New Hope for Bringing Sarcomas Under Control

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Colored scanning electron micrograph of sarcoma cells
Colored scanning electron micrograph of sarcoma cells

Targeted therapies for cancer have come to the forefront in recent years; however, for patients with sarcoma, there have been few options for personalized treatment until very recently. New studies are currently helping to refine and optimize treatments for sarcoma, particularly with genomic medicines being tested in phase 1/2 trials.

Sarcoma is a complex group of heterogeneous diseases that affects approximately 1% of adults in the United States. It is much more prevalent in children, making up about 15% of all childhood cancers, according to the Sarcoma Foundation of America (SFA).  The SFA estimates that 12,000 new cases are diagnosed in the United States each year, with 5,000 of those patients diagnosed annually eventually dying of the disease.1

“Understanding the biology of sarcoma has led to new drugs that target specific pathways.  So, it is a step away from chemotherapy, which has never been shown to prolong survival in metastatic disease,” said Gary Schwartz, MD, Chief of Memorial Sloan-Kettering's Melanoma and Sarcoma Service, New York, NY.

Currently, survival rates for sarcoma patients vary drastically based on the type of sarcoma, the location of the tumor, and the age of the patient.  Targeted therapies are now taking advantage of genetic alterations in tumor cells and are showing promise in treating certain subtypes of sarcoma.

“We have certainly seen subsets of patients who have done unusually well with newer targeted therapy, suggesting that survival will improve.  To measure this more precisely will take time and larger phase 3 studies, which always is a challenge in sarcoma,” said Mark Dickson, MD, a medical oncologist and sarcoma expert at Memorial Sloan-Kettering Cancer Center.

According to Dr. Dickson, it is quite likely that each sarcoma subtype will need to have therapy tailored to it.  However, this research is really only in its infancy.  “Progress in treatment for sarcoma is gradual but relentless,” he said in an interview with ChemotherapyAdvisor.com.  “It is quite likely that each sarcoma subtype has its own molecular pathways and we've made major strides in understanding those pathways.  For each pathway, we hope to find appropriate targeted drugs. Some of those pathways will apply to several different sarcoma subtypes, indicating that specific drugs can benefit larger groups of patients or patients with apparently disparate diseases.”

Dr. Dickson also indicated the evidence of this benefit has already been demonstrated in clinical trials with cixutumumab and temsirolimus; both entities have shown clinical efficacy in Ewing sarcoma and in patients with solitary fibrous tumors, including de-differentiated liposarcoma, which is one of the most common types of soft-tissue sarcomas. Dr. Dickson said amplification of the oncogene cyclin-dependent kinase 4 (CDK4) is commonly seen in de-differentiated liposarcoma.  He and his colleagues have found that treatment with the CDK inhibitor PD0332991 (palbociclib) is associated with a favorable progression-free survival (PFS) in patients with CDK4-amplified and retinoblastoma protein (RB)–expressing, well-differentiated liposarcoma (WDLS), and de-differentiated liposarcoma (DDLS) who have progressive disease despite systemic therapy.2)

The researchers screened 48 patients (44 of 48 patients had CDK4 amplification and 41 of 44 patients were RB positive) and 29 were evaluable for the primary endpoint at 12 weeks—PFS of 40% or greater (considered promising) and 20% or less (considered not promising).  For this study, if nine or more of 28 patients were progression-free at 12 weeks, then palbociclib would be considered active.  The study showed that PFS was 66% among the 29 patients at 12 weeks and significantly exceeded the primary endpoint.  There was one partial response in the group, and the median PFS was 18 weeks. 

Could Cixutumumab and Temsirolimus Be Options for Bone and Soft-tissue Sarcoma?

Dr. Schwartz and his colleagues recently completed a multicenter, open-label, phase 2 study at 19 cancer centers in the United States that included patients 16 years of age or older with a diagnosis of bone or soft-tissue sarcoma based on histological confirmation.3 All patients received weekly treatment with cixutumumab (6 mg/kg, intravenously) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. 

The patients were divided into three treatment groups based on the following criteria:

  • Group A: insulin-like growth factor-1 receptor (IGF-1R)–positive soft-tissue sarcoma
  • Group B: IGF-1R-positive bone sarcomas or
  • Group C: IGF-1R-negative bone and soft-tissue sarcoma

A total of 388 patients were screened for IGF-1R expression and 54 were assigned to each arm of the study between November 2009 and April 2012.

The researchers found that 17 (31%) of 54 patients in the IGF-1R-positive soft-tissue sarcoma group, 19 (35%) of 54 in IGF-1R-positive bone sarcoma group, and 21 (39%) of 54 in the IGF-1R-negative group were free from progression at 12 weeks.

“The whole field of sarcoma has evolved,” Dr. Schwartz told ChemotherapyAdvisor.com.  “Every oncologist should get their patients in clinical trials because standard chemotherapies just don't work.”

Hypofractionated Adjuvant Radiation Therapy May Benefit Some Elderly Patients with Soft Tissue Sarcoma

Researchers from the Tel-Aviv Sourasky Medical Center in Tel-Aviv, Israel, have recently completed a study that shows hypofractionated adjuvant radiation may be an effective treatment in terms of local control in elderly and debilitated patients with soft tissue sarcoma.4  Adjuvant therapy is an essential component of combined limb-sparing treatment for patients with soft tissue sarcoma, but elderly or medically compromised patients often have difficulty completing the 6-to-7 weeks of daily treatment, according to the researchers.

The study was conducted with 21 elderly patients with soft tissue sarcoma who received a short course of adjuvant radiotherapy (RT).  Investigators found that the hypofractionated irradiation regimen of 39 to 48 Gy in 13 to 16 fractions was well tolerated in this group.  There were three patients who developed grade 2/3 acute toxicity (mainly dermatitis), and only three patients suffered from delayed grade 2/3 toxicity, which included chronic pain, skin atrophy, and telangiectasia.

The study also revealed that all patients, except for one, were able to receive RT in the ambulatory setting.  Three local recurrences were detected with a mean follow-up of 532 days, and three of eight patients with distant metastases died of sarcoma. The investigators concluded that hypofractionated radiation was well tolerated with few long-term side effects.

Targeting Sarcomas: More to Come

Nikhil I. Khushalani, MD, Associate Professor of Oncology and Section Chief of Soft Tissue and Melanoma at Roswell Park Cancer Institute, Buffalo, NY, said a better understanding of the molecular changes underlying some sarcomas already has led to the development of successful targeted therapies, including sunitinib for alveolar soft tissue sarcoma and imatinib for dermatofibrosarcoma protruberans.  Other promising therapies include imatinib, sunitinib, and regorafenib for gastrointestinal stromal tumors, and crizotinib for anaplastic lymphoma kinase (ALK)–positive inflammatory myofibroblastic tumors. Dr. Khushalani also noted that several new agents such as aurora kinase inhibitors and poly ADP ribose polymerase (PARP) inhibitors are currently being tested in sarcomas.

“Similarly, we do tend to use histology of sarcomas to determine chemotherapy choices.  Gemcitabine plus docetaxel is active in leiomyosarcomas, especially those of uterine origin.   Synovial sarcomas appear to be more sensitive to high-dose ifosfamide.  For angiosarcomas, we consider anthracyclines or taxanes for first-line therapy.  These paradigms are different from the relatively non-specific approach that was used a few years ago,” Dr. Khushalani told ChemotherapyAdvisor.com.  “There is definite reason for optimism as our molecular techniques become more refined and more readily accessible.”




References

1. Sarcoma Foundation of America Web site. www.curesarcoma.org. Last accessed June 13, 2013.

2. Dickson MA, Tap WD, Keohan ML, et al. Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma. J Clin Oncol. 2013;31(16):2024-2028.

3. Schwartz GK, Tap WD, Qin LX, et al. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2013 Apr;14(4):371-382.

4. Merimsky O, Soyfer V, Corn BW, et al. Hypofractionated adjuvant radiation therapy of soft tissue sarcoma in elderly patients. J Clin Oncol. 2013;31: suppl; abstr e21521. 

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