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Decisions in the Clinic: Treating Patients With Sarcoma
Under what conditions will you treat newly diagnosed patients with sarcoma with initial radiotherapy or initial chemotherapy?
A key thing about sarcoma is that there are pediatric types and adult types. The treatment algorithm is different. Pediatric types (eg, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma) require chemotherapy curative treatment. For adult types (eg, undifferentiated pleomorphic, leiomyosarcoma, synovial sarcoma), randomized studies done in Europe showed that for people treated with surgery with/without radiation, the addition of chemotherapy did not improve the cure rate.
Adult types can go right to surgery for small tumors or tumors for which limb salvage is not practical. For large tumors, our surgeons prefer preoperative radiation. Advantages of neoadjuvant radiation vs postoperative radiation include ability to use a smaller radiation field and a lower dose. There is a clinical trial open at Emory’s Winship Cancer Institute and other sites looking at combinations of chemotherapy, targeted therapy with pazopanib, and radiation for primary sarcoma treatment (ClinicalTrials.gov Identifier: NCT02180867 ). The goal of the study is to assess whether adding the targeted agent pazopanib to standard treatment with radiation with/without chemotherapy improves outcomes compared with standard treatment alone.
It is important to note that primary sarcoma treatment is frustratingly influenced by non-evidence-based opinions. Many US sarcoma oncologists remain enthusiastic about chemotherapy as part of primary curative treatment, and American patients frequently receive chemotherapy for these tumors. I have seen plenty of presentations where 2 speakers on the stage offer opposite opinions on whether chemotherapy should be part of primary treatment for adult sarcoma types. It is not this way for any other solid tumor.
In your experience, what types of sarcoma are most difficult to treat, and why?
A lot of chemotherapy regimens for sarcoma are aggressive and toxic. People are up for trying different chemotherapeutic agents, but the standard agents used are those that give chemotherapy its bad reputation. Doxorubicin is toxic and the life limit is quickly reached. Ifosfamide is also very toxic, as is the docetaxel and gemcitabine combination. Even people who can withstand the toxicity for the first couple of doses are eventually worn down and must stop treatment. Then the tumor starts growing again.
I like drugs like Doxil and regimens that are sustainable over long periods with minimal toxicity. A problem, however, is proving they work by testing them out in clinical trials. Because there is no money to be made using these old drugs in ways that might be effective and easier on the patient, there are no industrial sponsors for such studies. Industry is interested in sponsoring new drugs that will be profitable, and even generic chemotherapy drugs are too expensive to purchase with a foundations grant. This makes it difficult to do a clinical trial of a combination like low-dose gemcitabine and vinorelbine to prove it works. For oncologists to confidently administer such regimens, evidence is needed via a clinical trial, but there is no one I know of willing or capable of paying for such a trial.
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?
I have been giving olaratumab with Doxil. I do not like monotherapy with conventional doxorubicin because it is too toxic, as previously mentioned. The improvement that olaratumab is supposed to bring is over the long-term and maybe I have not been giving it for long enough to see that. The olaratumab plus Doxil combination has, however, been well-tolerated by my patients so far and, given the lower cardiotoxicity of Doxil, should be sustainable over the intermediate- to long-term.
Although olaratumab is generally well-tolerated, with gastrointestinal effects being most common, we have learned to be more careful with its administration after a patient experienced an asystole arrest shortly after receiving his first few drops of olaratumab. That was completely unexpected by all involved. Fortunately, we managed to get the patient back.
A couple of new chemotherapeutic agents have been approved for sarcoma over the past 2 years, with trabectedin approved in early 2015 and eribulin in early 2016. Trabectedin is so toxic that it has been difficult to use for my patients. Eribulin, however, has been well-tolerated and I am going to start trying to use this agent earlier for people with liposarcoma and leiomyosarcoma. Usually, after a couple of drugs come to market, there is a lull and I am not aware of any new agents coming down the pike for sarcoma. I am sad that at Emory we do not currently have any clinical trials of new agents for sarcoma.
Immunotherapy has generated considerable excitement for other tumor types, but there has not been much momentum yet with sarcoma. There was a study of the anti-programmed cell death-1 (PD-1) therapy, pembrolizumab, for soft tissue sarcoma that rapidly opened and closed. My understanding is that the drug’s manufacturer did not think that the results warranted further pursuit.
I have tried pembrolizumab in 2 people with pleomorphic sarcoma and it did not work for either patient. Most likely, as more of these drugs are developed, manufacturers will come back and look at sarcoma as other markets fill up. I understand that we may get a clinical trial for an anti PD-1 therapy for alveolar soft part sarcoma, which is a super rare tumor type. I am not sure why someone thinks immunotherapy might work for it, but it is worth a try. There is also a PD-1 immunotherapy study for relapsed osteosarcoma at St Jude Children’s Research Hospital, but I cannot get my adult patients into that study, so I will have to wait to see how it turns out for the children enrolled.
Can you explain how the genomic heterogeneity of some sarcoma types affects your treatment decisions?
Genomic analysis can be useful in diagnosis. For example, certain gene translocations or mutations mark specific sarcoma types and pathologists look for those markers if they are uncertain of the diagnosis. While there has been a lot of publicity for genetic analysis with FoundationOne and similar testing, I have not found it to help me with selecting treatments for sarcoma.
The idea is that these tests might reveal some unsuspected Achilles heel and enable targeted treatment, but these tests are expensive, often costing more than $10,000, and I think it is exceedingly rare to find useful markers, especially with sarcoma.
The National Cancer Institute’s MATCH trial (ClinicalTrials.gov Identifier: NCT02465060) is currently looking at tumors to assess for molecular weaknesses and then matching patients with a targeted therapy that addresses this weakness. The study is still recruiting patients nationwide, and we have put people treated at Emory on this trial, but so far none of our participants at Emory have been found to have a molecular weakness that can be targeted with currently available treatments.
1) Judson I, Verweij J, Gelderblom H, et al; European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-23.
2) Seddon BM, Whelan J, Strauss SJ, et al. GeDDiS: A prospective randomised controlled phase III trial of gemcitabine and docetaxel compared with doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft tissue sarcomas (EudraCT 2009-014907-29) [ASCO abstract 10500]. J Clin Oncol. 2015;33(suppl):15.
3) FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma [news release]. Silver Spring, MD: US Food and Drug Administration; October 19, 2016. https://www.fda.gov/newsevents/newsroom/ pressannouncements/ucm525878.htm.