Richard F. Riedel, MD

Question

Under what conditions will you treat newly diagnosed patients with sarcoma with initial radiotherapy or initial chemotherapy?

Answer

The decision to use a particular modality of treatment — in this case radiation therapy or chemotherapy — depends on a number of factors, including the extent of disease and subtype of sarcoma being treated. For advanced/metastatic soft tissue or bone sarcoma, chemotherapy is the initially preferred treatment approach.

For localized soft tissue sarcoma, particularly a large, high-grade tumor, I routinely recommend preoperative radiation therapy followed by surgical resection. The use of chemotherapy as adjuvant treatment for soft tissue sarcoma, in my opinion, remains controversial, but certainly can be considered in the appropriate patient population.

Chemotherapy may also be considered for localized soft tissue sarcoma prior to surgical resection, as part of a neoadjuvant approach. Although the use of chemotherapy is debated for localized soft tissue sarcoma, there is no controversy regarding its use for localized bone sarcomas, specifically Ewing sarcoma and osteosarcoma. The use of chemotherapy in the localized disease setting for these patients is critical for successful outcomes.

To summarize, for bone sarcomas, such as osteosarcoma or Ewing sarcoma, I routinely consider induction chemotherapy followed by surgical resection and then consolidation chemotherapy. For localized soft tissue sarcoma, I think chemotherapy can be considered in the neoadjuvant or adjuvant setting, but recognize that its use — particularly in the adjuvant setting — is controversial and it has not been shown to consistently improve survival outcomes for patients consistently.

For metastatic soft tissue sarcoma, chemotherapy is preferred. Radiation therapy is not typically part of the initial treatment for localized osteosarcoma but can be considered as part of local control for Ewing sarcoma and then certainly as part of a palliative approach for patients with metastatic disease, particularly if they have a symptom that cannot be managed with medical therapy alone.

Question

In your experience, what types of sarcoma are most difficult to treat, and why?

Answer

I would say sarcomas as a whole are a challenging group of diseases to treat; I often inform patients that there are more than 100 different histological subtypes of sarcoma.

The most challenging histologies, in my opinion, are those that are inherently resistant to our currently available systemic therapies. For example, in the soft tissue sarcoma realm, alveolar soft-part sarcoma, clear-cell sarcoma, extraskeletal myxoid chondrosarcoma, and PEComa [perivascular epithelioid cell tumor] are entities for which there are no currently available FDA [US Food and Drug Administration]-approved therapies.

In these situations, I routinely consider clinical trial options or off-label use of existing therapies. Conventional chondrosarcoma is another entity that is particularly challenging. In general, the rarity and molecular heterogeneity of the disease, combined with the limited number and effectiveness of systemic therapies, makes sarcoma as a whole challenging. I would strongly advocate consideration for clinical trial enrollment for any patient diagnosed with sarcoma.

For many years, our soft tissue sarcoma clinical trials largely involved a “lumping” strategy, where patients with all different histological subtypes of sarcoma were lumped together. This strategy allowed for patients with a number of different histologies to enroll, but it made interpreting the results challenging, particularly if the results were negative.

More recently, we have started to transition to more histology-specific trials and, in some cases, molecularly defined trials. In the last few years, partly due to this transition, we had more FDA approvals in soft tissue sarcoma than over the previous 40 years.

There is a general recognition that sarcomas are molecularly and genetically heterogeneous and that understanding their differences will provide additional insight into therapeutic options. The reality, however, is that many of our therapies are still conventional chemotherapeutics, which are used independent of a biomarker predicting response. The most obvious exceptions to this are gastrointestinal stromal tumors, where mutational testing for KIT and PDGFR-α have the potential to guide therapeutic decisions with respect to the dose of imatinib used or whether to consider adjuvant therapy.

Question

Has the recent approval of olaratumab changed clinical care in your practice? What other treatments in the pipeline do you expect to have a clinical impact?

Answer

Olaratumab, a monoclonal antibody targeting PDGFR-α, was explored in a phase 1/2 study in soft tissue sarcoma. In the randomized phase 2 portion of the study, olaratumab in combination with doxorubicin was compared with doxorubicin alone. The study showed that the combination of doxorubicin with olaratumab improved progression-free survival by 2.5 months (P = .0615) and overall survival by 11.8 months (P = .0003) for patients when compared with doxorubicin alone.1

The magnitude of benefit that was seen for overall survival with the olaratumab-doxorubicin combination was particularly impressive. On average, people taking the combination lived about 11.8 months longer than those who got doxorubicin alone.

Although there is tremendous enthusiasm and excitement about these results, I think they need to be confirmed by the recently completed phase 3 ANNOUNCE study (ClinicalTrials.gov Identifier: NCT02451943). While awaiting results from the ANNOUNCE study, however, I will routinely consider olaratumab for any patient in whom use of an anthracycline, such as doxorubicin, is appropriate.

With respect to other agents in the pipeline, some encouraging data for a new agent known as aldoxorubicin have been reported. This is a novel version of doxorubicin that is attached to a linker that allows for binding to albumin and preferentially accumulates within tumors.

A phase 3 study is looking specifically at TRC105, a novel anti-endoglin antibody, in combination with pazopanib for angiosarcoma (ClinicalTrials.gov Identifier: NCT02979899). Immune-based approaches, which include vaccine-based strategies and checkpoint inhibitors, are also being developed.

Question

Can you explain how the genomic heterogeneity of some sarcoma types affects your treatment decisions?

Answer

Sarcomas are an extremely rare group of mesenchymal neoplasms that are characterized by marked molecular and genetic heterogeneity. Some sarcomas are characterized by unique chromosomal changes, such as synovial sarcoma, Ewing sarcoma, and alveolar rhabdomyosarcoma; others are characterized by a karyotypic aneuploidy, such as leiomyosarcoma or undifferentiated pleomorphic sarcoma.

Although our current systemic therapies remain largely conventional chemotherapies, we are hoping to move into the realm of precision medicine, where treatment is based on an individual tumor’s histology and, hopefully, on a molecular phenotype. These are areas of active exploration in clinical trials. In general, we have not been able to take advantage of the marked heterogeneity across the various sarcomas subtypes for therapeutic intent, but we look forward to that being part of our future approach.

There are ongoing clinical trials looking at molecularly derived therapeutic approaches across a range of cancers, including sarcomas. Two examples are the National Cancer Institute (NCI)’s MATCH study (ClinicalTrials.gov Identifier: NCT02465060) and the American Society for Clinical Oncology (ASCO)’s TAPUR (ClinicalTrials.gov Identifier: NCT02693535) study. I think these studies are going to give us a sense as to whether the strategy of tailoring therapy based on molecularly derived phenotypes — which, in essence, is the promise of precision medicine — actually benefits patients.

I am hopeful that in the next 10 years, we will have a complete paradigm shift with respect to how we think about cancer therapeutics. Right now our sarcoma treatment approaches are, however, largely based on histological diagnoses.