Parenchymal Versus Nonparenchymal Target Lesion Response in Clinical Trials for Metastatic Medullary Thyroid Cancer

Abstract

TO THE EDITOR: In their clinical trial of systemic targeted therapy in metastatic medullary thyroid cancer, Lam et al did not find an association between objective index target lesion response based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria and serum biomarker (calcitonin and carcinoembryonic antigen) response. Similar results have been reported for another clinical trial of systemic targeted therapy for metastastic medullary thyroid cancer. Among the 21 medullary thyroid cancer patients in the trial by Lam et al, 20 patients (95%) had undergone prior surgery, the nature and extent of which was not specified. Nonparenchymal metastases to lymph nodes were noted in 19 patients (90%), whereas parenchymal metastases to lung, liver, and bone were seen in seven (33%), 13 (62%), and 13 (62%) patients, respectively, among the 21 study participants. It remains unclear if any of the 19 patients with overt lymph node metastases underwent lymph node dissections and why no attempt was made to surgically remove those lymph node metastases from the neck that were sufficiently large to fulfill RECIST criteria. Conceivably, parenchymal target lesions are perfused better than nonparenchymal target lesions. As a matter of fact, pretherapeutic calcitonin and carcinoembryonic antigen serum levels correlate more closely with largest tumor diameter in the thyroid parenchyma (r 0.83 to 0.84; explaining 69% to 71% of the variance in primary tumor size) than with lymph node metastases (r 0.47 to 0.59; explaining no more than 44% of the variance in the number of lymph node metastases). This observation raises the possibility of a differential target lesion response in parenchymal (lung, liver, or bone) compared with nonparenchymal (lymph nodes) organs in patients with medullary thyroid cancer. Such a differential response was recently described for differentiated thyroid cancer where the most noticeable organ-specific response was observed in the lung (median change of 22%) compared with in lymph nodes (median change, 0%; P .02). If the assumption of a better tissue-specific response of parenchymal relative to nonparenchymal target lesions to systemic targeted therapy was also confirmed for metastatic medullary thyroid cancer, this certainly would have major ramifications for the design and conduct of future clinical trials, prompting performance of compartment-oriented surgery to clear the neck of gross lymph node metastases followed by systemic targeted therapy for distant metastases, for which these therapies may be more effective. In experienced hands, the surgical morbidity attendant on compartment-oriented lymph node dissection compares favorably with the toxicity associated with systemic targeted therapy.