Agents For Soft Tissue Sarcoma Research Articles

A clinical tool to predict overall survival of elderly patients with soft tissue sarcoma after surgical resection

With the aging world population, the incidence of soft tissue sarcoma (STS) in the elderly gradually increases and the prognosis is poor. The primary goal of this research was to analyze the relevant risk factors affecting the postoperative overall survival in elderly STS patients and to provide some guidance and assistance in clinical treatment. The study included 2,353 elderly STS patients from the Surveillance, Epidemiology, and End Results database. To find independent predictive variables, we employed the Cox proportional risk regression model. R software was used to develop and validate the nomogram model to predict postoperative overall survival. The performance and practical value of the nomogram were evaluated using calibration curves, the area under the curve, and decision curve analysis. Age, tumor primary site, disease stage, tumor size, tumor grade, N stage, and marital status, are the risk variables of postoperative overall survival, and the prognostic model was constructed on this basis. In the two sets, both calibration curves and receiver operating characteristic curves showed that the nomogram had high predictive accuracy and discriminative power, while decision curve analysis demonstrated that the model had good clinical usefulness. A predictive nomogram was designed and tested to evaluate postoperative overall survival in elderly STS patients. The nomogram allows clinical practitioners to more accurately evaluate the prognosis of individual patients, facilitates the progress of individualized treatment, and provides clinical guidance.

The Prognostic Significance of Surgical Treatment for Excessive Elderly Soft Tissue Sarcoma Patients over 90 Years Old: A Clinicopathological Study of 16 Cases.

The incidence of soft tissue sarcomas (STSs) among older patients is increasing. Although surgical treatment of elderly patients with STS has been reported to improve their prognosis, most of these studies included patients with STS aged <85 years. This study aimed to analyze the clinical features and prognostic factors of STS in elderly patients aged ≥90 years. We retrospectively identified patients aged ≥90 years with STS who were treated at our two hospitals between 1994 and 2022. Data on clinical information and detailed assessments were collected. We evaluated the features and factors affecting the prognosis of patients with older-extremity STS. In addition, we compared the clinical courses and results of patients treated with surgery and radiotherapy for primary tumors. Among 454 patients with STS, 16 were aged ≥90 years. Kaplan-Meier curves for overall survival showed a significantly poorer prognosis in patients who did not receive surgical treatment (p = 0.0348) and those who received radiotherapy (p = 0.0070). Moreover, we investigated the difference in prognosis between surgical treatment and radiotherapy, excluding two cases with distant metastasis at initial diagnosis and one case with no treatment. Kaplan-Meier curves for overall survival showed a significantly better prognosis in patients who underwent surgical treatment (p = 0.0161). Univariate analysis revealed that only primary tumor size was a significant predictor of poor prognosis (p = 0.0426). In patients with STS aged ≥90 years old, aggressive surgical treatment may improve the prognosis more than radiotherapy.

A post hoc analysis of the EPAZ trial: The role of geriatric variables in elderly soft tissue sarcoma patients on toxicity and outcome

ObjectiveThe EPAZ study (NCT01861951) showed recently that pazopanib was non-inferior to doxorubicin in patients ≥60 years treated in first line for advanced soft tissue sarcoma . The current post-hoc analysis aimed to assess the prognostic impact of frailty. MethodsGeriatric assessments were evaluated at baseline. Age >75 years, liposarcoma, ECOG = 2, G8 ≤14, instrumental activities of daily living (IADL) ≥1 and Charlson Comorbidity Index ≥2 were tested for their impact on progression-free survival (PFS), overall survival (OS), CTCAE grade 3/4 adverse events (AEs) or serious AEs (SAEs), using univariate and multivariate analysis models. Resultsunivariate analysis showed an increased risk of grade 3/4 AEs and SAEs for ECOG = 2, G8 score ≤14 or IADL ≥1, independent of treatment. The multivariate analysis exhibited for pazopanib a significantly reduced risk for grade 3/4 AEs (HR 0.53; p = 0.033), and in patients with G8 ≤14 an increased risk for SAEs (HR 2.67; p = 0.011).In the multivariate analysis, G8 ≤14 was a negative prognostic factor for PFS (HR 1.82; p = 0.009) and IADL ≥1 for OS (HR 2.02; p = 0.007). ECOG = 2 was the strongest negative predictor for PFS (HR 4.39; p = 0.001) and OS (HR 3.74; p = 0.004). Neither age nor Charlson Comorbidity Index showed any impact on PFS, OS, incidence of grade 3/4 AEs or SAEs. ConclusionsThis post hoc analysis demonstrated that age is not a denominator for outcome or toxicity in elderly patients with soft tissue sarcoma . Instead, geriatric and functional assessments should be used to counsel patients and tailor therapy to individual needs. Moreover, pazopanib has a reduced risk for grade 3/4 AEs compared to doxorubicin.

1550P A post hoc analysis of the EPAZ trial: The prognostic role of geriatric variables in elderly soft tissue sarcoma (STS) patients

The EPAZ study (NCT01861951) recently showed that pazopanib was non-inferior to doxorubicin in patients ≥ 60 years treated in first line for advanced STS [1]. The current post hoc analysis aimed to assess the prognostic impact of frailty.

Editorial Comment from Dr Matsumoto to Adult genitourinary sarcoma: The era of optional chemotherapeutic agents for soft tissue sarcoma.

Editorial Comment from Dr Matsumoto to Adult genitourinary sarcoma: The era of optional chemotherapeutic agents for soft tissue sarcoma.

Editorial Comment from Dr Arai to Adult genitourinary sarcoma: The era of optional chemotherapeutic agents for soft tissue sarcoma.

Editorial Comment from Dr Arai to Adult genitourinary sarcoma: The era of optional chemotherapeutic agents for soft tissue sarcoma.

Adult genitourinary sarcoma: The era of optional chemotherapeutic agents for soft tissue sarcoma.

To report our institutional experience with treatment of primary genitourinary soft tissue sarcoma. We retrospectively reviewed the medical records of adult soft tissue sarcoma patients treated between March 2005 and May 2019. The primary tumor sites included the prostate, kidney, urinary bladder and the paratesticular structures. A total of 19 patients - 16 men (84%) and three women (16%) - were enrolled in the study. The median age was 41years (range 20-79years). The most common primary site was the prostate (in eight patients; 42%), and prostatic sarcoma patients were younger than patients with sarcomas of other origins. The most common histological subtype was leiomyosarcoma (in five patients; 26%). The overall survival rates after 1, 3 and 5years were 61.5%, 34.4% and 25.8%, respectively. The median survival time was 20.7months (95% confidence interval 5.9-35.5months). Univariate analysis showed that an absence of metastasis at diagnosis and complete surgical resection were predictive of favorable survival. In the chemotherapy group, the objective response rate was 20.5%. Pazopanib was administered to nine patients in the late-line setting, and the objective response rate was 11.1%; six grade≥3 adverse events were observed in three patients. Inoperable metastatic genitourinary soft tissue sarcoma remains difficult to treat, as previously reported. Further investigation on this malignancy, including optimization of currently available antitumor drugs and the development of novel therapeutic agents, is required.

Patterns of Care and Survival in Elderly Patients With Locally Advanced Soft Tissue Sarcoma.

The aim of this study was to analyze patterns of care in elderly soft tissue sarcoma (STS) patients and their impact on clinical outcome and treatment-related toxicity. We retrospectively collected data of >65-year-old patients diagnosed with locally advanced STS between 1991 and 2017 in a single institution. The study included 111 patients: 105 (94.6%) patients underwent surgery, associated with preoperative (n=19, 17.1%) or postoperative radiotherapy (n=72, 64.8%). Anthracycline-based chemotherapy was prescribed in 41.4% of patients (n=46). Acute grade ≥3 postoperative radiotherapy-related radiation dermatitis and all grades of chemotherapy-induced neutropenia were significantly correlated to age >80 years (P=0.02) and >70 years (P=0.045), respectively. The mean follow-up was 4.1 years (range, 0.1 to 17.7). Three-year and 5-year local recurrence-free survival were 80.3% and 75.7%, respectively; neither treatment-related nor patient-related characteristics affected local recurrence. Three-year and 5-year distant relapse-free survival were 59.6% and 44.6%, respectively. On multivariate Cox regression, undifferentiated pleomorphic sarcoma histology and Charlson Comorbidity Index >7 were independent factors associated with distant relapse-free survival (P=0.026 and P=0.0001). Overall survival was 62% and 46.6% at 3 and 5 years, respectively. On multivariate Cox regression, surgery and Charlson Comorbidity Index <7 were independent factors associated with overall survival (P=0.006 and P=0.0001). In this study, elderly STS patients receiving a tailored treatment encompassing surgery, radiotherapy, and/or chemotherapy obtained an improved outcome, although caution is advised because of increased toxicity in relation to age. Comorbidities should be considered to offer the best treatment option to this frail patient population.

Extremity soft tissue sarcoma in the elderly: Are we overtreating or undertreating this potentially vulnerable patient population?

As the U.S. population ages, differences in oncologic outcomes among the elderly have been recognized. Our objective was to analyze the clinical, pathologic, and treatment outcomes for elderly soft tissue sarcoma (STS) patients, hypothesizing significant differences in the management and response to therapy. Using the National Cancer Database, we identified 33 859 patients with nonmetastatic extremity STS. We defined elderly as ≥74 years in age and compared patient and treatment variables between adult and elderly patients. Cox-proportional hazards analysis was used to determine predictors of overall survival (OS). We identified 8504 elderly patients. Significant differences in histologic subtype, grade, and facility type between elderly and nonelderly patients (P < 0.05) exist. Elderly patients were less likely to undergo R0 resection (P = 0.001) and had a higher 90-day mortality (P = 0.001). Surgical elderly patients experienced superior OS compared with nonsurgical patients (P = 0.001). Among elderly patients, younger age, and female sex, lower Charlson-Deyo score, lower grade, smaller tumors, surgical resection, negative surgical margins, and radiation therapy were associated with better OS. Key differences exist in elderly extremity STS patients, including a narrower benefit/risk ratio with surgical management. These data highlight that elderly patients represent a distinct cohort for whom more careful selection appears indicated.

1605PD - Health-related quality of life (HR-QoL) in elderly soft tissue sarcoma (STS) patients from the randomized phase II EPAZ study comparing pazopanib (PAZ) and doxorubicin (DOX) in first line

1605PD - Health-related quality of life (HR-QoL) in elderly soft tissue sarcoma (STS) patients from the randomized phase II EPAZ study comparing pazopanib (PAZ) and doxorubicin (DOX) in first line

Randomized comparison of pazopanib (PAZ) and doxorubicin (DOX) in the first line treatment of metastatic soft tissue sarcoma (STS) in elderly patients (pts): Results of a phase II study (EPAZ).

11506Background: The systemic treatment standard of advanced, inoperable STS in elderly pts is single agent DOX. We tested the hypothesis whether PAZ has comparable efficacy to DOX in elderly STS p...

Subgroup analysis of elderly patients treated within the randomized phase 3 doxorubicin versus doxorubicin plus evofosfamide (SARC021) trial.

11575Background: Approximately 50% of patients diagnosed with soft tissue sarcoma (STS) are aged ≥65 years (yrs). The management of elderly STS patients (≥65yrs) is challenging and there are few pr...

Hepatoprotective effect of N-acetylcysteine in trabectedin-induced liver toxicity in patients with advanced soft tissue sarcoma.

Trabectedin is one of the few active agents in soft tissue sarcoma (STS) but hepatotoxicity is frequent and represents a dose-limiting factor. Protective strategies aiming at counteracting this important side effect have a crucial clinical impact. Due to its antioxidant properties, N-acetylcysteine (NAC) has a recognized hepatoprotective effect and this provides the rationale for testing NAC in the management of trabectedin-induced hepatotoxicity. Patients with recurrent or metastatic soft tissue sarcoma, consecutively observed at our institution, who were considered eligible to trabectedin, received concomitant NAC if they had impaired hepatic or renal function at baseline or developed hepatotoxicity during treatment. The study aim was to retrospectively explore trabectedin administration in terms of number of cycles, mean dose, and dose intensity (DI) in patients who received NAC as compared with those who did not. Secondary end points were progression-free survival (PFS) and overall survival (OS). A total number of 18 patients were enrolled in this study. Nine received NAC and nine did not. The median number of administered trabectedin cycles, mean trabectedin dose/cycles, and median DI was comparable in the two groups (p = 0.450, p = 0.534, and p = 0.450, respectively). The PFS and OS curves overlapped. This explorative study suggests that NAC can have a hepatoprotective activity in patients receiving trabectedin allowing to maintain an adequate dose intensity and continuative administration in patients with impaired liver and renal function or developing treatment-induced hepatotoxicity. A prospective randomized trial is warranted.

Impact of geriatric factors on surgical and prognostic outcomes in elderly patients with soft-tissue sarcoma.

Patients aged ≥65 years requiring surgery for soft-tissue sarcoma are a concern in an aging society. We aimed to reveal the association of clinical/geriatric factors with survival period or postoperative events in such patients who underwent surgery. We enrolled patients aged ≥65 years who underwent surgery for localized soft-tissue sarcoma at five institutions. We retrospectively collected clinical/geriatric factors and laboratory data, and analyzed their association with outcomes using univariate and multivariate analyses. Among the 202 patients included, mean age at presentation was 73 years. Surgical margin was R0 in 139 patients (69%). The Eastern Cooperative Oncology Group performance status was ≥2 in 15 (7%). Thirty patients (15%) showed thinness (body mass index <18.49 kg/cm2). High-sensitivity-modified Glasgow prognostic score ≥1 was seen in 52 patients (26%). Multivariate analysis showed that R1 surgical margin was significantly correlated with poor sarcoma-specific survival (hazard ratio for R1 vs. R0, 3.17; P = 0.001) and event-free survival (hazard ratio for R1 vs. R0, 2.56; P < 0.001). Higher Eastern Cooperative Oncology Group performance status was significantly associated with poor sarcoma-specific survival (hazard ratio for ≥2 vs. 0 or 1, 2.15; P = 0.038), and higher sensitivity-modified Glasgow prognostic score was significantly associated with poor event-free survival (hazard ratio for ≥1 vs. 0, 1.74; P = 0.046). Severe thinness (body mass index <16.00) was a risk factor for postoperative events (odds ratio for body mass index <16.00 vs. ≥16.00, 8.15, P = 0.010). Negative surgical margin was associated with better survival. Coexisting conditions had an impact on outcomes in elderly soft-tissue sarcoma patients.

Tumour vascular-disrupting agents in soft-tissue sarcoma

Tumour vascular-disrupting agents in soft-tissue sarcoma

Favorable outcome after complete resection in elderly soft tissue sarcoma patients: Japanese Musculoskeletal Oncology Group study

The surgical management of soft tissue sarcoma (STS) in elderly patients has only been addressed in a few studies. The objective of the current study was to assess surgical outcomes in patients with STS aged 70 years and older and the association of older age with the survival after complete resection. A retrospective analysis was conducted in 158 elderly patients with localized STS who visited 11 institutions participating in Japanese Musculoskeletal Oncology Group between 1995 and 2006 and were treated by surgical resection. Univariate and multivariate analyses were performed to identify prognostic factors. Median follow-up period was 38 months. Histologically high-grade tumors were detected in 71% of the patients. Wide resection with adequate margins was performed in 66% of the cases. Systemic chemotherapy was performed in only 5 patients. Univariate analysis identified histological grade and gender as statistically significant prognostic factors for sarcoma-specific survival. Multivariate analysis did not identify significant prognostic factors for sarcoma-specific survival, although high grade sarcoma emerged as a potentially significant prognostic factor (P = 0.050). Local recurrence was detected in 19% of the patients. Multivariate analysis of local recurrence-free survival showed that tumor site and surgical margins were statistically significant prognostic factors. Older age was not identified as a prognostic factor for sarcoma-specific survival, which is not consistent with the findings of previous studies showing that older age was associated with decreased sarcoma-specific survival. Complete resection should be indicated and can lead to optimal treatment outcome for properly selected elderly patients.

The Past, Present, and Future of Cytotoxic Chemotherapy and Pathway-Directed Targeted Agents for Soft Tissue Sarcoma

The individual rarity of the many subtypes of soft tissue sarcomas has historically mandated an empiric approach to systemic therapy. Doxorubicin, first reported to have activity in sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other drug or combination having shown an overall-survival advantage. Other cytotoxic agents, such as paclitaxel for angiosarcoma or gemcitabine with docetaxel for leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies. Trabectedin, particularly active against leiomyosarcoma and myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer cytotoxic agents, including ifosfamide derivatives, are in current phase III testing. Although advances is systemic therapy of soft-tissue sarcomas have been hampered by their biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule therapies for gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma and anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic tumor. Molecular therapies that have shown activity in diverse sarcoma populations include mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF-R) inhibitors. Among the latter, pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced sarcoma, and is now approved for use in the sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular tumor continue towards a goal of individualized sarcoma therapy.

A Phase I Study of the Combination of Temsirolimus with Irinotecan for Metastatic Sarcoma

mTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.

The Past, Present, and Future of Cytotoxic Chemotherapy and Pathway-Directed Targeted Agents for Soft Tissue Sarcoma

The individual rarity of the many subtypes of soft tissue sarcomas has historically mandated an empiric approach to systemic therapy. Doxorubicin, first reported to have activity in sarcomas 40 years ago, remains the generalizable first-line treatment of choice for many subtypes, with no other drug or combination having shown an overall-survival advantage. Other cytotoxic agents, such as paclitaxel for angiosarcoma or gemcitabine with docetaxel for leiomyosarcoma, are commonly used for certain histologic subtypes based on relatively small studies. Trabectedin, particularly active against leiomyosarcoma and myxoid liposarcoma, is approved in many countries worldwide but not yet in the United States or Australia. Newer cytotoxic agents, including ifosfamide derivatives, are in current phase III testing. Although advances is systemic therapy of soft-tissue sarcomas have been hampered by their biologic heterogeneity, this diversity also serves as fertile ground for discovery and validation of targetable molecular drivers. The most notable success in this regard has been the development of small molecule therapies for gastrointestinal stromal tumors. Other targets of recent interest include mouse double minute 2 homolog (MDM2) in dedifferentiated liposarcoma and anaplastic lymphoma kinase (ALK) in inflammatory myofibroblastic tumor. Molecular therapies that have shown activity in diverse sarcoma populations include mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF-R) inhibitors. Among the latter, pazopanib demonstrated a progression-free survival over placebo in prior-treated patients with advanced sarcoma, and is now approved for use in the sarcomas in many countries. Efforts to understand the key molecular aberrations in any particular tumor continue towards a goal of individualized sarcoma therapy.

Abstract 5047: Survival signal pathways as potential therapeutic targets in soft tissue sarcoma cell lines

Abstract Introduction: Soft tissue sarcomas (STS) are rare malignancies but have poor survival rate. Surgery with standard chemotherapy has been the mainstay of treatment but newer strategies are necessary to improve survival. The investigations for targeted therapy are underway but little is known about potential targets until now. We previously presented potential molecular targets in osteosarcoma (OS) cell lines (101st AACR annual meeting 2010, abstract No.2451). We tried to compare the protein and mRNA profilings between the OS and STS cell lines to suggest the feasibility for developing molecular targeted agents in STS. Methods: We examined the protein expression of c-Met, Akt, mTOR, and their phosphorylated status, and PTEN in seven OS (MG-63, HOS, KHOS/NP, SK-ES-1, U-2OS, Saos-2, and G-292) and five STS cell lines (SK-UT-1, A-673, SW-871, SW-982, HT-1080) using western blotting. The gene expression profilings of the cell lines were performed by 44K microarray (Agilent Inc.). Results: Microarray data showed that whole genome expression pattern of STS was different from OS cell lines. But, the expressions of 94 mRNAs within the signal transduction pathways, which represent the currently utilized drug targets, revealed similar pattern between two groups of cell lines. To verify the possibility of developing molecular targeted agents in STS, we examined the activation patterns of signal transduction pathway proteins in each STS cell line. All STS cell lines except A-673 with low c-Met, but high p-Met, expressed moderate level of c-Met and p-Met. PI3K was expressed in all cell lines, with higher p-PI3K in SK-UT-1 and A-673 than in other STS cell lines. All but SW-872 cell line expressed Akt, and SK-UT-1, SW-872 and HT-1080 had higher levels of p-Akt. SW872 showed negligible PTEN and high level of p-Akt. SW982 generally repressed level of p-Met, p-PI3K, p-Akt, p-mTOR comparing with other STS cell lines. Meanwhile, mTOR and p-mTOR were expressed relatively even in all STS cell lines. Conclusion: We presented that STS cell lines had variously activated signal pathway status as in OS cell lines. Common potential targets such as mTOR was revealed, and the specific targets including PI3K or Akt were also presented. It suggests the possibility of developing specific molecular targeted agents in each type of STSs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5047. doi:10.1158/1538-7445.AM2011-5047