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.