PET/CT and Biomarkers Predict Treatment Response in Metastatic Colon Cancer

Durham, NC – A new study published online today in The Oncologist journal shows that an assessment of metabolic response in patients with metastatic colon cancer (mCC) treated with a single course of chemotherapy could predict the downstream efficacy of the treatment. A team of researchers from various institutions in Denmark, led by Bodil Engelmann, MD, at Næstved Hospital in Copenhagen, performed a prospective, monocentric study to determine the predictive value of a number of established biomarkers as well as the results of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron-emission tomography/computed tomography (PET/CT) in the early response of mCC to treatment with widely used chemotherapeutic drugs.

Colorectal cancer (CRC) is one of the deadliest malignancies worldwide, with about a quarter of patients presenting with malignant disease upon initial diagnosis. Despite a growing number of therapeutic regimens for the disease, the 5-year survival remains low at less than 10%. Given the variety of treatment options, improving clinicians’ ability to predict patients’ responses to various treatments would allow them to alter the therapeutic course for patients with unresponsive tumors. This new study suggests an approach that overcomes some of the limitations of the current gold standards for disease assessment, which are either limited to treatments that ultimately affect tumor size or those that cannot be applied, in many cases, until three months have elapsed after treatment.

A total of 26 mCC patients from a single hospital completed the study, which involved pretreatment PET/CT and treatment with repeating cycles of capecitabine/oxaliplatin (CAPOX) and bevacizumab. Early and late PET/CT evaluations were performed, as well as peripheral blood collection at 20 days after the first treatment cycle and 20 days after the fourth cycle. In addition to functional imaging using FDG PET/CT, the group assessed the levels of the glycoprotein carcinoembryonic antigen (CEA), tissue inhibitor of metalloproteinases-1 (TIMP-1), liberated domain 1 of urokinase plasminogen activator receptor [uPAR(I)] and the mutation status of KRAS and BRAF oncogenes, all of which are known predictors of treatment response and/or prognosis.

When patients were divided into responders and nonresponders, the early metabolic response category assessed by PET could predict the late morphological response category determined by CT in 73% of cases, with 80% sensitivity and 69% specificity. Early determination of metabolic nonresponse was significantly predictive of disease progression, with nonresponders having a greater than 3 times higher risk of progression compared to responders. A nonsignificant reduction in overall survival was also observed among metabolic nonresponders compared with responders, according to early PET evaluation. A 10-mm diameter increase in the largest lesion observed at pretreatment PET/CT was significantly predictive of poorer survival, as was the number of metastatic sites observed. High levels of TIMP-1 at both pretreatment and early post-treatment evaluations were significantly associated with an increased risk of death. Additionally, treatment significantly decreased TIMP-1 levels at the early evaluation.  While CEA levels were characteristically high in almost all the mCC cases, there was no association between their levels and patient survival, although CEA did decrease following treatment in a borderline statistically significant manner. Finally, high uPAR(I) levels at both pretreatment and early evaluation were predictive of poorer survival, and the levels of this biomarker also decreased after treatment.

The group’s findings have the potential to alter the approach to palliative treatment for mCC by allowing clinicians to anticipate unfavorable outcomes soon after treatment initiation. According to Dr. Engelmann, "Metabolic therapy response assessed by FDG PET/CT after only one treatment series identifies patients with mCC that do not show radiologically detectable tumor shrinkage after four treatment series. FDG-PET/CT can help to assign these patients to more effective treatments early in the course of their disease."

Otto S. Hoekstra, MD, a member of The Oncologist’s editorial board, noted, “Biomarkers to predict therapy response are essential to optimize personalized medicine. The Engelmann study showed that PET, applied after a single cycle of first-line systemic therapy predicted progression-free survival. These findings on the potential impact of in vitro biomarkers including TIMP-1 and uPAR(I) should stimulate research on the potentially additive value of combined in vivo and in vitro biomarkers.”