1Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital, Hyderabad
Advanced stage soft tissue sarcoma (STS) comprising of inoperable and/or wide spread metastases, though often pronounced as one disease, we know that about 50 subtypes exist; treatment outcomes are varied, and remain incurable. Though the incidence is less in the clinic, disappointment and dissatisfaction to treatment is high in many cases. What do we currently do in clinical practice when we see a patient of advanced soft tissue sarcoma? Ask the following questions: Is the tumour High grade or Low grade? First line or second line? Is the patient fit? One additional yet important question is what is the histology like? Collate all the answers and prescribe a suitable chemotherapy regimen explaining the risks and benefits. Options remain limited at relapse.
We have made substantial progress in our understanding and approach towards many other cancers, but what for advanced STS? Can we use some kind of biomarkers and identify patients who are candidates for best response to chemotherapy? Can we de-escalate treatment in some and preserve quality of life? Where are small molecule tyrosine kinase inhibitors? What had the immune check point inhibitors offered in this setting? Let’s have a quick look in to these issues in the treatment of adult soft tissue sarcomas.
Histopathological subtyping of STS tends to offer tailored treatment approach but strong evidences from clinical trials mandating clinical practice in the first line or later lines of chemotherapy are only few. Rarity of these tumours and the requirement of multi-centre collaboration could be a barrier to generate a strong body of evidence. An attempt had been made to identify histology as a marker to choose chemotherapy and substantial evidence exists to support this approach. Retrospective analyses identified that the combination of Ifosfomide and Doxorubicin were very effective in Myxoid Liposarcoma (MLPS) ; Gemcitabine based chemotherapies brought responses in Leiomyosarcomas (LMS).  In patients with advanced MLPS, first line response rates of about 60% and overall survival of about 30 months was observed with Ifosfomide and Doxorubicin in retrospective studies.  In addition to being chemo sensitive, liposarcoma (LPS) is known to be radiosensitive also. Poor response to chemotherapy was observed in clear cell sarcomas whereas the Gemcitabine/Docetaxel chemotherapy was found to be ineffective in MLPS. Similar observations of differential response to chemotherapy agents among different types of STS were reported in other retrospective and Phase 2 studies. Clinical utility of Trabectedin has been limited to LMS, Liposarcoma with myxoid/round cell histology and translocation related sarcomas. The exact reason for such differential response is not known but possible differences in oncogenesis, tumour microenvironment, and varied genetic landscape for different tumours could a possible explanation.
Small molecule tyrosine kinase inhibitors targeting Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF) receptors were looked up with expectations but they could only of benefit to certain subtypes. In the phase II EORTC study, Pazopanib was found to have modest activity in advanced LMS and Synovial Sarcoma (SS) but not in LPS in second line setting.  Similar findings were made in a randomised controlled trial also.  Pazopanib improved both disease free survival (DFS) and overall survival (OS) in non lipogenous tumours after first line chemotherapy. Alveolar Soft Part Sarcoma and Clear cell sarcoma were found to gain disease control and survival with Pazopanib. Other rarer subtypes like Solitary Fibrous Tumours respond modestly to Pazopanib, Sunitinib and Sorafenib [7,8]; Alveolar Soft part Sarcomas have been shown to respond to Pazopanib, Sunitinib as well as selective Mesenchymal-epithelial Transmission (MET) receptor inhibitors in cases with MET overexpression; mTOR inhibitors showed activity in rarer PEComas.  Anaplastic Lymphoma Kinase (ALK) gene rearranged Imflammatory Myofibroblastic Tumours have shown to respond to Crizotinib and more recently to Ceretininb, offering a hope for longer disease control upon crizotinib resistance.  Pazopanib was recently shown to be noninferior to Doxorubicin in terms of PFS in first line therapy in patients with anthracycline sensitive type of advanced STS [(LMS, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS)] aged above 60 years. 
Emphasis has been made for ancillary tests on the tissue including cytogenetics/ Fluoresence insitu Hybridization/ molecular markers to arrive at a definitive diagnosis; this could subsequently aid to select patients for the most appropriate therapy.
The initial study of Pembrolizumab in advanced STS included pre-treated patients with different soft tissue and bone sarcomas; activity of Pembrolizumab was seen in patients with UPS and de differentiated Liposarcoma.  Single agent Nivolumab and single agent Ipilimumab could not offer any benefit; combination of Ipilimumab and Nivolumab showed some responses but toxicities were high.  Combination of Axitinib and Pembrolizumab showed modest response in a small study in patients with Alveolar Soft Part Sarcoma. Concurrent administration of Nivolumab and sunitinib resulted in six-month PFS of 50% in later lines of chemotherapy in a small cohort of patients.  Combination of immune check point inhibitors with either single drug chemotherapy or metronomic chemotherapy has been tried with disappointing results.  Overall, immune check point inhibitors are yet to make their mark in advanced STS care. The possible exception is undifferentiated pleomorphic sarcoma, where the tumour mutation burden is seen to be high.
Histology and Grade are still the two most important factors in selecting most appropriate treatment for advanced STS. It would be ideal to conduct histological sub type- specific clinical trials to further understand the differential chemosensitivity to various chemotherapy combinations. A major challenge in conducting such clinical trials is the ability to enrol adequate number of patients to generate adequately powered data. Rarity of these tumours is the most important barrier and multi centre collaboration is the only way forward to overcome this barrier. Responses to chemotherapy or tyrosine kinase inhibitors or immune check point inhibitors appear to be related to histological subtype at least as of now; emphasis has to be made on using all ancillary tests in order to label the diagnosis. The in-depth analysis of genetic makeup of different subtypes of STS may identify newer targets for therapy. Predictive markers for immune check point inhibitors including programmed death ligand 1 (PDL1) expression, Tumour Mutation Burden, Microsatellite Instability (MSI) may be extensively studied.
Finally, for everything to be applicable to us and our patients, we need to generate our own data, whenever it happens! It can happen sooner if all of us want to see.
Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni