Wang Huijuan Ma Zhiyong, Second Department of Respiratory Medicine, Cancer Hospital of Zhengzhou University
Lung cancer is the malignant tumor with the highest incidence and mortality rate worldwide, among which non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and nearly half of the patients are diagnosed with advanced stage (stage IIIB/IV) at the time of consultation, and a significant number of early-stage patients develop recurrence and metastasis after treatment. These patients have a median survival time of 4-5 months and a 1-year survival rate of 20% when given only the best supportive care. Cytotoxic chemotherapy remains the standard of care for patients with advanced NSCLC, and results from bulk clinical studies have confirmed the efficacy of platinum-containing double agents. As clinical treatment advances, the detection of tumor histological type, molecular targets including EGFR and EML4-ALK are also gaining importance as important factors before selecting clinical treatment options. In conclusion, the treatment of advanced NSCLC has undergone a series of important changes, with the emergence of these changes, more options for the treatment of advanced NSCLC and longer survival times for patients. These changes have led to an individualized path for the treatment of advanced NSCLC. Zhiyong Ma, Department of Internal Medicine, Henan Cancer Hospital
Establishment of the status of chemotherapy in advanced NSCLC
A meta-analysis published in the BMJ in 1995 demonstrated for the first time that chemotherapy could benefit the survival of patients with advanced NSCLC, and this analysis included 1,190 patients from 11 clinical studies. In this analysis, only patients treated with cisplatin-based chemotherapy regimens were found to have a survival benefit compared with best supportive care (HR=0.73, p<0.001), while no survival benefit was observed in patients receiving other regimens such as perphenazines or alkylating agents. Patients who received platinum-containing regimens of chemotherapy had a 10% increase in 1-year survival and a 1.7-month longer median survival (overall survival, OS) compared with best supportive care. Although just a short 1.7 months, this is a major breakthrough in the history of chemotherapy for advanced lung cancer and gives investigators hope that advanced NSCLC can benefit from prolonged survival with chemotherapy. The clinical significance of this study far outweighed its findings and has since opened the way for chemotherapy in advanced lung cancer.
In 2008, updated data from this analysis reaffirmed the survival benefit of chemotherapy in patients with advanced NSCLC, and more studies and patients were included in this analysis (2,714 patients in 16 studies). In this updated analysis, it was also demonstrated that the chemotherapy-induced survival benefit was independent of patient gender, age, histologic type, stage, and PS score status, meaning that all subgroups of patients with advanced NSCLC benefited from chemotherapy, with only the absolute 1-year survival benefit induced by chemotherapy significantly correlated with the patient’s PS score status. However, it was not clear in this analysis whether there was a difference in the impact on survival between patients receiving different chemotherapy regimens, combination chemotherapy or single agent chemotherapy. Subsequent phase III clinical studies have demonstrated that third-generation chemotherapeutic agents combined with platinum-based first-line therapy significantly increased the objective responserate rate (ORR) and prolonged overall survival in patients with advanced NSCLC compared with single-agent chemotherapy or platinum-based combination with second-generation chemotherapeutic agents, and that third-generation chemotherapeutic agents combined with platinum-based regimens are gradually replacing the previous alkylator-based chemotherapy regimens for advanced NSCLC. NSCLC chemotherapy regimens.
The ORR of third-generation chemotherapeutic agents (e.g., paclitaxel, doxorubicin, vincristine, irinotecan, gemcitabine, pemetrexed, and albumin paclitaxel) in combination with platinum-based first-line treatment for advanced NSCLC is 20%-35%, with a median progression-free survival (PFS) of 4-6 months, median OS of 8-10 months, and 1 year survival rate of 30-40%. And no differences in efficacy were found among treatment regimens.
With the establishment of third-generation chemotherapy drugs combined with platinum as the first-line standard treatment regimen for advanced NSCLC, how to further improve the efficacy of chemotherapy and prolong the survival time of patients on this basis has become a hot spot for clinical research. Can a 3rd agent be added to the standard treatment regimen to improve the efficacy? Many oncologists have explored this and have conducted relevant clinical trials. However, the results have almost always been disappointing, with studies showing that adding a 3rd agent to an existing platinum-containing diphasic regimen as first-line chemotherapy did not extend patient survival time, except for an improvement in ORR, and that the toxic side effects of chemotherapy increased significantly, with more patients failing to tolerate treatment. Two meta-analyses published in 2004 and 2008 both showed that the addition of a third cytotoxic agent to the standard platinum-containing triplet regimen did not increase the survival benefit in patients with advanced NSCLC. The results of these studies not only dispel the speculation that more first-line chemotherapy agents are more effective, but also further strengthen the position of third-generation agents in combination with platinum as the first-line treatment for advanced NSCLC. The results of these studies not only break the speculation of the efficacy of first-line chemotherapeutic agents, but also further strengthen the position of third-generation drugs combined with platinum as the first-line treatment for advanced NSCLC.
Table: Results of phase III clinical studies of platinum-containing duo regimens for first-line treatment of advanced NSCLC
Study
Regimen
n
RR, %
Median overall survival time (months)
ECOG 1594 [Schiller 2002]
Cisplatin + paclitaxel
Cisplatin + gemcitabine
Cisplatin + docetaxel
Carboplatin + paclitaxel
288
288
289
290
21
22
17
17
7.8
8.1
7.4
8.1
TAX-326
Cisplatin + docetaxel
Cisplatin + vinorelbine
Carboplatin + docetaxel
406
394
404
32
25
24
11.3
10.1
9.4
EORTC [Smit 2003]
Cisplatin + paclitaxel
Cisplatin + gemcitabine
Paclitaxel + gemcitabine
159
160
161
32
37
28
8.1
8.9
6.7
ILCP [Scagliotti 2002]
Cisplatin + gemcitabine
Carboplatin + paclitaxel
Cisplatin + vinorelbine
205
204
203
30
32
30
9.8
9.9
9.5
SWOG [Kelly 2001]
Cisplatin + vinorelbine
Carboplatin + paclitaxel
202
206
28
25
8.0
8.0
FACS [Ohe 2007]
Cisplatin + irinotecan
Carboplatin + paclitaxel
Cisplatin + gemcitabine
Cisplatin + vinorelbine
145
145
146
145
31
32
30
33
13.9
12.3
14.0
11.4
Scagliotti [Scagliotti 2008]
Cisplatin + gemcitabine
Cisplatin + pemetrexed
863
862
28
31
10.3
10.3
Socinski [Socinski 2012]
Carboplatin + albumin-boundpaclitaxel
Carboplatin + paclitaxel
521
531
33%
25%
12.1
11.2