeneous mass in the left iliac muscle). Pathological examination of the specimen confirmed undifferentiated pleomorphic sarcoma: resected specimen (c); hematoxylin-eosin staining (×400) (d). CT images of the lung: (e) pulmonary metastasis in the lower lobe of the right lung (arrow) observed before treatment; (f) rapid regression after three months of eribulin treatment. MRI: Magnetic resonance imaging; CT: computed tomography.
Oncological outcomes. The median survival period was 13.3 (range=0.2-60) months. Regarding oncological outcomes at the last follow-up, 9 patients survived (though with active disease), and 37 patients died of the disease.
Prognostic factors. The univariate analysis showed that performance status and maximum tumor response were significant prognostic factors for overall survival rate (p=0.005 and p<0.001, respectively) (Table III). Through multivariate analysis, both performance status and maximum tumor response were identified as significant prognostic factors (p=0.02 and p<0.001, respectively).
Cox proportional hazards analysis for overall survival.
Survival rates. The 5 year overall survival rate was estimated to be 9.85%, using the Kaplan-Meier method (Figure 2). There was no significant difference in the 5 year overall survival rate between patients aged <65 years and those aged ≥65 years (p=0.96) (Figure 2). In contrast, a significant difference was observed in performance status scores of 1 vs. 2 (p=0.005) and maximum tumor response (PR/SD vs. PD; p<0.001) (Figure 2). The overall 5 year survival rate of patients with poor performance status scores was lower than that of patients with good performance status scores (6.36% vs. 31.6%). Furthermore, the overall 5 year survival rate of patients with a poor drug response was lower than that for patients with a good drug response (8% vs. 12.3%).
Survival curves of patients. (a) Overall survival curve. (b) Survival curves for patients aged <65 and ≥65 years. (c) Survival curves for patients with performance status 1 and 2. (d) Survival curves for patients with maximum drug response PR/SD and PD. PR: Partial response; SD: stable disease; PD: progressive disease.
Discussion
Prolonged SD has been reported in patients with pulmonary metastases from epithelioid sarcoma in the forearm after treatment with eribulin (17). Furthermore, in a woman with a giant cell tumor in the soft tissue of the intrinsic back musculature with both postoperative local recurrence and lung metastasis, pazopanib was efficacious in prolonging SD (18). A recent meta-analysis revealed that tumor response of advanced cancers, particularly in immune checkpoint inhibitor trials, significantly influenced overall survival (19). Therefore, we hypothesized that a good response to each cutting-edge drug (pazopanib, eribulin, or trabectedin) would likely be a prognostic factor to optimize outcomes in patients with metastatic and inoperable sarcomas. The scope of this study did not extend to whether the metastatic sarcoma drug response improved prognosis.
In this study, we analyzed the effectiveness of systemic treatment using pazopanib, eribulin, and trabectedin in 46 patients with metastatic and inoperable sarcomas. Patients of different ages presented with varying performance status scores, a history of doxorubicin therapy, and a history of radiotherapy. Eight patients without a history of doxorubicin therapy received pazopanib, eribulin, or trabectedin. Additionally, 14 patients were aged over 65 years, and 33 patients had a performance status score of 2.
The 5-year overall survival rate of patients with metastatic and inoperable sarcomas after pazopanib, eribulin, and trabectedin treatment was 9.85%, based on the curves obtained using the Kaplan-Meier method, with a median overall survival period of 13.3 months. While chemotherapy using pazopanib, eribulin, and trabectedin is the primary treatment for patients with metastatic or inoperable disease, the overall survival of these patients has been reported to be approximately 12 months (9). Our results may have yielded a slightly higher overall survival rate than those reported by previous studies owing to the limited number of patients enrolled in this study.
Multivariate analyses conducted using Cox proportional hazards regression modeling revealed that the factors that were highly associated with survival duration included performance status scores and maximum tumor response. Contrarily, survival duration was not significantly associated with age, sex, primary tumor location, adverse effects, history of doxorubicin therapy, or history of radiation therapy.
Overall survival improvement has only been reported in patients with advanced L-sarcoma (liposarcoma and leiomyosarcoma) treated by eribulin, compared to those treated with dacarbazine (7). There have been a few reports of prolonged overall survival following pazopanib and trabectedin treatment. However, based on the results of this study, a good response to pazopanib, eribulin, and trabectedin may improve the prognosis of patients with metastatic and inoperable sarcomas.
Advanced age has been reported to be a poor prognostic factor in soft tissue sarcomas (20), likely because of low physical function and general limited tolerance to treatment. Despite this, the present study indicated a lack of significant differences between patients aged over 65 years and those aged below 65 years. Performance status was also found to be a prognostic factor in the multivariate analysis. Hence, the success of individualized chemotherapy using pazopanib, eribulin, and trabectedin may depend on patient performance status, corroborating the results of a previous study (21).
Pazopanib, eribulin, and trabectedin are prescribed to patients with inoperable metastatic sarcomas regardless of a history of treatment with other systemic chemotherapy, while these three drugs are also done to patients with various carcinomas (22-25). However, anthracycline-based chemotherapy is frequently recommended because no regimen has been proven to be superior to doxorubicin as the first-line treatment for locally advanced and/or metastatic soft tissue sarcomas (4). When patients cannot receive anthracycline-based treatment because of a high risk of adverse effects, such as cardiac insufficiency, eribulin is particularly expected to be administered as first-line treatment. In practice, 4 out of 19 patients who received eribulin treatment were administered eribulin as first-line treatment, with 2 of the 4 patients showing PR. Furthermore, there was no significant difference between history of doxorubicin therapy and overall survival. As a result, we believe that eribulin may have a promising effect, regardless of treatment history.
Regarding the history of radiotherapy, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of near-complete pathological response, suggesting that this combination may be ideal for patients with metastatic soft tissue sarcoma (26). Furthermore, regarding brain tumors and breast cancer, some reports indicate that combination therapy with eribulin and radiation may serve as an optimal therapeutic strategy (27, 28). Moreover, the combination of trabectedin and radiotherapy is reported to be an ideal therapeutic option for symptomatic relief in patients with metastatic soft tissue sarcoma (29). However, based on the results of our study, there was no significant relationship between history of radiotherapy and overall survival.
In this study, age, sex, primary tumor location, adverse effects, history of doxorubicin therapy and radiotherapy were not found to be related to overall survival. However, performance status and maximum drug response were found to be prognostic factors that influenced overall survival in the multivariate analysis. In addition, there was no significant relationship between performance status scores and the maximum drug response (Table IV). Oncologists have been able to more readily administer second- or third-line treatment for advanced sarcoma owing to the formal approval of new drugs (pazopanib, eribulin, and trabectedin) since 2012. These new drugs have also been reported to contribute to the maintenance of disease control after second-line treatment in approximately 40% of patients (9). Therefore, systemic therapy using pazopanib, eribulin, and trabectedin may be beneficial for patients with metastatic and inoperable sarcomas if there is partial drug response or evidence of SD.
Association with maximum tumor response in sarcomas.
We must acknowledge the limitations of this study, including the small number of patients enrolled and the retrospective study design. First, evaluation of trabectedin treatment was limited because the number of patients was too small (n=7). Therefore, our results should be validated in a prospective study involving a large number of patients from multiple medical institutions in order to claim statistical validity exactly. Furthermore, this study included patients with various types of sarcomas in multiple locations due to metastatic disease. The most frequent histopathological types in this study were undifferentiated pleomorphic sarcoma (26%) and malignant peripheral nerve sheath tumors (11%). Patients with L-sarcoma should have been mainly enrolled for this study, based on a previous report (7). Moreover, no specific treatment strategy for metastatic and inoperable bone and soft tissue sarcomas exists.
Conclusion
Performance status and maximum drug response were the only two factors found to be closely associated with prognoses of metastatic and inoperable sarcomas. If the performance status is good, the effect of systemic chemotherapy using pazopanib, eribulin, and trabectedin, regardless of age, may be ideal because the overall survival will be significantly prolonged. Based on the findings of this study, we strongly suggest that the effect of pazopanib, eribulin, and trabectedin is optimized if the performance status and maximum drug response are good, regardless of patient age and sex, primary tumor location, adverse effects, and history of doxorubicin and radiotherapy.
Furthermore, prospective cohort studies enrolling numerous patients in multiple medical institutions will be required to verify the relationship between performance status, maximum drug response, and prognosis in the future.
Acknowledgements
The Authors are grateful for the support and various discussions with other members of the Department of Orthopedic Surgery.
Footnotes
Authors’ Contributions
Tadashi Iwai designed this study and performed the statistical analysis. Tadashi Iwai prepared figures and tables. Tadashi Iwai wrote the original draft manuscript. Manabu Hoshi and Hiroaki Nakamura oversaw the study and revised the manuscript. All Authors reviewed the manuscript.
Conflicts of Interest
The Authors declare no competing interests.
- Received July 12, 2023.
- Revision received August 23, 2023.
- Accepted September 1, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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