Treatment Of Metastatic Sarcoma Research Articles

PD-L1 Expression in Sarcomas: An Immunohistochemical Study

Abstract Introduction/Objective Immunotherapy is increasingly used for the treatment of metastatic melanoma and carcinomas. PD-I (programmed death 1) and its associated ligand (PD-L1) inhibits the activation of T lymphocytes. This inhibition can be impacted by a number of drugs. Response to these drugs is predicted by assessment of PD-L1 expression. PD-L1 expression varies between 19% and 92% in melanomas and carcinomas. PD-L1 expression is less well documented for sarcomas. Methods Fifty-one sarcomas of various histopathologic types were immunohistochemically stained (IHC) for PD-L1 using the antibody clone SP263 (Ventana, Tuscan, AZ). Membrane staining of tumor cells was quantitated as a percentage of total tumor cells. Sarcomas were judged as non-expressors (less than 1%) low-expressors (1 to 50%) and high expressors (greater than 50%). The percentage of each type of sarcoma judged as an expressor was determined. Results The percentage of each type of sarcoma expressing PD-L1 is reported and 20% of sarcomas expressed PD- L1. The percentage of sarcomas expressing PD-L1 varied significantly between types but the majority of sarcomas were non-expressors. Conclusion PD-L1 IHC expression is valuable in predicting response to immune-modulating drugs. Such therapies may be useful for treatment of metastatic sarcomas. Expression of PD-L1 in carcinomas and melanomas is variable ranging from 19% to 92%. In our study, a minority (20%) of sarcomas expressed PD-L1. Other studies have shown similar results with between 1.4 and 59% (average 24%) of sarcomas expressing PD-L1. Expression appears to be type specific. These finding suggest that PD-L1 based therapy may be less useful in sarcomas than in other malignancies.

PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma.

The prevention and treatment of metastatic sarcoma are areas of significant unmet need. Immune checkpoint inhibitor monotherapy has shown little activity in sarcoma and there is great interest in identifying novel treatment combinations that may augment responses. In vitro and in vivo, we investigated the potential for an oncolytic vaccinia virus (GLV-1h68) delivered using isolated limb perfusion (ILP) to promote antitumor immune responses and augment response to PD-1 blockade in sarcoma.Experimental Design: In an established animal model of extremity sarcoma, we evaluated the potential of locoregional delivery of a vaccinia virus (GLV-1h68) alongside biochemotherapy (melphalan/TNFα) in ILP. Complementary in vitro assays for markers of immunogenic cell death were performed in sarcoma cell lines. PD-1 monotherapy had minimal efficacy in vivo, mimicking the clinical scenario. Pretreatment with GLV-1h68 delivered by ILP (viral ILP) significantly improved responses. Furthermore, when performed prior to surgery and radiotherapy, viral ILP and PD-1 blockade prevented both local and distant relapse, curing a previously treatment-refractory model. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in the number and penetrance of intratumoral CD8+ T cells and expansion and activation of dendritic cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines. Viral ILP augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation.

Resection of Pulmonary Metastases in Osteosarcoma. Is it Justified?

Osteosarcoma shows a high propensity to metastasize to the lung. Pulmonary metastases occur in approximately 40% of patients with osteosarcoma during the course of their disease, and the lung is the only site of metastatic disease in the majority of these cases. Chemotherapy continues to be the standard treatment for metastatic sarcoma, but when it is the only treatment modality, it still results in poor survival rates. In order to improve the outcome, a combination of chemotherapy followed by surgical resection of the metastases has been advocated for selected cases. Substantial evidence documents the potential benefit of pulmonary metastasectomy in osteosarcoma, resulting, in various series, in a 5-year overall survival of 30-40%. Aggressive surgery in combination with chemotherapy appears to be justified for metastatic osteosarcoma in selected patients, and it is associated with acceptable morbidity. Synchronous metastases, a short interval from diagnosis to presentation of pulmonary metastasis, a higher number (>4) of metastases, bilateral and central location, pleural infiltration, poor response to preoperative chemotherapy and concurrent (resectable) extra-pulmonary disease have all been associated with a less favorable outcome. Complete surgical resection is essential for giving a chance of long-term survival. Lateral thoracotomy with salvage of as much lung parenchyma as possible is the procedure of choice. Repeat surgery for re-recurrences is feasible and beneficial, resulting in prolonged survival in a number of cases.

Manipulating the Immune System With Checkpoint Inhibitors for Patients With Metastatic Sarcoma.

Sarcomas are a rare group of malignant tumors of mesenchymal origin that comprise 1% of all adult cancers. Despite initial surgery, distant metastatic disease will develop in approximately 25% of patients, and standard chemotherapy has limited durable efficacy. There is a dire need for more effective and less toxic therapies for the treatment of metastatic sarcoma. The immune system plays a major role in cancer control and progression. There have been tremendous breakthroughs in other malignancies by manipulating the immune system with checkpoint inhibitors. These agents, either alone or in combination with other approaches such as radiation, chemotherapy, targeted agents, or immunotherapeutics, have generally led to improved efficacy in selected malignancies thus far. Although promising, these drugs can cause specific immune-related adverse events that require prompt recognition and treatment. In addition, characterizing response and progression radiographically has become somewhat more challenging. Identifying predictive biomarkers of benefit will be essential. There remains optimism and hope that the strides made in other cancers will be emulated in sarcoma.

The Danish experience with trabectedin treatment for metastatic sarcoma: Importance of hyponatremia

Background. Trabectedin was in Europe approved for treatment of metastatic soft tissue sarcoma (STS) in 2007 based on results of a phase II study with relatively few patients. The purpose of this nationwide retrospective study was to assess efficacy and safety of using trabectedin in the entire unselected cohort of patients with metastatic sarcoma and to test known, as well as new prognostic factors that may affect overall survival (OS).Patients and methods. Between January 2008 and April 2013, 117 patients were treated with trabectedin for metastatic sarcoma in the three specialized sarcoma centers in Denmark. Known prognostic factors such as age, gender and performance status, the histopathology as well as other new factors such as response to previous chemotherapy and hyponatremia were tested.Results. Median age was 59 years. Lipo- and leiomysosarcomas (L-sarcomas) represented 43% of the cases and 18% had hyponatremia before the start of trabectedin. The median number of previous lines of chemotherapy was two (range 0–6) and the median number of chemotherapy cycles given before trabectedin was nine (range 0–85). The median number of trabectedin cycles was three (range 1–17). The median OS for the whole cohort was seven months. Poor performance status, non-L-sarcomas, and hyponatremia were statistically significant adverse prognostic factors with median survival of: 4, 5, and 2 months compared to 9, 12 and 13 months, respectively. Moreover, having achieved clinical benefit [complete response (CR), partial response (PR) or stable disease (SD)] from previous chemotherapy was a favorable prognostic factor for response to trabectedin. In multivariate analysis hyponatremia was the only independent significant poor prognostic factor affecting OS.Conclusions. This retrospective study confirmed the previously published safety and efficacy of trabectedin in patients with metastatic sarcoma and showed hyponatremia to be a strong independent statistically significant poor prognostic factor.

Aggressive Surgical Treatment of Metastatic Sarcoma

Aggressive Surgical Treatment of Metastatic Sarcoma

Surgical Management and Minimally Invasive Approaches for the Treatment of Metastatic Sarcoma

Soft tissue sarcomas describe a very heterogeneous group of soft tissue tumors mainly arising in the lower extremities. If diagnosed at an early stage and a complete resection of the primary tumor is achieved, the patients' prognosis is excellent. However, metastatic tumor spread is common with only limited treatment possibilities. Despite an improved insight into tumor biology of sarcomas, no notable improvement has been gained in the last 20 years regarding prognosis of patients. Metastatic lung disease has long been the preserve of systemic treatments, local treatments being considered in a purely palliative intention. Several studies have objectified benefit to the local treatment of metastases, especially in an oligometastatic state. The development of techniques for stereotactic radiotherapy on the one hand and the refusal or contraindication for surgery on the other hand inaugurated studies in this direction. Besides surgery and radiotherapy, other local modalities have been investigated in the last few years such as thermal therapy (radiofrequency and laser ablation) or combined modalities (isolated limb perfusion and deep-wave hyperthermia plus chemotherapy) to help patients with metastatic soft tissue sarcoma. Minimally invasive, image-guided therapies such as thermal ablation should be considered particularly in patients who are not suitable surgical candidates or may have exhausted all other viable surgical options. Some of these techniques will be reviewed in this article, and their value for the patients will be evaluated in the light of indication from tumor biology and technical feasibility. These highly selected and specific procedures should only be performed after decision making in an interdisciplinary sarcoma-board.

Abstract 5629: Arginine depravation therapy with arginine deiminase and autophagy inhibition is a novel therapeutic approach for the treatment of metastatic sarcomas that lack argininosuccinate synthetase expression

Abstract While sarcomas are a rare group of tumors, the poor response to current clinical regimens represents an important unmet need in oncology. A better therapeutic understanding of the biology and metabolism of sarcoma growth is necessary to develop novel therapies to treat patients with this group of tumors. Argininosuccinate synthase 1 (ASS1) is the rate-limiting enzyme in the conversion of citrulline to arginine. When ASS1 is not expressed arginine becomes an essential amino acid to a cancer cell that must be delivered from the diet. Immunohistochemical analysis of 701 patient specimens representing 45 subtypes of sarcoma demonstrates that ASS1 is not expressed in over 85% of sarcomas (619 of 701 patient samples). This suggests that sarcomas may be sensitive to the arginine deprivation therapy using pegylated arginine deiminase (ADI-PEG20). Treatment of a panel of leiomyosarcoma, osteosarcoma, alveolar soft part sarcoma, malignant peripheral nerve sheath tumor and Ewing's sarcoma cell lines with ADI-PEG20 resulted in cell cycle arrest but not apoptosis when ASS1 expression was low, whereas the ASS1 high osteosarcoma cell line MG63 continued to divide. Response in sarcoma cell lines is dependent on ASS1 expression, as bone sarcomas, soft tissue sarcomas, complex cytogenetic sarcomas and translocation dependent sarcomas all demonstrate cell cycle inhibition upon treatment with ADI-PEG20. The IC50 for treated cell lines treated with ADI-PEG20 ranged from 0.02-0.1ug/mL in ASS1 low sensitive cell lines. Treatment of sarcomas that lack ASS1 with ADI-PEG20 induces autophagy. Depletion of arginine by ADI-PEG20 in ASS1 negative sarcomas when combined with chloroquine, an inhibitor of autophagy, induces cell death as measured by Annexin V. Xenograft of the ASS1 low expressing osteosarcoma cell line MNNG into nude mice followed by treatment with ADI-PEG20 demonstrated a significantly slower tumor growth rate as compared to PBS treated controls. Experiments are now ongoing in mice using the combination of chloroquine and ADI-PEG20. Successful control of tumor burden by using arginine deprivation therapy and autophagy inhibition in our preclinical studies will help to justify and orient future clinical trials for this innovative treatment for patients with sarcoma that lack ASS1 expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5629. doi:1538-7445.AM2012-5629

Evaluation of Menogaril in Patients with Metastatic Sarcomas and No Prior Chemotherapy Exposure

Menogaril, an anthracycline analog of nogalamycin, is reported to have greater cytotoxicity against certain malignant cell lines and less cardiotoxicity in rabbits than doxorubicin. To evaluate the possible therapeutic benefit of this drug, we studied menogaril in 21 patients with metastatic sarcomas who had received no prior chemotherapy. Menogaril was administered intravenously over 1 h every 3-4 weeks at a dose of 200 mg/m2 in 500 ml of 5% dextrose in water. One patient experienced a partial regression of pulmonary metastases from malignant fibrous histiocytoma of bone (response rate of 5% with 95% confidence interval of 0.1-23.8%). Two additional patients experienced minor reductions in tumor size. The remaining 18 patients had no improvement from menogaril. The median time to disease progression was 7 weeks in all patients treated. Toxicity was acceptable, consisting primarily of leukopenia with 12 patients (57%) and 19 patients (90%) developing nadir leukocyte counts less than 2000 and 3000/microL, respectively. Cardiac toxicity was not encountered; however, only seven patients received greater than or equal to 3 cycles of menogaril. We conclude that menogaril does not appear to be useful at this dose and schedule in the treatment of metastatic sarcomas despite the use of near maximal doses in patients with no prior chemotherapy exposure.

A randomized study of continuous infusion vindesine versus vinblastine in adults with refractory metastatic sarcomas

A randomized study was conducted in 33 adult patients with refractory metastatic sarcomas to compare the therapeutic efficacy of continuous vindesine versus continuous vinblastine. Of 30 evaluable patients, 15 patients received vindesine as a continuous 5-day infusion at 1.2 mg/m2 repeated every 3 weeks, and 15 patients received vinblastine at 1.5 mg/m2/day every 3 weeks. Ten patients had stable disease, while 20 patients showed progressive disease. No objective responses were observed. There was adequate myelosuppression and both drugs were well tolerated with few catheter-related problems. It does not appear that vindesine or vinblastine, given by continuous 5-day infusion, is active in the treatment of metastatic sarcomas in adults.

Selective renal artery embolization. Treatment for metastatic sarcoma with hematuria

Selective renal artery embolization. Treatment for metastatic sarcoma with hematuria

Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide

During the initial therapeutic evaluations of adriamycin and DIC, efficacy was noted with each in the treatment of advanced sarcomas. Preclinical studies suggested possible synergism without additive toxicity. This lead to our evaluating the two agents in combination in metastatic sarcomas. Adriamycin at 60 mg/m2 was given I.V. on day 1 and DIC 250 mg/m2 I.V. on days 1 to 5, with the entire regimen repeated every 21 days. The dosage of both drugs was reduced 25% in patients with extensive prior therapy. Of 120 patients entered, 100 were evaluable for therapeutic efficacy. Five complete and 36 partial remissions (> 50%) were observed for a response rate of 41% including the following diagnoses: synovial cell sarcoma 2/2; rhabdomyosarcoma 3/5; undifferentiated sarcoma 6/13; fibrosarcoma 5/11; osteogenic sarcoma 8/18; liposarcoma 3/7; mesothelioma 3/7; neurofibrosarcoma 4/10; leiomyosarcoma 6/16; angiosarcoma 1/5; chondrosarcoma 0/4, and miscellaneous sarcomas 0/2. The median duration for complete remission was 5+ months (range—3+ to 7+ months) and for partial remission was 31/2+ months (1–10+ months) with 29/41 still in remission. Toxicity was limited predominantly to vomiting, alopecia, and myelosuppression. Leukocyte depression was maximum by median day 15, with prompt recovery permitting retreatment at a 3-week interval in all but 8% of courses. Combination therapy with adriamycin and DIC appears to be an effective and promising regimen in the treatment of metastatic sarcomas.