Soft Tissue Sarcoma: FDG-PET/CT Defines Treatment Responders, Non-Responders
The diagnosing, staging and monitoring of cancer benefits from early response assessment. This includes patients with high-grade soft tissue sarcoma (STS), malignant tumors, which develop from fat, muscles, nerves, joints, blood vessels, bones and deep skin tissues. Until recently, oncologists typically had to wait months to see if treatment for this rare, and often deadly, disease was effective. PET/CT has changed that scenerio. Researchers now can assess a patient’s response or lack of response to treatment within one week of completing the first chemotherapy treatment. This is good news for both physicians and patients; physicians can make quicker, more efficient and complete treatment evaluations and alterations which may mean a better quality of life for many sarcoma patients. Another plus for U.S. based facilities is that Medicare coverage for STS was just added for initial treatment strategy.The fight against cancer is a global one. In 2007, cancer accounted for approximately 13 percent of all deaths worldwide, or 7.9 million people, according to World Health Organization (WHO). Faced with seemingly insurmountable odds, research is intent on finding new, more targeted and effective therapies that can help identify and treat cancer earlier and better. If cases are detected and treated early, before cancers can metastasize, WHO estimates that about one-third of the world’s cancer burden could be decreased.
Earlier detection and more targeted treatment would be beneficial, too, for high-grade soft tissue sarcomas, especially since the malignant tumors are often difficult to distinguish from other malignancies. As a result, they are often misdiagnosed and perhaps, a bit under-reported. In the United States, about 50,000 patients and their families are struggling with sarcoma. About 10,000 new cases are diagnosed each year (fewer than 1 percent of malignancies diagnosed annually in the United States), and about 5,000 die each year from sarcoma, according to the National Cancer Institute.
More than half of soft tissue sarcomas, about 60 percent, occur in the arms and legs. Other common sarcoma sites include the trunk (20 percent of cases), the abdomen (15 percent) and the head and neck region (5 percent). Soft-tissue sarcomas comprise between 4 and 8 percent of all cancers for children under 14 years old.
Once detected, high-risk STS patients are often treated with chemotherapy and radiation therapy prior to surgery to remove the malignancies. But such treatments, while they may improve patient outcomes, particularly in the setting of a pathological response, also are associated with significant toxicities which negatively affect the quality of life—something that can be severely impacted during the typical three-month wait to see if therapy is even working. “These are very high-risk malignancies, which are often treated with systemic therapy,” says Fritz Eilber, MD, assistant professor of surgery, division of surgical oncology, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA). “The problem with sarcomas is that chemo doesn’t always work that well—and knowing who it works well for is important.”
Matthias R. Benz, MD, of the department of molecular and medical pharmacology at the Jonsson Comprehensive Cancer Center and colleagues questioned how early a response to treatment could be detected in this patient population, since neoadjuvant therapy—a course of chemotherapy or radiation prior to tumor resection—is highly toxic and frequently ineffective. If FDG-PET/CT could identify histopathologic responders early during the course of therapy, successful treatments could be carried out in responders but discontinued in non-responders, who would undergo surgery earlier or alternate neoadjuvant therapy.
Could response be determined after a single administration of chemotherapy, thereby potentially minimizing the associated toxicities a patient normally experienced? The answer surprised them.
“We knew [FDG-PET/CT] appeared to be better than changes in size [via CT] at predicting response in this group of patients, so if PET was more accurate at predicting response, the question was how early could we tell? Could we tell after just one course of drugs?” says Eilber, who was a corresponding author of the study.
Benz and colleagues sought to investigate whether FDG-PET/CT, after the initial cycle of therapy, can provide accurate response predictions in high-grade, soft tissue sarcoma patients (Clin Cancer Res. 2009; 15: 2856-2863). From February 2006 to March 2008, investigators enrolled 50 patients with resectable high-grade STS scheduled for neoadjuvent therapy and subsequent tumor resection. All patients were given a baseline FDG-PET/CT, then again after the first treatment cycle and upon completion of neoadjuvent therapy. Patients with greater than or equal to 95 percent pathologic necrosis were classified as treatment responders, and FDG-PET/CT results were compared to histopathologic findings. CT imaging intra-venous contrast was administered to all patients prior to imaging. It was found that CT had no value at response prediction.
The results showed that FDG-PET/CT missed no treatment responders. At early follow-up, FDG-uptake decreased more in eight responders than in 42 non-responders. All responders, and 14 of 42 non-responders, had a greater than or equal to 35 percent reduction in FDG-uptake. Of the cohort, 28 did not respond to their initial treatment—which physicians determined within one week of initial treatment via FDG-PET/CT.
“A 35 percent reduction in tumor FDG-uptake at early follow-up appears to be a sensitive predictor of histopathologic tumor response,” the authors wrote. “Early treatment decisions such as a discontinuation of chemotherapy in non-responding patients could be based on FDG-PET criteria. The high negative predictive value of FDG-PET suggests that patients who do not achieve an early metabolic response should be switched to different therapeutic approaches or could be treated surgically earlier, which in turn could reduce toxicity associated with neoadjuvant treatments.”
“What the results showed is that if you didn’t get a decrease in activity by at least 35 percent, you never responded pathologically. That’s important because it saves a lot of people treatment,” Eilber says. “So the idea of using molecular imaging to identify whether drugs are working or not working for these patients is critical as these are high-risk malignancies—patients only have X amount of time—why waste their time on something that is not going to work? The earlier we can figure that out, the better.”
He noted that since the endpoints were pathological response—not survival—however, it should be noted that pathologic response has been correlated in the past to survival for these patients. “Although changes in tumor FDG uptake and histopathologic response were independently correlated with recurrence and survival, clinical follow-up is needed to confirm whether the current results are predictive of patient progression free and overall survival,” the study authors wrote.
Benz and colleagues plan to follow the patients; Eilber believes that it may one day become the standard of care, helping to deliver more personalized treatment for each patient.
“[FDG-PET/CT] is an earlier way to assess response—it’s early obviously in the evolution and we still need further evaluation with long-term outcomes, but I expect it to become a common practice,” Eilber notes, adding that by choosing FDG-PET/CT as the imaging test, the intent was to show that this could be done today at any hospital, without having to wait for a new tracer to become available.
These study results have shown that changes in tumor size cannot predict histopathologic responses and patient outcome early during the course of therapy. But since anatomical tumor delineation by CT remains “the corner stone of surgical planning, the combination of FDG-PET for response assessments with CT for surgical planning represents a powerful tool in the management of sarcoma patients,” Eilber and colleagues concluded.
“If you are a patient undergoing chemotherapy which could have long-term, serious side effects and it’s making you very sick, wouldn’t you want to know if the treatment works?” says Eilber. “Why do that if it’s not working?”