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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?
It depends on the stage of the sarcoma. If patients have metastatic sarcoma or a large tumor that is borderline resectable, we will give them systemic chemotherapy preoperatively or treat them systemically for metastatic disease.
I tend not to use radiation very much for initial treatment unless it is for palliation, such as for painful bone metastases. Sarcoma is generally a disease that involves microscopic metastases or metastatic disease. Sarcomas are typically radiotherapy-resistant tumors, so I am not a big advocate of initial radiation for patients with sarcoma. I do not think there’s much benefit to it.
I do believe in chemotherapy for this disease in the metastatic setting and for larger tumors. For those tumors larger than 5 cm or even 10 cm, we would treat preoperatively with chemotherapy to cytoreduce the tumor and the theoretical risk of metastatic disease.
After the patient completes preoperative chemotherapy, we are hopefully left with a solitary mass that is now resectable.
In your experience, what types of sarcoma are most difficult to treat, and why?
Sarcoma is really complex. It is really 60 different diseases that have different degrees of sensitivity to chemotherapy. [Some of the most difficult to treat] are metastatic sarcoma or tumors that are not resectable and require a cytoreductive approach, but none of the sarcomas are easy to treat.
In terms of chemotherapy sensitivity, synovial cell sarcoma tends to be more chemotherapy-sensitive. When patients with synovial cell sarcoma have metastatic disease or micrometastases, we do treat them aggressively with chemotherapy.
When it comes to liposarcomas, which I see a lot of, these have a very different histology and are biologically very different. Liposarcomas tend to be chemotherapy-resistant, so we tend not to use chemotherapy. We have some targeted drug approaches, targeting cyclin-dependent kinase 4 (CDK4) or MDM2 in clinical trials.
In fact, I advocate clinical trials for all patients with sarcoma because generally chemotherapy has been ineffective.
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?
Of course, the approval of olaratumab has changed practice in oncology. Olaratumab targets a protein called PDGFR [platelet-derived growth factor receptor]-α. We are giving doxorubicin with olaratumab based on the survival benefit seen with this combination in a clinical trial that I actually worked on. We initially developed the drug with ImClone, and then it became a Pfizer drug.
I am the senior author on the Lancet paper that published the survival data, which I think are very compelling. It is the first time in oncology we have a drug that prolongs survival [for soft-tissue sarcoma].
There are other recently approved drugs, such as trabectedin, which have been shown to improve progression-free survival for leiomyosarcoma but not overall survival. Eribulin has been shown to offer modest improvement in survival for liposarcoma. These drugs are, however, toxic. Trabectedin can cause hepatotoxicity and marrow suppression. Eribulin is associated with bone marrow toxicity and the overall survival benefit is quite modest.
[In a phase 3 trial], progression-free survival with eribulin was not any different than with dacarbazine, which is an old drug. But for an unclear reason, eribulin did improve overall survival, especially in liposarcoma.
I think there are some new drugs we are going to hear more about going forward, such as immunotherapy, though have yet to understand how immunotherapy works in sarcoma. The initial results have been pretty disappointing.
But again, subtypes of sarcoma are very different from tumor to tumor, and there may be certain subtypes that are more sensitive to immunotherapy. For those sarcomas that are not sensitive, major research efforts are underway to understand why they are not sensitive and to learn how to make them more sensitive to targeted immunotherapeutic approaches.
There are other targeted drugs we are looking at, but understanding the biology of sarcoma is critical. When we identify a target, you will be surprised at the opportunities that exist. For example, we know certain sarcomas have loss of SMARCB1 protein that makes them sensitive to tazemetostat, which is an epigenetic modifier.
Tazemetostat had promising results in a small subset of patients with rhabdoid sarcomas. There are also data for a drug targeting MDM2 in certain types of liposarcomas, but there may be some toxicity issues, especially against platelets.
Can you explain how the genomic heterogeneity of some sarcoma types affects your treatment decisions?
Sarcoma is a challenge in general. There are about 13,000 cases a year spanning up to 60 different subtypes. A sarcoma oncologist needs to understand that even though you call a tumor “sarcoma,” you are really talking about 60 different cancer types, each with a different genomic background.
Because of differences in the tumor’s genomic background, drugs that work for one sarcoma may not work for another sarcoma. It takes a lot of practice and training to understand which genes drive the tumor and whether drugs are available to target those genes and stop those cancer cells from growing or kill them.
That understanding, however, can open the door to a lot of therapeutic opportunities. Not only is there genomic heterogeneity between sarcoma types, there is genetic heterogeneity among tumors within the same sarcoma type. That is not just true of sarcoma — it is true of all cancers that we treat.
Does it affect our treatment decisions in sarcoma? Well, we think about it, but I don’t think it affects our decision about what to do or whether to treat at the moment.
We do, however, have to start thinking about the genetic heterogeneity within a sarcoma type because eventually we will have to select drugs that target not just 1 gene but instead target many of the drivers of that tumor type.
It is hard to adjust therapy for the heterogeneity within 1 type of sarcoma, but clearly we can tailor our therapies to account for the heterogeneity between the 50 or 60 sarcoma subtypes. We can come to understand the genomic background of each type of sarcoma and then develop or use drugs that specifically target genes known to regulate the patient’s sarcoma subtype.
1) Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-97.
2) Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-37.