Academic Medical Oncologists Complement Role of Community Oncologists in Sarcoma Treatment

Brian A. Van Tine, MD, PhD

Assistant Professor of Medicine

Division of Medical Oncology, Department of Medicine

Washington University School of Medicine

St. Louis, MO

One of the privileges of working in an academic medical center is the luxury of being able to subspecialize in the treatment of sarcoma. Nationwide, there may be 40 to 50 medical oncologists who focus on the treatment of adult soft tissue and bone sarcoma. With most of the specialists concentrated in just a few centers on the East and West coasts, access to teams with multidisciplinary experience in the treatment of sarcoma is sometimes difficult.

The National Comprehensive Cancer Network (NCCN) guidelines state that, “All patients (with sarcoma) should be evaluated and managed by a multidisciplinary team with expertise and experience in sarcoma, prior to the initiation of therapy.”¹

The reasons for this statement are many. First, the average medical oncologist in private practice sees only 1-2 cases of sarcoma a year. Since mesenchymal tumors (ie, sarcoma) include more than 50 histological subtypes with varying natural histories, genetics, prognostic factors, and sensitivities to treatment, the specific treatment planning requires an in-depth knowledge of sarcoma biology. Though sarcoma is often referred to as a chemotherapy-resistant disease, it may be more correct to say it is chemotherapy-selective cancer. Thus, this necessitates the participation of a sarcoma expert with extensive experience in selecting agents for the specific subtype of sarcoma to best benefit a patient. For example, while ifosfamide is highly active in synovial sarcoma (now called X:18 sarcoma), it is much less responsive in the treatment of leiomyosarcoma. Second, the surgical and radiation planning and chemotherapy sequencing for many of the tumors is complex and requires multidisciplinary planning. Third, and most importantly, the pathology of a sarcoma is best reviewed by a pathologist with extensive experience in the diagnosis of sarcoma.² Histology drives not only treatment decisions but also clinical trial opportunities; therefore, having the most accurate diagnosis is imperative.

It must be clearly pointed out that NCCN guidelines say patients should be evaluated and managed by a sarcoma specialist—not treated. As most sarcoma specialists would agree, standard-of-care regimens are easily given by referring physicians and most likely should be. Otherwise, we would each be treating 400-500 patients, and that is not the role for an academic physician. The major role of the academic sarcoma medical oncologist is the design and implementation of clinical trials that allow for rapid enrollment to move the field forward. Due to the rarity of the disease, most clinical trials for sarcoma patients are limited to the larger academic centers for financial reasons. As such, there is an even greater need to partner with the community oncologist to give the standard-of-care agents.

Important Clinical Trials Are in Progress

One of the greatest successes of the sarcoma field has been in the treatment of gastrointestinal stromal tumors (GISTs).³ The successful treatment of this tumor, once named gastrointestinal leiomyosarcoma, with imatinib necessitated a name change, since imatinib is not effective in other leiomyosarcomas. As most community oncologists are aware, first-line treatment of GIST is imatinib, the second line is sunitinib, and the third line is regorafenib, with other tyrosine kinase inhibitors being used in specific circumstances.

Since the GIST population is now commonly treated in the community with standard-of-care agents, our ability to enroll this patient population in a clinical trial has become more difficult. For example, there is a phase III second- line trial of sunitinib versus masitinib (NCT01694277) that is very slow to enroll because most patients have been treated with sunitinib prior to either visiting or returning to an academic center (Table). Also, there is an international trial of first-line imatinib versus masitinib (NCT00812240) that is now opening. The only way this trial can accrue rapidly is through a partnership with community oncologists making sure that GIST patients are aware of it.

The treatment for soft tissue sarcoma has not had a major advancement since the introduction of gemcitabine and docetaxel in the 1990s, aside from the recently FDA-approved tyrosine kinase inhibitor pazopanib that was approved based on progression-free survival.⁴ With an overall survival of 12-16 months after the diagnosis of metastatic disease, the standard-of-care agents, though active, are not optimal. Thus, the standard of care for metastatic soft tissue sarcoma is still a clinical trial at any line of therapy. The sarcoma community has recently demonstrated that it can do large randomized phase III clinical trials in record time thanks to the participation of the community oncologists who make the initial referrals.

Table. Selected Clinical Trials in Sarcoma

Patient Population

Patients (N)

Agents Under Study

Sponsor(s)

Stage (NCT ID)

GIST after progression with imatinib 400 mg as first-line treatment

208

Masitinib vs sunitinib

AB Science

Phase III (NCT01694277)

GIST in first-line treatment

222

Masitinib vs imatinib (400 mg or 600 mg)

AB Science

Phase III (NCT00812240)

Soft tissue sarcoma, locally advanced unresectable or metastatic

620

TH-302 + doxorubicin vs doxorubicin

Threshold Pharmaceuticals/ SARC

Phase III (NCT01440088>

Liposarcoma or leiomyosarcoma, locally advanced or metastatic

141

Trabectedin (3 dosage levels) vs dacarbazine

Xian-Janssen Pharmaceutical Ltd

Phase III (NCT01692678)

Osteosarcoma, pulmonary recurrent, ≥13 y

50

Inhaled lipid cisplatin

Eleison Pharmaceuticals LLC

Phase II (NCT01650090)

For sarcoma patients, there are many important ongoing phase II and III clinical trials. These include the Threshold phase III clinical trial (NCT01440088) of doxorubicin with TH-302, a hypoxia-released nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard. The partnership between community oncologists and sarcoma specialists has allowed this trial to be on track to completion well ahead of schedule. Based on promising phase II data, the combination of doxorubicin and TH-302 lacks the toxicity and complexity of treatment with ifosfamide and may be a new active agent for the treatment of soft tissue sarcoma. Another phase III trial of note is the trabectedin trial (NCT01692678) for third-line leiomyosarcoma and liposarcoma. This agent, available in the United States only in clinical trials, is widely used in the rest of the world. Finally, there are many ongoing phase I/II trials that are sarcoma-specific at most academic medical centers with sarcoma specialists.

The treatment of adult osteosarcoma, Ewing sarcoma, and rhabdo- myosarcoma is complex. When an adult patient is diagnosed with one of the “pediatric sarcomas,” it is imperative to get input from a team that has vast experience in the treatment of these diseases. The treatment for these diseases may include enrollments on Children’s Oncology Group (COG) protocols depending on the age of the patient, since some COG protocols enroll to age 30. A new phase II clinical trial (NCT01650090) involving inhaled cisplatin after resection of metastatic lung osteosarcoma demonstrates a new approach being done on trial. Hence, new opportunities are arising for this patient population, and a partnership needs to be maintained between community oncologists and academic sarcoma specialists to best benefit patients.

Support Groups Available

Recently, the sarcoma community has organized through three main groups, the Sarcoma Alliance for Research through Collaboration (SARC) (http://sarctrials.org/sarc), the Sarcoma Foundation of America (http://www.curesarcoma.org) and the Sarcoma Alliance (http://sarcomaalliance.org). In addition, there are many foundations that support our efforts, including the Liddy Shriver Sarcoma Initiative (http://sarcomahelp.org). SARC (http://sarctrials.org/Open-SARC-Trials) has a website that lists all the collaborative groups’ clinical trials, and the Sarcoma Alliance is a patience advocacy group run by patients and practitioners that supports patients on their journey. The resources available to patients through these groups, especially the Sarcoma Alliance, can aid community oncologists with their sarcoma patients.

It is only through a partnership between community oncologists, sarcoma specialists, patients, and support organizations that we will be able to develop effective therapies for the various types of sarcoma. The role of a sarcoma medical oncologist is to be a community resource, a clinical trialist, and a partner with the community oncologist to ensure that sarcoma patients have the best outcomes possible.

References

1. von Mehren M, Benjamin RS, Bui MM, et al: Soft tissue sarcoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012;10(8): 951-960.
2. Hajdu SI, Shiu MH, Brennan MF. The role of the pathologist in the management of soft tissue sarcomas. World J Surg. 1988;12(3):326-331.
3. Rajendra R, Pollack SM, Jones RL: Management of gastrointestinal stromal tumors. Future Oncol. 2013;9(2):193-206.
4. van der Graaf WT, Blay JY, Chawla SP, et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9828):1879-1986.