The advent of tyrosine kinase inhibitors has dramatically changed the overall survival of patients with GIST…. This remarkable innovation has set the stage for the second biggest advance in sarcomas, which is the absolute destruction of the nihilism surrounding this disease.
—George D. Demetri, MD
In 2014, about 15,000 people in the United States will be diagnosed with some form of sarcoma, and of those, approximately 5,000 adults and children are expected to die of the disease. Sarcomas are a heterogeneous group of mesenchymal malignancies that have historically been difficult to diagnose and treat, resulting in confusion, fear, and poor survival outcomes for patients with metastatic disease while nonetheless bringing cures to many patients with early-stage disease.
To bring our readers up to date on the current state of sarcoma treatment and the advances that lie ahead, The ASCO Post recently spoke with George D. Demetri, MD, Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston.
What has been the most important advance in sarcoma during your career?
Unquestionably, the most important advance was the demonstration that tyrosine kinase inhibitors can durably control disease in patients with gastrointestinal stromal tumors (GIST). In fact, nearly 20% of advanced GIST patients taking imatinib (Gleevec) treated on our very first clinical study have now survived more than 14 years, which is absolutely remarkable. The advent of tyrosine kinase inhibitors has dramatically changed the overall survival of patients with GIST, not only in the advanced-disease setting, but also in the high-risk adjuvant setting.
Moreover, this remarkable innovation has set the stage for the second biggest advance in sarcomas, which is the absolute destruction of the nihilism surrounding this disease. When I was in training, most people looked at sarcomas as this clinical black box of futility, except for a couple of pediatric sarcomas, such as Ewing’s or osteosarcoma, which were potentially curable by conventional chemotherapy.
Another important stride was the recognition that sarcoma subtypes are vastly different from one another, and now we finally have the tools to separate these subtypes and categorize them into bins that are rational and potentially targetable. This has been a dramatic conceptual change that began in sarcomas and has now permeated all of oncology. In many ways, sarcomas led the way forward for the modern approach to solid tumor oncology.
Improvements in Diagnosis
Diagnosis in this disease has always been difficult. Have we made headway in that clinical challenge?
Yes, we’ve made headway, thanks to the dedication and improved tools for our pathologists. The diagnostic technology has improved dramatically, not just immunohistochemistry, which was a big deal in the 1990s, but the fluorescence in situ hybridization (FISH) and genomic sequencing technologies. Simply put, the quality of sarcoma diagnoses are improving every day at reference centers.
To that end, an important issue is whether the U.S. Food and Drug Administration (FDA) tackles the nationwide problem of variable results coming out of laboratory-developed tests so that we have full confidence that the labs to which we entrust our patients’ materials are accurate and reliable. In sarcoma, we’ve been used to the idea that expert reference centers obviate the need for every community hospital to have robust expertise in sarcoma pathology, which is impossible.
We only need the expertise of a few expert reference centers around the country to handle the samples and aid in the diagnosis. Then the community doctors become part of this larger network and implement the guidance of the reference centers into the care of their patients. If we centralize the system, the whole oncology community throughout the country can get by with a limited number of such centralized expert reference centers.
Avoiding Loss of Function From Surgery
Loss of a limb is one of the complicated issues in sarcoma. Has limb-sparing surgery improved markedly over the past decade?
We rarely see amputations in sarcomas any more, as expert surgeons have been able to reconstruct limbs and avoid the need for amputation. However, there are a small number of cases in which prosthesis might be more functional than a limb after treatment. For instance, you can’t really irradiate a foot and have it remain highly functioning, so at that point, amputation might be called for.
That said, prosthetic and robotic technology has advanced to a point of sophistication that actually gives the patient requiring amputation an outstanding quality of life. We have examples of competitive athletes with prosthetics, so it’s a much easier doctor-patient conversation that it was a decade or so ago.
New Therapy Options for Sarcomas Other Than GIST
You’ve stated that the most important advance in sarcoma is the use of tyrosine kinase inhibitors such as imatinib in GIST. Are there any other promising agents in the sarcoma field?
Yes, there are many new targeted therapies in development. The most recently approved agent is the tyrosine kinase inhibitor pazopanib (Votrient), which was the first FDA-approved drug since the early 1980s for use in soft-tissue sarcomas. This drug was the result of an international academic industrial collaboration that was originally designed jointly by colleagues at the European Organisation for Research and Treatment of Cancer (EORTC) and GlaxoSmithKline. The international sarcoma community works very well together, and that is something that I’m very proud to be a part of.
It’s important to note that the activity of pazopanib in a broad range of sarcomas is nowhere near that of imatinib in GIST, because most other soft-tissue sarcomas have more complex “wiring” problems than the single oncogene “driver” that is at the heart of most GISTs. Nonetheless, pazopanib’s activity in sarcomas was sufficient to garner FDA approval, which is a good step forward in these diseases.
Are there ongoing studies in sarcoma that the readers should be aware of?
There are numerous promising and exciting areas of active clinically relevant research in sarcomas. For instance, liposarcoma is the “proof-of-concept” disease for a new class of drugs to inhibit MDM2.
Liposarcoma is one of only a very few types in which the MDM2 gene is amplified, but there are many other cancers in which MDM2 might play a role, and where inhibiting the protein derived from this gene might be helpful to many other cancers beyond sarcomas. In most liposarcomas, there are too many copies of the MDM2 gene, which creates too many copies of a protein that “neutralizes” p53.
So the idea behind this might be phrased “the enemy of my friend is my enemy.” In other words, if having normal p53 as my friend, too much MDM2 is my enemy; by inhibiting MDM2 we hope to reconstitute the tumor-suppressor action of p53. We’ve seen this promising activity in translational studies on human tumors. MDM2 inhibitors are currently being produced by several biotech and pharmaceutical companies, and we’re testing them in late-stage phase I and II studies.
Also, about 9 of 10 liposarcomas express CDK4. As readers of The ASCO Post know, CDK4 inhibition has achieved “breakthrough drug” status in hormone receptor–positive breast cancers, and several ongoing studies are evaluating different CDK4 inhibitor drugs. This is another exciting therapeutic avenue in sarcomas, and we’re also looking at the promising possibilities offered by combination targeting to inhibit both MDM2 and CDK4.
Very interesting work has also come out of the University of Michigan, Massachusetts General Hospital, and St. Jude Children’s Research Hospital, which have independently identified and confirmed PARP inhibition as a previously unsuspected way to treat Ewing sarcoma. My colleague, Edwin Choy, MD, PhD, at Massachusetts General Hospital and our team at Dana-Farber/Harvard have developed a very exciting clinical trial of the PARP inhibitor olaparib, to set up Ewing sarcoma to be more sensitive to chemotherapy, which appears very positive already. There are other larger-scale trials using other PARP inhibitors as well, to explore whether this might be helpful to patients, and the early data certainly appear encouraging.
It’s a very exciting and hopeful time for patients as well as physicians in sarcoma research.
Transforming This Disease
Any last thoughts on this difficult clinical area?
I started in this field in the 1980s, during which there were very few treatment options other than empiric, highly toxic chemotherapy. Our multidisciplinary team did cure a certain number of these sarcomas, but more importantly, we took the best qualities of the early chemotherapies and built upon them, and now we’re building better therapies on the backs of the new-millennium targeted therapies. I truly believe that we are transforming this disease in a way that will bring the same extraordinary advances seen in hematologic malignancies, such as leukemias and lymphomas.
It’s also important to note that we could not have made these advances without the Internet. The fact that patients with rare diseases now have the ability to connect with each other and share information with their physicians has accelerated the ability of patients to find our research and help us place those patients into the clinical trial system. This has been key to the past 15 years of advances in sarcomas and other rare cancers. ■
Disclosure: For Dr. Demetri’s full disclosure of all potential conflicts of interest, click here.