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Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 528-534

Chemotherapy for advanced non-small cell lung cancer with a focus on squamous cell carcinoma

1 Department of Respiratory Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
2 Department of Respiratory Medicine, Murakami Memorial Hospital, Asahi University, Gifu, Japan

Date of Web Publication25-Jul-2016

Correspondence Address:
Kozo Kuribayashi
Department of Respiratory Medicine, Hyogo College of Medicine, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo 663-8501
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.174185

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 > Abstract 

Lung cancers are broadly divided into small-cell lung cancer (SCLC) and non-SCLC (NSCLC), and the treatments for each differ. NSCLC includes squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and others. However, because there is little difference in treatment efficacy between these histological types, they have collectively been treated as a single entity. Cytotoxic anti-cancer agents, mainly platinum-based drugs, are the first-line treatment for unresectable advanced NSCLC, and the standard therapy is combination chemotherapy with two drugs, usually involving one platinum-based and one unrelated cytotoxic drug. Such regimens have been used for all the different histological types. In recent years, however, genetic abnormalities in NSCLCs known as driver mutations have been identified. These include epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, which are responsible for both carcinogenesis and cancer growth and survival. The advent of molecular targeted therapies that target these mutations has clearly improved the prognosis for NSCLC. However, effective molecular targeted drugs or novel anti-cancer agents that greatly prolong survival have not yet been developed to treat squamous cell carcinoma or 30% of adenocarcinomas. For patients with these types of cancers, it is important to use existing cytotoxic anti-cancer agents appropriately in their treatment. In this paper, we review the treatment options for unresectable advanced NSCLC on the basis of recent findings, with a particular focus on squamous cell carcinoma, for which groundbreaking drugs have yet to be discovered.

Keywords: Cisplatin, cytotoxic agents, driver mutations, paclitaxel, personalized therapy

How to cite this article:
Kuribayashi K, Funaguchi N, Nakano T. Chemotherapy for advanced non-small cell lung cancer with a focus on squamous cell carcinoma. J Can Res Ther 2016;12:528-34

How to cite this URL:
Kuribayashi K, Funaguchi N, Nakano T. Chemotherapy for advanced non-small cell lung cancer with a focus on squamous cell carcinoma. J Can Res Ther [serial online] 2016 [cited 2022 Dec 1];12:528-34. Available from: https://www.cancerjournal.net/text.asp?2016/12/2/528/174185

 > Introduction Top

A prospective study of 14,000 lung cancer cases in Japan [1] found that 90% comprised nonsmall-cell lung cancer (NSCLC), including 65.8% adenocarcinoma, 29.8% squamous cell carcinoma, 3.5% large-cell carcinoma, and 0.9% adenosquamous carcinoma. The remaining 10% comprised small-cell lung cancer (SCLC). There was no gender difference in the incidence of adenocarcinoma; however, other histological types (including squamous cell carcinoma) were more common in men.

Numerous driver mutations have recently been identified in NSCLCs (particularly adenocarcinoma), including epidermal growth factor receptor (EGFR) mutations and the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase fusion gene.[2],[3] This has presented new opportunities for targeted therapeutic interventions. While traditional cytotoxic chemotherapies usually kill rapidly dividing cells by interfering with cell division, targeted therapies are target cancer cells with more precision and potentially fewer side effects. However, approximately 30% of adenocarcinomas are negative for known driver mutations, and there are currently no molecular targeted drugs that are effective against squamous cell carcinoma, which accounts for approximately 25% of NSCLCs. Over 50% of NSCLS are therefore untreatable with molecular targeted therapies and are instead treated with cytotoxic anti-cancer agents.

In this paper, we review the use of chemotherapy for NSCLCs that are either negative or indeterminate for driver mutations, particularly squamous cell carcinomas.

 > Chemotherapy for Advanced Nonsmall-Cell Lung Cancer Outside Japan Top

In a meta-analysis of 16 clinical trials involving 2714 patients with advanced NSCLC, chemotherapy increased 1-year survival by 9%, which was significantly <20–29% via best supportive care.[4] [Figure 1] shows the history of Phase III randomized trials outside Japan. In North America, the Southwest Oncology Group (SWOG) 9509 trial compared VC (VNR [vinorelbine; 25 mg/m 2/week] + cisplatin [CDDP; 100 mg/m 2 on day 1], 4-week cycle) to PC (paclitaxel [PTX; 225 mg/m 2 on day 1] + carboplatin [CBDCA: area under the curve (AUC); 6 on day 1], 3-week cycle) for patients with advanced NSCLC, and found that PC was as effective as VC and had high tolerability.[5] The results of the Eastern Cooperative Oncology Group (ECOG) 1594 trial, a randomized study that compared patients treated with CDDP (100 mg/m 2 on day 1) + gemcitabine (GEM; 1000 mg/m 2, on days 1, 8, and 15), 4-week cycle; CDDP (75 mg/m 2 on day 1) + docetaxel (DTX: 75 mg/m 2 on day 1), 3-week cycle; or CBDCA (AUC 6 on day 1) + PTX (225 mg/m 2 on day 1), 3-week cycle; against a reference arm treated with CDDP (75 mg/m 2 on day 2) + PTX (135 mg/m 2 on day 1), 3-week cycle, suggested that all these regimens were equally effective.[6] In the SWOG and ECOG trials, the reference arm was CBDCA (AUC 6 on day 1) + PTX (225 mg/m 2 on day 1), 3-week cycle.
Figure 1: Trends in first-line chemotherapy for advanced nonsmall cell lung cancer outside Japan

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In a meta-analysis of 13 trials involving 4556 patients, Le Chevalier et al. found that platinum regimens that included GEM lowered the risk of death by 10% (hazard ratio [HR]: 0.90) compared with doublet combinations of platinum compounds (CDDP or CBDCA) that did not include GEM.[7] These findings suggest that CDDP + GEM ought to be a standard regimen for first-line treatment of advanced NSCLC. The subsequent JMDB trial, a Phase III study comparing CDDP (75 mg/m 2 on day 1) + GEM (1250 mg/m 2, on days 1 and 8), 3-week cycle; to CDDP (75 mg/m 2 on day 1) + PEM (pemetrexed 500 mg/m 2, on day 1), 3-week cycle; in chemotherapy-naive patients with 1725 performance score 0–1 stage IIIB/IV NSCLC showed that CDDP + PEM was not inferior to CDDP + GEM in terms of the primary endpoint of survival time (median survival 10.3 months vs. 10.3 months, HR: 0.94, 95% confidence interval [95% CI]: 0.84–1.05), and that the hemotoxicity of CDDP + PEM was significantly milder than that of CDDP + GEM. In the same trial, subset analysis by histological type [Figure 2] showed that while overall survival (OS) for squamous cell carcinoma patients (n = 473) treated with CDDP + PEM was significantly lower than those treated with CDDP + GEM (median survival 9.4 months vs. 10.8 months, HR: 1.23, 95% CI: 1.00–1.51), it was significantly higher for nonsquamous cell carcinoma patients (n = 1000) (median survival 11.8 months vs. 10.4 months, HR: 0.81, 95% CI: 0.70–0.94).[8] This difference in PEM efficacy for different histological types was also demonstrated in results from several PEM monotherapy trials, which showed that it is more effective against nonsquamous cell carcinoma. Hence, CDDP + PEM is regarded as the standard first-line therapy for advanced nonsquamous cell NSCLC. The JMDB trial established that histology is a deciding factor for the choice of chemotherapy for NSCLC.
Figure 2: Subset analysis of JMDB trial

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 > Chemotherapy for Advanced Nonsmall-Cell Lung Cancer in Japan Top

[Figure 3] shows comparative trials of chemotherapy for advanced NSCLC in Japan. The Four-Arm Cooperative Study, a Phase III randomized comparative trial, compared four groups of advanced NSCLC patients aged <75 years who were treated with a third-generation anti-cancer agent combined with a platinum-based agent.[9] This trial investigated the OS in three different trial treatment arms: CBDCA (AUC 6 on day 1) + PTX (200 mg/m 2 on day 1), 3-week cycle (TC: CBDCA + PTX); CDDP (80 mg/m 2 on day 1) + GEM (1000 mg/m 2, on days 1 and 8), 3-week cycle (GP: CDDP + GEM); and CDDP (80 mg/m 2 on day 1) + VNR (25 mg/m 2 on days 1 and 8), 3-week cycle (NP: CDDP + VNR). The reference arm received CDDP (80 mg/m 2 on day 1) + irinotecan (60 mg/m 2 on days 1, 8, and 15, 4-week cycle (IP: CDDP + irinotecan). The trial concluded that all had statistically similar efficacy and were equally viable options. The Japanese Taxotere Lung Cancer Study Group, a Phase III randomized comparative trial to verify the superiority of OS with CDDP (80 mg/m 2 on day 1) + DTX (60 mg/m 2 on day 1), 3- or 4-week cycle, compared to CDDP (80 mg/m 2 on day 1) + VDS (vindesine; 3 mg/m 2 on days 1, 8, and 15), 4-week cycle, for patients aged 20–75 years with advanced NSCLC, found that OS was significantly prolonged in the CDDP + DTX arm at 11.3 months compared to 9.6 months in the CDDP + VDS arm.[10]
Figure 3: Trends in first-line chemotherapy for advanced nonsmall cell lung cancer in Japan

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The West Japan Oncology Group trial (WJOG) trial (WJOG 3605 trial: LETS Study) verified the noninferiority of OS with CBDCA (AUC 5 on day 1) + oral S-1 (40 mg/m 2 twice per day on days 1–14) compared to CBDCA (AUC 6 on day 1) + PTX (200 mg/m 2 on day 1), 3-week cycle, which is popular for its milder side effects. In this trial, CBDCA + oral S-1 showed an OS of 15.2 months compared with 13.3 months for CBDCA + PTX (HR: 0.928, 95% CI: 0.730–1.179).[11] The most common grade 3/4 side effect in the CBDCA+oral S-1 arm was thrombocytopenia (32.7%), while leukopenia (32.6%), neutropenia (76.7%), and febrile neutropenia (7.2%) appeared significantly more frequently in the CBDCA + PTX arm. The incidences of all grades of the subjective side effects of neuropathy, joint pain, and hair loss in the CBDCA + oral S-1 arm were 15.8%, 7.9%, and 9.3%, respectively, whereas in the CBDCA + PTX arm they were 81.0%, 67.4%, and 76.7% respectively. As for quality of life (QOL), patients in the CBDCA + oral S-1 arm had significantly better scores with respect to neuropathy. In the Tokyo Cooperative Oncology Group (TCOG) trial that compared the efficacy of CDDP (60 mg/m 2 on day 8 every 5 weeks) + oral S-1 (80 mg/m 2/day [40 mg/m 2 b.i.d. on days 1–21]) to that of CDDP (80 mg/m 2 on day 1) + DTX (60 mg/m 2 on day 1), 3-week cycle (TCOG0701: CATS Trial), OS was 16.1 months for the CDDP + oral S-1 arm and 17.1 months for the CDDP + DTX arm, demonstrating its noninferiority (HR: 1.013, 95% CI: 0.837–1.227).[12] These two Phase III randomized comparative trials demonstrated the efficacy and tolerability of combined therapy with the third-generation anti-cancer agent oral S-1 and either CDDP or CBDCA as a platinum-based agent.

Nano-albumin-bound PTX (nab-PTX), a novel taxane that has PTX and nanoparticles bound to human serum albumin, was approved to treat NSCLC in 2013. Nab-PTX is more effective and tolerable at higher doses than PTX against tumor metastatic potential,[13] and expectations for it are high. The CA031 joint international trial was a Phase III randomized controlled trial to verify the superiority of the response rate to CBDCA (AUC 6 on day 1) + nab-PTX (100 mg/m 2 weekly, 3-week cycle (nab-PTX arm), compared to CBDCA (AUC 6 on day 1) + solvent-based (sb)-PTX (200 mg/m 2 on day 1), 3-week cycle, as the reference arm.[14] In that Japanese trial, the response rate was found to be better for nab-PTX at 33.0% compared to 25.0% for sb-PTX. However, the OS rate was found to be lower, and the superiority in terms of cost was not substantial. As for grade 3/4 side effects, thrombocytopenia (18.0%) and anemia (27.0%) were significantly more frequent in the nab-PTX arm, while neutropenia (58.0%), neuropathy (11.0%), muscle pain (2.0%), and joint pain (2.0%) were significantly more common in the sb-PTX arm. An evaluation using the functional assessment of cancer therapy-taxane showed that the severity of peripheral neuropathy was significantly lower in the nab-PTX arm than in the sb-PTX arm (P< 0.001). Subgroup analysis of patients <70 years showed that OS was significantly higher in the nab-PTX arm at 19.9 months compared to 10.4 months in the sb-PTX arm (HR: 0.583, 95% CI: 0.388–0.875).[15]

 > First-Line Treatment of Squamous Cell Lung Cancer Top

According to the 2014 Guidelines on the Management of Lung Cancer, the drug therapy treatment strategy for NSCLC now considers histological type following the JMDB study as described above,[16] while a meta-analysis of four trials involving 2200 patients demonstrated that bevacizumab causes more bleeding in squamous cell carcinoma cases where its use is therefore not recommended.[17] Whether or not aforementioned driver mutations are present in squamous cell carcinoma is unclear, and the utility of molecular targeted drugs aimed at these mutant proteins is thus uncertain. As described above, drug therapy therefore mainly consists of the platinum doublet in combination with an existing cytotoxic anti-cancer drug.

The choice of CDDP or CBDCA as the platinum-based agent depends on many factors. Ardizzoni et al. carried out a meta-analysis of response by histological type in nine trials involving 2968 patients [Figure 4], and found that although the CDDP base was superior to the CBDCA base for nonsquamous cell carcinoma, both treatments were equally effective for squamous cell carcinoma.[18]
Figure 4: Meta-analysis of first-line clinical trials for advanced nonsmall cell lung cancer: Subgroup analysis for carboplatin base versus cisplatin base (risk of mortality)

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Regarding platinum-based agent combinations with third-generation anti-cancer agents, S-1 is particularly effective against squamous cell carcinoma. In the aforementioned LETS study, an analysis of therapeutic response by histological type found that OS for squamous cell carcinoma was 10.6 months in the CBDCA + PTX arm, but 14.0 months in the CBDCA + S-1 arm, suggesting that its efficacy may be superior (HR: 0.713, 95% CI: 0.476–1.068).[19] The WJOG7512L Phase III randomized comparative study is currently underway to evaluate BSC or S-1 + BSC after treatment with CBDCA + S-1 for squamous cell carcinoma (UMIN 000010396).

Nab-PTX is also expected to provide an effective treatment for squamous cell carcinoma; its response rate in the CA031 joint international trial described above was 41%, which was significantly higher than 24.0% observed for sb-PTX. Analysis of Japanese patients also showed a high response rate (50%) in squamous cell carcinoma cases.[20] Nab-PTX is currently undergoing a Phase III randomized comparative trial in the United States to evaluate weekly nab-PTX+BSC administration compared to BSC after treatment with CBDCA + nab-PTX for squamous cell carcinoma (NCT02027428).

Attention is now being focused on whether maintenance therapies that have only shown efficacy against nonsquamous cell carcinoma will also prove useful in squamous cell carcinoma. Unlike nonsquamous cell carcinoma, the driver mutations to target in squamous cell carcinoma are currently unknown, although anti-EGFR antibody drugs have shown promise. Cetuximab was the first anti-EGFR antibody to be studied for NSCLC. In the FLEX trial, when the EGFR antibody cetuximab was combined with CDDP + VNR in EGFR-positive patients with advanced NSCLC who had never received drug therapy, OS was extended, albeit slightly (median OS: 11.3 months for the CDDP + VNR + cetuximab group vs. 10.1 months for the CDDP + VNR group; HR: 0.871, 95% CI: 0.762–0.996; P = 0.044).[21] Furthermore, a meta-analysis of four Phase II and III trials, including this trial, found that the therapeutic effect was particularly high against squamous cell carcinoma.[22] However, cetuximab's benefits are limited and its administration regimen is complex. Moreover, approximately 40% of patients developed grade 4 neutropenia. Thus, it was removed from the 2015 edition of the National Cancer Comprehensive Network guidelines for being less tolerable than other regimens.

Another anti-EGFR antibody, necitumumab, has been tested in squamous cell carcinoma patients. A Phase III randomized trial was designed to treat patients who achieved at least stable disease after treatment with CDDP + GEM + necitumumab with necitumumab monotherapy until disease progression, with CDDP + GEM as the reference arm. OS, the primary endpoint, was 9.9 months in the reference arm and 11.5 months in the trial treatment arm (HR: 0.84, 95% CI: 0.74–0.96). The secondary endpoint of progression-free survival (PFS) was 5.5 months in the reference arm and 5.7 months in the trial treatment arm, which was significantly improved (HR: 0.85, 95% CI: 0.74–0.98); tolerability was also good.[23]

 > Second-Line Treatment of Squamous Cell Lung Cancer Top

Other therapies have been attempted in lung squamous cell carcinoma patients.

The CheckMate 017 trial involving subjects with stage IIB or IV squamous cell NSCLC who received combination chemotherapy with platinum-based agents compared OS in nivolumab-treated versus DTX-treated groups.[24] OS of the DTX group was 6.0 months while that of the nivolumab group was 9.2 months (HR: 0.59, 95% CI: 0.44–0.79, P = 0.00025). The PFS and response rate were also significantly better in the nivolumab group. A Phase II trial is underway in Japan to confirm the efficacy of nivolumab against squamous cell carcinoma in similar subjects.[25] The primary endpoint, response rate as evaluated by an independent evaluation committee, was 25.7%, and the secondary endpoint, response rate evaluated by the physician in charge of the trial, was 20.0%. PFS was 4.2 months, while the median response period and OS were not reached (median follow-up period 10.4 months). The application is awaiting approval.

Ramucirumab is a fully human monoclonal antibody drug that binds specifically to the extracellular domain of vascular endothelial growth factor receptor-2, blocking the binding of its ligands.[26]

A trial to investigate whether DTX + ramucirumab extended OS compared to DTX alone as a second-line treatment after platinum-based chemotherapy for stage IV NSCLC was conducted.[27] This trial was performed without regard to tissue type. OS was 9.1 months in the DTX group and 10.5 months in the DTX + ramucirumab group (HR: 0.86, 95% CI: 0.75–0.98, P = 0.023). In sub-analysis by tissue type, the nonsquamous cell control group OS was 9.7 months while that of the trial group was 11.1 months (HR: 0.83, 95% CI: 0.71–0.97), whereas the OS of a squamous cell control group was 8.2 months while that of the trial group was 9.5 months (HR: 0.88, 95% CI: 0.69–1.13). Favorable results and high tolerability in the ramucirumab group were found for both tumor types.

Currently, a randomized Phase II trial comparing DTX + placebo to DTX + ramucirumab against platinum-pretreated stage IV NSCLC is underway in Japan. PFS was reported to be 4.21 months in the control group and 5.22 months in the ramucirumab group (HR: 0.82, 95% CI: 0.59–1.16).[28]

The EGFR tyrosine kinase inhibitor afatinib is an irreversible ErbB family inhibitor that selectively inhibits signals from all EGFR family homodimers and heterodimers.[29] The LUX-Lung 8 trial compared the effects of afatinib and erlotinib against stages IIIB and IV squamous cell carcinoma that had become progressive disease after treatment with four courses of combination chemotherapy with platinum-based agents. Mean PFS was longer with afatinib than with erlotinib (afatinib, 2.4 months [95% CI: 1.9–2.9]; erlotinib 1.9 months [1.9–2.2]; HR: 0.82 [95% CI: 0.68–1.00], P = 0.0427).[30] Based on the results of this trial, the Food and Drug Administration and the European Medicines Agency approved afatinib for advanced SCLC.

 > Discussion Top

The Phase III clinical trials of S-1 and nab-PTX in Japan, which are both expected to be effective against squamous cell carcinoma, were performed almost simultaneously [Table 1], and there is little difference between them in terms of the historical treatment background. These trials examined either all histological types or squamous cell carcinoma alone [Table 2]. A range of chemotherapy regimens are used as long as possible as posttreatment after disease progression, and this may explain the better OS times compared with those in overseas trials.
Table 1: Enrollment periods for recent Japanese lung cancer clinical trials

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Table 2: Results of Japanese Phase III clinical trials for advanced nonsmall cell lung cancer

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When evaluating OS, the rate of transition to second-line therapy is important and should be considered when implementing first-line therapy. In fact, in the analysis of squamous cell carcinoma in the LETS study, one reason the OS in the CBDCA + S-1 arm was longer than in the CBDCA + PTX arm was that 78.2% of patients in the former underwent second-line therapy compared to 66.1% of those in the latter.[19] It is very possible that if first-line chemotherapy is well tolerated and QOL can be assured, an increase in the proportion of patients moving on to second-line therapy would extend their OS.

So far, no molecular abnormalities or novel molecular-targeted drugs have been introduced that may affect the treatment choice for squamous cell NSCLC, and first-line chemotherapy in advanced cases still depends on the appropriate use of existing cytotoxic anti-cancer drugs as combination chemotherapy with platinum. However, among the possible combination therapies with a platinum agent and a third-generation anti-cancer agent, there are some agents such as S-1 and nab-PTX that are particularly effective against squamous cell NSCLC. The efficacy and safety of anti-EGFR antibody drugs and other agents are also under investigation, even though their efficacy as maintenance therapy has yet to be established in cases of squamous cell NSCLC.

 > Conclusions Top

Many driver mutations for adenocarcinoma have been discovered in recent years, and therapeutic outcomes have improved dramatically. However, approximately, 30% of adenocarcinomas are negative for driver mutations, and there are yet no molecular targeted drugs that are effective against squamous cell carcinoma. The accumulation of evidence with respect to these NSCLCs and the development of novel treatment methods will lead to true progress in the treatment of lung cancer.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Table 1], [Table 2]

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