3. Discussion
This case required a differential diagnosis between primary lung cancer and malignant pleural mesothelioma, because of the diffuse right-side pleural thickening and effusion shown on her chest images. Immunostaining for at least 2 carcinoma markers (Ber-EP4: positive; CEA: slightly positive) and 2 mesothelial markers (calretinin and D2-40: both negative) was useful for this patient’s diagnosis (3). Elevated serum CEA (a negative tumor marker for mesothelioma) also helped rule out malignant pleural mesothelioma. She was diagnosed as non-Sq NSCLC for having no cytological cornification, in a difficult condition of determining exact histological type with artifact.
Administering PMT after an induction combination of cisplatin and pemetrexed reportedly has a survival benefit for patients with advanced non-Sq NSCLC (4), and so PMT has become a standard chemotherapy for those patients. In the above-mentioned phase III trial, the median number of maintenance cycles in the PMT arm was 7.9; 28% in the PMT arm received > 10 cycles of maintenance therapy, 10% received >20 cycles, and 4% received > 30 cycles. Median overall survival (from the start of maintenance treatment) in the PMT arm was 13.9 months (4, 5). In the present case, the patient could have received the 32 cycles of PMT after the induction chemotherapy of cisplatin and pemetrexed for four cycles. She had mild AEs—grade 2 hepatic dysfunction and grade 1 edema—which were in line with previous reports of PMT (4, 5). Considering the absence of severe AEs, the high effectiveness of PMT, and her strong motivation for the therapy, she could have received PMT for a longer period.
As pemetrexed has been shown to be effective against non-Sq NSCLC (6, 7) and malignant pleural mesothelioma (8), and is therefore often used to treat these diseases. CR outcomes have been attributed to pemetrexed in some reports of non-Sq NSCLC and malignant pleural mesothelioma (9, 10). In this case, the patient reached in a CR, with the disappearance of pleural malignancy, by PMT use, in addition to keeping a longer CR than in previous reports—73 months after discontinuing PMT. This case implies the possibility of a permanent cure of non-Sq NSCLC through the cytotoxic chemotherapy; PMT.
Pemetrexed is a multitargeted antifolate that inhibits multiple enzymes, such as thymidylate synthase (TS) and dihydrofolate reductase (DHFR). TS and DHFR expressions negatively correlate with the treatment efficacy of pemetrexed in NSCLC patients; non-Sq NSCLC patients with low TS and DHFR expression levels tend to have high responsiveness (10, 11, 12). In addition, up-regulated TS gene expression has a function in acquired pemetrexed resistance in NSCLC (10, 13). In contrast, NSCLC that harbors translocation of the anaplastic lymphoma kinase (ALK ) gene has been shown to be highly responsive to pemetrexed (14), which suggests that this patient’s tumor is likely to have aALK translocation, although the lack of an appropriate specimen precludes testing for ALK translocation. If the patient ever has a disease recurrence, she might undergo re-biopsy to ascertainALK translocation, and TS and DHFR expression.