Non-resectable Soft Tissue Sarcomas Research Articles

Building liquid-liquid perfusion interface (LLPI) –based patient-derived tumoroids (PDTs) model system as clinical research tools for testing cancer therapeutics.

e15192 Background: Current in vitro cancer model systems are inadequate in their representation and application of an actual tumor. Use of three-dimensional PDTs that consists of stroma and the microenvironment vastly addresses these shortcomings. However, a complete picture of the intratumoral interactions and functions requires optimal supply of oxygen to address problems associated with poor cellular oxygenation. Soft tissue sarcomas are malignant tumors that develop in the tissues that surround and support bones and organs. For non-resectable soft tissue sarcomas, model systems and treatment options are either limited or not available. We are establishing our Matrigel-based PDTs on a Liquid-Liquid Perfusion Interface (LLPI) using a synthetic hemoglobin as a blood substitute to build a comprehensive model system that is an amalgamation of an in vitro-in vivo system. Our objective is to replicate tumor complexity and use our model to serve as an effective and reliable platform to test and investigate therapeutic options. Methods: Soft tissue sarcoma PDT models with LLPI were built and used for testing under the following groups: Drug treatments with Doxorubicin (10nM), HSP90 inhibitor (1)10 nM, (2) 100 nM and (3) 1 mM) and combination (Doxorubicin + HSP90) for 10 days was compared on Sarcoma PDT models with and without oxygenation to test the impact of oxygen on tumor volume. Currently we are pursuing downstream analysis using apoptosis, proliferation and cytokine profiling and dynamic oxygen analysis of the TME. Results: We compared the effect of Doxorubicin with HSP90 inhibitor on a Sarcoma PDT model with and without oxygenation to observe the impact of oxygen on tumor growth. We observed similar rate of cell growth in the untreated samples in both model systems. In the non-oxygenated PDTs Doxorubicin-HSP90 combination was effective in reducing tumor volume. In the oxygenated PDTs the efficacy of the combination therapy (Doxorubicin+HSP90) was no longer observed. Conclusions: The oxygenation status impacts the effect of Doxorubicin, HSP90 combination, a critical influence that would not have been observable without the use of oxygenated PDT model system. The impact of intratumoral variations on oxygenation levels warrants testing other existing and novel therapeutics on oxygenated PDT model systems to investigate the extent of the influence of oxygenation on the tumor biology. [Table: see text]

The Midwest Sarcoma Trials Partnership: Bridging Academic and Community Networks in a Collaborative Approach to Sarcoma.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Deep-learning and MR images to target hypoxic habitats with evofosfamide in preclinical models of sarcoma.

Rationale: Hypoxic regions (habitats) within tumors are heterogeneously distributed and can be widely variant. Hypoxic habitats are generally pan-therapy resistant. For this reason, hypoxia-activated prodrugs (HAPs) have been developed to target these resistant volumes. The HAP evofosfamide (TH-302) has shown promise in preclinical and early clinical trials of sarcoma. However, in a phase III clinical trial of non-resectable soft tissue sarcomas, TH-302 did not improve survival in combination with doxorubicin (Dox), possibly due to a lack of patient stratification based on hypoxic status. Therefore, we used magnetic resonance imaging (MRI) to identify hypoxic habitats and non-invasively follow therapies response in sarcoma mouse models.Methods: We developed deep-learning (DL) models to identify hypoxia, using multiparametric MRI and co-registered histology, and monitored response to TH-302 in a patient-derived xenograft (PDX) of rhabdomyosarcoma and a syngeneic model of fibrosarcoma (radiation-induced fibrosarcoma, RIF-1).Results: A DL convolutional neural network showed strong correlations (>0.76) between the true hypoxia fraction in histology and the predicted hypoxia fraction in multiparametric MRI. TH-302 monotherapy or in combination with Dox delayed tumor growth and increased survival in the hypoxic PDX model (p<0.05), but not in the RIF-1 model, which had a lower volume of hypoxic habitats. Control studies showed that RIF-1 resistance was due to hypoxia and not other causes. Notably, PDX tumors developed resistance to TH-302 under prolonged treatment that was not due to a reduction in hypoxic volumes.Conclusion: Artificial intelligence analysis of pre-therapy MR images can predict hypoxia and subsequent response to HAPs. This approach can be used to monitor therapy response and adapt schedules to forestall the emergence of resistance.

Soft Tissue Cancer Management: Isolated Limb Infusion for Sarcoma

Background: Sarcoma is a heterogeneous group of malignancies comprising almost 80 subtypes of bone and soft tissue cancers. Previously, all subtypes were managed identically. Advancements in biological and genetic studies have revealed that sarcoma subtypes display varying characteristics and therefore require tailored treatments. Locally advanced soft tissue malignancies of both the trunk and the extremities can present significant challenges for treatment. At present, a negative surgical resection margin is the only definitive treatment despite attempts to use neoadjuvant and adjuvant therapies. In patients with locally advanced non-resectable soft tissue sarcoma (STS), the current practice would advocate amputation. However, studies suggest that limb salvage may be possible with radiotherapy or regional chemotherapy using isolated limb perfusion or isolated limb infusion (ILI). An ideal treatment modality for non-resectable STS would strive for preservation of anatomy and functionality as well as improve quality of life. The aim of the study was to investigate the efficacy of isolated limb infusion as an alternative treatment modality for non-resectable locally advanced STS. Methods: The efficacy of ILI was retrospectively investigated in 10 patients with STS. All patients received ILI with melphalan and actinomycin at the North Estonia Medical Centre Foundation, Tallinn, Estonia from September 1, 2014 to May 31, 2018. The procedures were performed in a lower extremity in 8 patients and in an upper extremity in 2 patients. The 6-month overall response rate was 78% and the overall limb salvage rate was 100%. The distant metastatis-free survival was longer for responders than for non-responders. Results and Conclusions: ILI is an alternative treatment modality for regional disease control and limb preservation in patients with cutaneous and soft tissue malignant neoplasms of the extremities. The short-term response rates are encouraging and the median overall survival shows good results in this highly complex patient population.

A phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas.

11550Background: Topotecan and pazopanib (PAZ) individually have clinical benefit in patients (pts) with sarcomas. PAZ is a multi-tyrosine kinase inhibitor and topotecan affects endothelial cells, ...

Lower limb function and quality of life after ILP for soft-tissue sarcoma

BackgroundIsolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival.MethodsWe retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the “all cancer patients” reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals.ResultsSurprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment.ConclusionsThese results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas

Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. NCT01782313.

A phase 2 trial of 5-imino-13-deoxydoxorubicin (GPX-150) in metastatic and non-resectable soft tissue sarcomas.

11019Background: 5-imino-13-deoxydoxorubicin (GPX-150) is a doxorubicin (dox) analog that has been modified to retain the ability to inhibit topoisomerase 2a while simultaneously lacking the inhibi...

A phase II study of tivozanib in patients with metastatic and non-resectable soft tissue sarcomas.

A phase II study of tivozanib in patients with metastatic and non-resectable soft tissue sarcomas.

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.

10515 Background: Despite a multi-modality approach, many patients (pts) with early stage soft tissue sarcomas (STS) will develop recurrent or metastatic disease. Treatment options for these pts ar...

Head and neck sarcoma: report of a case treated by intensity-modulated radiation therapy

We report on a 71-year-old woman with parapharyngeal sarcoma. Surgery could not be performed because of the size and location of the tumor. After failure of four cycles of chemotherapy, intensity-modulated radiation therapy (IMRT) achieved complete clinical response and partial magnetic resonance imaging response (80%) at 24 months of follow-up. The results of radiotherapy, especially IMRT, for nonresectable head and neck soft tissue sarcoma are discussed.

Evaluation of 47 Soft Tissue Sarcoma Resection Specimens after Isolated Limb Perfusion with TNF-α and Melphalan: Histologically Characterized Improved Margins Correlate with Absence of Recurrences

Isolated limb perfusion (TM-ILP) is an effective limb-sparing treatment for primarily nonresectable soft tissue sarcomas (STS). Surgical margins of STS after ILP were yet not systematically studied. In 47 patients with nonresectable STS, TM-ILP with subsequent tumor resection was performed. Surgical margins were systematically analyzed by light microscopy using the TNM and the Enneking classification. Furthermore, margins were analyzed for tumor regression in terms of improved resectability. Results were correlated with clinical and pathological parameters. Of 47 STS, 44 were classified as high-grade (93.6%) with a median tumor size of 10.0 cm. Primary limb-salvage rate was 85.1%. According to TNM resection margins were complete in 70.2% (R0) and incomplete in 29.8% (R1=21.3%, R2=8.5%). According to Enneking, 27.7% intralesional, 42.6% marginal, 21.3% wide, 2.1% radical, and 6.4% unclassifiable margins were found. Prior surgery and/or radiotherapy significantly decreased margin quality. Ten patients with incomplete resection (three intralesional, seven marginal) had no viable tumor at the plane of dissection, which was designated as "improved margins." Whereas those patients remained relapse free, five patients with viable tumor (not improved margins) at the resection margin had local recurrences. Poor margins were associated with local and distant recurrences and limited disease-specific survival. TM-ILP is effective for achieving limb salvage. Histopathology of surgical margins demonstrates cases with so-called "improved margins" after TM-ILP, which are related to a better outcome even in intralesionally resected tumors. Improvement of margins should be further evaluated as a potential relevant prognostic parameter.

Isolated limb perfusion with tumor necrosis factor and melphalan for non‐resectable soft tissue sarcomas: Long‐term results on efficacy and limb salvage in a selected group of patients

Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a limb salvage therapy for non-resectable soft tissue sarcomas (STS) of the extremities. It is indicated for patients for whom amputation or debilitating surgery is the only alternative. It can be used either as an exclusive therapy (in palliation) or as a neo-adjuvant treatment, followed by marginal resection of tumor remnants with minimal functional impairment. Between February 1992 and March 2006, 57 TM-ILPs were performed on 51 patients with 88% high grade and 84% advanced stage tumors. Mean follow-up is 38.9 months (4-159, median 22 months). Twenty-one percent patients had significant early complications, with 3 major re-operations, and 23% suffered long-lasting complications. Complete response was observed in 25%, partial response in 42%, stable disease in 14% and progressive disease in 14%. Resection of the tumor remnants was possible in 65%. A complementary treatment was necessary in 31%, mostly radiation therapy. A local recurrence was observed in 35%, after a mean of 20.3 months (2-78), and distant relapse was seen in 45%, after a mean of 13.4 months (5-196). Mean Disease-free survival was 14.9 months, and overall 5-year-survival 43.5%. Amputation rate at 5 years was 24%. TM-ILP is a conservative treatment with a high complications rate, but it can be successful even for the most severe STS of extremities. As a consequence the limb can be spared from amputation or debilitating surgery on the long term in about 75% of patients.

43 ORAL The Swiss experience with isolated limb perfusion with high-doses tumor necrosis factor-alpha and melphalan, a limb salvage strategy for non-resectable soft tissue sarcomas of the extremities

S. Cherix1, M. Speiser2, M. Matter3, L. Guillou4, D. Lienard5, F. Lejeune5, R. Mirimanoff6, S. Leyvraz5, P. Leyvraz1. 1University Hospital, Orthopaedics and Traumatology, Lausanne, Switzerland; 2Universty of Lausanne, Medecine, Lausanne, Switzerland; 3University Hospital, General Surgery, Lausanne, Switzerland; 4University Hospital, Pathology, Lausanne, Switzerland; 5University Hospital, Medical Oncology, Lausanne, Switzerland; 6University Hospital, Radiation Oncology, Lausanne, Switzerland

Palliative radiotherapy as treatment for non‐resectable soft tissue sarcomas in the dog – a report of 15 cases

Fifteen dogs with various non-resectable soft tissue sarcomas were treated with a palliative protocol of Cobalt(60) radiation. Twelve (80%) of the 15 tumours were fibrosarcomas and haemangiopericytomas. Total tumour radiation dose was 24 Gy, given in three 8 Gy fractions, on days 0, 7, 21 or weekly. Thirteen tumours (87%) responded with stable disease; median time to progression and median survival time were 263 and 332 days, respectively. Radiation toxicity was negligible. The survival and local control with this palliative protocol are almost comparable with curative intent primary radiotherapy.

Wild-type p53 gene transfection in human cultured sarcomas: effect of CDDP.

We examined the susceptibility of five human bone and soft tissue sarcoma cell lines to transfection with recombinant p53 adenovirus vector (AxCA-p53). Transfection efficiency was more than 90% at 72 h with AxCA-lacZ at a multiplicity of infection (MOI) of 50 in all the cell lines, except for MG-63 (p53 gene mutated) cells. Western blot analysis showed overexpression of both P21/Waf1 and Bax protein in all the cell lines, implying sufficient and successful p53 gene transfection. AxCA-p53 transfection at MOI of 50 resulted in a significant decline of viable cells at 72 h, due to apoptosis, in NY (mutated) and Saos-2 (deletion), but not in the other three lines. The two apoptosis-induced cell lines showed a gradual increase in Bax expression up to 72 h and non-detectable expression of Bcl-XL from 48 h, suggesting the involvement of an apoptosis-inducing mechanism. Pre-treatment with cis-diamminedichloroplatinum (II) (CDDP) at 0.1 microg/ml significantly suppressed tumor cell viability in NY and HuO-3N1 (mutated), but not in the other three lines including HT-1080 carrying the wild-type p53 gene, implying the existence of different mechanisms for the tumor suppressive effect of p53 gene transfection and CDDP. These results indicate that wild-type p53 gene transfection with CDDP is a promising therapy for some, but not all, non-resectable bone-and soft tissue sarcomas, regardless of intrinsic p53 gene status.

Limb salvage by neoadjuvant isolated perfusion with TNFα and melphalan for non-resectable soft tissue sarcoma of the extremities

Aims Patients with non-resectable soft tissue sarcomas of the extremities do not live longer if they are treated by amputation or disarticulation. In order to avoid major amputations, we tested isolated limb perfusion (ILP) with tumour necrosis factor α (TNF)+melphalan+/−interferon-γ (IFN) as a pre-operative, neoadjuvant limb salvage treatment. Methods Twenty-two patients were included (six men and 16 women; three upper limb and 19 lower limb tumours). The AJCC stage was IIA in four patients, III in seven and IV in 11. Thirteen cases were recurrent or progressive after previous therapy; five tumours had a diameter ≥20 cm, and four were multiple or regionally metastatic. There were six malignant fibrous histiocytomas, five liposarcomas, four malignant peripheral nerve sheath tumours, three rhabdomyosarcomas, two leiomyosarcomas, one recurrent extraskeletal osteosarcoma and one angiosarcoma. Results Twenty-four ILPs were performed in the 22 patients, and 18 (82%) experienced an objective response: this was complete in four (18%) and partial in 14 (64%). Three patients had a minimal or no response and the tumour progressed in one case. All patients had fever for 24 hours but only one developed a reversible grade 3 distributive shock syndrome with no sequelae. There was no grade 4 toxicity. Seventeen patients (77%) underwent limb-sparing resection of the tumour remnants after a median time of 3.4 months: 10 resections were intracompartmental and seven extracompartmental. Surgery included flaps or skin grafts in five patients, arterial replacement in two and knee arthrodesis in one. Adjuvant chemotherapy was given to eight patients and radiotherapy to six. In one patient amputation was necessary after a second ILP. Secondary amputations were performed for recurrence in two patients, resulting in an overall limb salvage rate of 19/22 (86%). After a median follow-up of 18.7 months, 10 recurrences were recorded: seven were both local and systemic and three were only local. The median disease free and overall survival times have been >12.5 and 18.7 months respectively: this is similar to the outcome after primary amputations for similar cases. Conclusion ILP with TNF and chemotherapy is an efficient limb sparing neoadjuvant therapy for a priori non-resectable limb soft tissue sarcomas.

Chemotherapy

Chemotherapy

217 The European experience in TNFα isolated limb perfusions for nonresectable extremity soft tissue sarcomas: 85% response rate; 87% limb salvage

Goal Achieve limb salvage in patients with irresectable soft tissue sarcoma (STS) of an extremity by ILP with TNFα ± IFN-gamma and Melphalan. Material and Methods 120 patients (pts) with nonresectable STS of the extremities were treated without IFN (65) or with 0.2 mg IFN (55) s.c. on the 2 days prior to a 90 minutes ILP with 0.2 mg IFN, 4 mg TNF (leg) or 3 mg TNF (arm), and 10 mg/L (leg)—13 mg/L (arm) limb volume of Melphalan at 39–40 °C. In 20% of the patients there were multiple sarcomas in the extremities. Residual tumors were resected (after 2–6 months) after maximal shrinkage (often 90%–100% necrotic). TNFα/IFN Boehringer Ingelheim GmbH. Results In 55 patients treated with TNF + IFN + Melphalan: 20 CR (36.4%), 29 PR (52.7%),6 SD (11%); in 65 patients treated with TNF + Melphalan: 20 CR (30.8%), 33 PR (50.8%), 12 NC (18.4%). Median follow up of first 55 pts 18 + months (9 + −40 + months). Most tumors became resectable 2–3 months after ILP. Limb salvage rate was 49/55 (87.3%) and 56/65 (86%). Toxicity was moderate (grade I-II) and transient grade III liver toxicity. There were no toxic deaths. Conclusion Isolated limb perfusion with TNFα, ± IFN-gamma and Melphalan is safe and very effective against locally advanced extremity soft tissue sarcomas.

Solid Tumors

Soft-tissue tumors are similar in their behavior. Benign tumors can be easily resected in most cases, whereas malignant tumors are relentless in their locally invasive characteristics. A clear understanding of the constraints of the pathologist in reaching a confirmed diagnosis and a logical plan utilizing surgery as the major modality of therapy are necessary for successful management of these tumors. It appears that radiation combined with hyperthermia is beginning to play a significant role in the local control of soft-tissue sarcomas and that single or multi-agent chemotherapy may be of benefit in treatment of nonresectable or metastatic soft-tissue sarcomas. For the immediate future, surgery remains the only nonexperimental modality of therapy, but the rapid advances in the other therapy methods are encouraging.