Wang Huijuan Ma Zhiyong, Department of Respiratory Medicine, Henan Cancer Hospital, Zhengzhou University
Selecting first-line chemotherapy regimen based on histological type Zhiyong Ma, Department of Internal Medicine, Henan Cancer Hospital, Henan Province, China
With the advancement of lung cancer treatment, new therapeutic agents continue to enter the clinic. Pemetrexed, as a new multi-targeted, anti-folate metabolizing cytotoxic drug, was initially applied in the clinic as a standard second-line monotherapy regimen for advanced NSCLC. In a subgroup analysis of the Phase III clinical study of pemetrexed versus docetaxel for the second-line treatment of advanced NSCLC (JMEI), efficacy was found to correlate with the histologic type of lung cancer, with patients with non-squamous cancer outperforming those with squamous cancer, and the JMBD study was designed based on this.
The JMBD study was the first randomized phase III clinical study to select a first-line chemotherapy regimen based on tissue typing, and included a total of 1,725 patients with advanced NSCLC randomized to receive first-line gemcitabine/cisplatin and pemetrexed/cisplatin regimens of chemotherapy. The results found that survival time was significantly longer in non-squamous patients treated with first-line pemetrexed/cisplatin regimen chemotherapy compared to those treated with gemcitabine/cisplatin regimen (11.8 vs 10.4 months, P = 0.005), while the results were reversed in patients with squamous cancer (10.8 vs 9.4 months, P = 0.05). In a subgroup analysis of a randomized phase III clinical study of pemetrexed second-line treatment and maintenance therapy, a significant survival benefit was also suggested in patients with non-squamous cancer treated with pemetrexed, thus validating the consistent efficacy of pemetrexed in patients with non-squamous cancer. As a result, the pemetrexed/cisplatin regimen has become the standard first-line chemotherapy regimen for patients with advanced nonsquamous carcinoma.
Albumin paclitaxel came to the attention of investigators as a new agent for lung cancer treatment because its combination with carboplatin was found to improve the efficacy of advanced squamous lung cancer in a randomized phase III clinical study, from 24% to 41% in patients with squamous cancer compared with the paclitaxel/carboplatin regimen (P<0.001< span="">). This is the first chemotherapy regimen to demonstrate improved efficacy in patients with advanced squamous lung cancer; unfortunately the improved efficacy did not translate into a survival benefit, and the albumin paclitaxel/carboplatin regimen had a similar PFS to the paclitaxel/carboplatin regimen for first-line treatment of squamous lung cancer (5.6 vs. 5.7 months, HR: 0.865), but patients had a 10% improvement in median OS (10.7 vs. 9.5 months, HR. 0.890). Therefore, the albumin paclitaxel/carboplatin regimen is also recommended for the first-line treatment of patients with advanced squamous lung cancer.
Current guideline recommendations for first-line treatment of advanced squamous lung cancer include: platinum in combination with docetaxel, paclitaxel, gemcitabine vincristine, etoposide, vincristine and albumin paclitaxel. The first-line treatment recommendation for advanced non-squamous cancer is platinum in combination with pemetrexed ± bevacizumab.
Selection of first-line chemotherapy regimens based on different histologic types improves ORR for first-line treatment of advanced NSCLC and may lead to longer survival in some patients. However, the selection of treatment regimens based on histologic type classification is still a crude model of lung cancer classification. What are the molecular mechanisms underlying the differences in efficacy between patients with different histologic types treated with the same drug? Current basic research has shown that the efficacy of pemetrexed correlates with the expression level of thymidylate synthase (TS), with low-expressing tumors showing better efficacy for pemetrexed, and it is the difference in TS expression levels between squamous and adenocarcinoma that leads to the difference in clinical efficacy. However, this does not seem to explain why there is a survival advantage for adenocarcinoma patients treated with pemetrexed combined with cisplatin regimen in first line, while the efficacy and survival advantage of combined carboplatin treatment does not differ from gemcitabine combined with carboplatin. So does it suggest that pemetrexed combined with cisplatin is more appropriate first-line chemotherapy for lung adenocarcinoma patients in clinical treatment?
Table: Results of phase III clinical study of pemetrexed for advanced non-squamous cancer
Study
Regimen
n
RR, %
Median OS, mos
JMEI (second line)
Pemetrexed
Docetaxel
205
194
11.5
9
9.3
8.0
JMEN (maintenance)
Pemetrexed
Placebo
325
156
3.4
0
15.5
10.3
JMDB (first line)
Cisplatin + Pemetrexed
Cisplatin + gemcitabine
618
634
28.6
22.2
11.0
10.1