Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

[A case of tuberculosis that occurred during treatment of hepatocellular carcinoma with sorafenib].

A 66-year-old man with hepatocellular carcinoma (HCC) and suspicion of lung metastasis consulted us because of an abnormal chest shadow as seen on a radiograph. He had been treated with sorafenib for 2 months. A chest CT scan showed cavitating nodules in the left upper lobe that were present before therapy with sorafenib, and infiltrative shadows in the subpleural areas of the right upper lobe. The shadows were diagnosed, at least in part, as pulmonary tuberculosis by using a nucleic acid amplification test for Mycobacterium tuberculosis in the sputum that yielded a positive result. Treatment with antituberculosis drugs resulted in a good clinical response. However, the patient died of HCC. We concluded that the nodule in the right upper lobe was old pulmonary tuberculosis, because it did not change during the course of the disease and because the cavities in the left upper lobe were active lesions. Sorafenib is a molecularly targeted agent that has been proven effective for treating advanced HCC with extrahepatic metastasis. It may also cause necrosis within lung metastases as an anti-tumor effect. Therefore, pulmonary tuberculosis, including reactivation, should be considered in the differential diagnosis when treating a patient with sorafenib.