Skip to main content
NCBI home page
Medicine logoLink to Medicine
. 2022 Aug 26;101(34):e30159. doi: 10.1097/MD.0000000000030159

The optimal neoadjuvant regimen for nonsmall cell lung cancer: A meta-analysis

Yi Liu a, Chong Zhao b, Qiuliang Lu a, Yirong Hu c,*
PMCID: PMC9410656  PMID: 36042672

Objective:

To compare the efficacy and complications of different neoadjuvant to determine the optimal regimens for nonsmall cell lung cancer (NSCLC) patients.

Methods:

A systematic search of the Web of Science, and PubMed databases was conducted through June 3, 2021, reporting a comparison of chemotherapy, chemoradiotherapy, and immunotherapy.

Results:

Of 3462 studies, 25 were considered for evidence synthesis. 1035 patients who received chemotherapy or radiotherapy before surgery did not prolong the overall survival (OS) compared with 1038 patients who received surgery alone (hazard ratio [HR] 1.13, 95% CI 1·00–1·28, P = 0·05). 1192 patients received chemoradiotherapy and 864 patients received chemotherapy or radiotherapy; chemoradiotherapy prolonged the OS compared with chemotherapy (HR 0.52, 95% CI 0·29 to 0.95, P = .03). Compared with 110 patients who received other therapy, 93 patients who received immunotherapy had prolonged the OS (HR 1.56, 95% CI 1·08–2·25, P = .02). Chemoradiotherapy increased the pathological response rate (HR 1.68, 95% CI 1·33–2·12, P < .0001), and grade 3 and 4 adverse effects were not increased (HR 5.90, 95% CI 0.88 to 39.60, P = .007). Immunotherapy increased the pathological response (HR 2.79, 95% CI 1·71–4·54, P < .0001), with no significant effects on grades 3 and 4 adverse(HR 0.71, 95% CI 0·19–2·64, P = .61).

Conclusion:

Our data showed that chemotherapy may prolong OS and PFS, but not statistically significant; however, the combination of chemotherapy and radiation did show an advantage, and immunotherapy may be also the choice for neoadjuvant therapy.

Keywords: complications, meta-analysis, neoadjuvant, non-small cell lung cancer, overall survival

1. Introduction

Almost one-quarter of all cancer deaths are due to lung cancer, and 5-year relative survival rates are merely 21% for all stages combined.[1] More than 80% of patients affected by nonsmall cell lung cancer (NSCLC), early-stage lung cancer can be treated by innovative imaging-guided resection, minimally invasive approach, or multiple approaches with very good short-term outcomes, enhanced recovery, and prolonged overall survival.[2] As symptoms present late in the disease, the majority of patients (approximately 70%) already suffer from the locally advanced or metastatic disease at diagnosis and have an extremely limited possibility of being cured.[3] Neoadjuvant therapy has acceptable treatment-related toxicity and adverse event profile, it increases the likelihood of achieving an R0 resection and a pathological complete response for cancer therapy, including gastric cancer, breast cancer, etc.[4,5] Innovative systemic treatments and perioperative medical care have changed the role of surgery in the treatment of lung cancer. Treatments such as radiotherapy, chemotherapy, molecular targeted therapies, immunotherapy, and a combination of chemotherapy and radiotherapy are optional and performed depending on the histological type, pathological stage, presence of gene mutations, and overall condition of the patient.[3,6–8] Herbs or their derivatives were also found to exert antiproliferation and potential antineoplastic activity[9,10]; however, the genotoxicity, mutagenicity, and mechanisms on cancer cells needed more in-depth research.[11–13] These treatment strategies have been widely adopted for neoadjuvant therapies and can markedly improve the prognosis of patients with the various stage of lung cancer.[14–16] Neoadjuvant therapy aims to shrink the tumor size and increase the success rate of the surgery treatment.

However, the optimal neoadjuvant regimen for locally advanced resectable NSCLC remains controversial. Previous studies indicated preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC, but toxic effects could not be assessed,[17] neoadjuvant radiotherapy alone does not improve resectability or survival, radiotherapy and chemotherapy combined are used for patients, the meta-analysis showed that chemoradiotherapy significantly increased the pathological complete response in mediastinal lymph nodes,[18] study suggests that hyperfractionated accelerated radiotherapy in combination with chemotherapy is an effective strategy to treat patients with locally advanced lung cancer with the advantage of a smaller dose and shorter duration,[19] on the other hand, a study showed that combination may increase the adverse effect.[20] Recently, immune-oncology drugs have proven their efficacy in the treatment of NSCLC, numerous clinical trials are underway to investigate the efficacy of neoadjuvant immunotherapy in resectable NSCLC, and to compare these approaches with placebo or other treatments.[3,14,21] Here, we performed a meta-analysis to explore the optimal neoadjuvant regimen for NSCLC.

2. Materials and Methods

2.1. Search strategy

We performed this meta-analysis by searching Web of Science, PubMed, and EMBASE databases for studies published through June 3, 2021. Additional records were identified by screening the reference in the identified studies. The search term was “nonsmall cell lung cancer neoadjuvant.”

2.2. Inclusion and exclusion criteria

Two investigators independently screened the data, and when different opinions occurred, an agreement was reached by discussion. The inclusion criteria were the followings:[17] comparing different neoadjuvant regimens; (2) nonsmall cell lung cancer was pathologically confirmed; (3) sufficient data that were reported or could be calculated. Major exclusion criteria were (1) incomplete data for analysis; (2) books and documents, meeting abstracts, comments, meta-analysis, reviews, and articles cannot extract sufficient data; (3) adjuvant but not neoadjuvant therapy; (4) small cell lung cancer; (5) gray literature; (6) papers written in other languages that cannot be translated into English; and (7) duplicate data.

2.3. Data extraction

Overall survival (OS), response rate, and complications were the main indices to evaluate the treatments. Authors’ names, publication year, patient number, neoadjuvant regimen, and complications were collected from the included studies. Complications included leucopenia, anemia, thrombocytopenia, nausea/vomiting, diarrhea, alopecia, elevated aminotransferase, and elevated total bilirubin. Clavien–Dindo Grading System was used to classify the complications. We divided the complications into the minor and severe groups, the minor group included Clavien–Dindo grade I and II, and the severe group include grades III, IV, and V. There was no Clavien–Dindo grade V complication in all patients.

2.4. Statistical analysis

All data were entered into Review Manager Software (The Cochrane Collaboration, version 5.3). Odds ratio (OR) with 95 % confidence interval (CI) were analyzed. Statistical heterogeneity among studies was evaluated utilizing I2 statistics and P values. When I2 < 50% indicated homogeneity among studies, the fixed effects model method was applied. When I2 ≥ 50%, the random-effects model was used. Publication bias was evaluated using a funnel figure. A sensitivity analysis was performed to assess the stability of the results. The statistical analysis was performed using Review Manager Software (The Cochrane Collaboration, version 5.3).

3. Results

3.1. Study selection and characteristics

A total of 3462 records were identified through datasets, 1020 records were excluded after initial analysis and further screening was performed. Finally, 25 research were included in this meta-analysis[14,22–43] (Fig. 1). Of these studies, 7 focus on immunotherapy,[14,23,24,34,40,43,43] 8 focus on chemoradiotherapy,[19,20,29,31,33,38,39,41] 5 focus on chemotherapy or radiotherapy.[22,27,28,32,37] Include patients varied from ten to hundreds, all the studies were recorded in the 21st century (Table 1). We compared the effectiveness of different treatments for neoadjuvant, overall survival, response rate, and complications were evaluated.

Figure 1.

Figure 1.

Open in a new tab

Flow diagram of the details of the study.

Table 1.

Summary of included studies.

Stydy Year Nation Treatment Control Follow up (median)
Prescription Case Response Grade 3-4 adverse events PFS OS Prescription Case Response Grade 3-4 adverse events PFS OS
Zhao, X 2016[42] China Antiangiogenic therapy and chemotherapy 16 50% 0% Chemotherapy 10 40% 0%
Ratto, G. B 2011[34] European Leukapheresis and chemotherapy 13 54% 0% Chemotherapy 32 56% 0% 44.4
Girard, N 2010[20 France Chemoradiotherapy 32 87% Chemotherapy 14 57%
Hamouda, W 2007[28] Egypt Radiotherapy 32 22% chemotherapy 34 41% 15
Pezzetta, E 2005[31] Switzerland Radiochemotherapy 46 chemotherapy 36 53
Kumar, R 2020[19 India Chemotherapy and hyper-fractionatedaccelerated radiation therapy 30 28% 16% 12 Chemotherapy and conventional chemo-radiotherapy 30 20% 8% 12
Xiong, L 2020[3,40] China Erlotinib 15 67% Cisplatin-based doublet chemotherapy 16 19%
Altorki, N. K 2021[14 USA Durvalumab plus radiotherapy 30 53.30% 20% Durvalumab 30 6.70% 17%
Zhong, W. Z 2019[43] China Erlotinib 31 10% 0% 21.5 45.8 Gemcitabine Plus Cisplatin 23 0% 29% 11.4 39.2 32.5
Berghmans, T 2012[22] European Gemcitabine–vinorelbine–cisplatin 71 65% 36.6 Mitomycine–ifosfamide–cisplatin 69 60% 47.2 60
Cascone, T 2021[23] USA Nivolumab plus ipilimumab 21 38% 10% Nivolumab 23 22% 13% 22.2
Chen, W. Q 2018[24] China Erlotinib 43 67% 21% Pemetrexed combined with cisplatin 43 44% 14%
Scagliotti, G. V 2012[37] European Chemotherapy 129 35% 41% 48 93.6 Surgery alone 141 11% 34.8 57.6 39.6
Pisters, K. M 2010[32] USA Chemotherapy 169 41% Surgery alone 168 64
Gilligan, D. 2007[27] European Chemotherapy 258 49% 54 Surgery alone 261 55 41
Pless, M 2015[33] European Chemoradiotherapy 117 71% 37.1 Chemotherapy 115 50% 26.2 52.4
Thomas, M 2008[38] German Chemoradiotherapy 264 50% 10% Chemotherapy 260 46% 0.50% 70
Toyooka, S 2012[39] Japan Chemoradiotherapy 35 45.70% Chemotherapy 15 13.30%
Katakami, N 2012[29] Japan Chemoradiotherapy 28 25% 92.90% Chemotherapy 28 25% 46.40%
Yang, C. F 2015[41] USA Chemoradiotherapy 834 58% Chemotherapy 528 46%
Roth 1994[36] USA Chemotherapy 28 64 Surgery alone 32 11 37
Rosell 1994[35] Spain Chemotherapy 30 20 26 Surgery alone 30 5 8
Depierre 2002[25] France Chemotherapy 179 26.7 37 Surgery alone 176 12.9 26 80
Nagai 2003[30] Japan Chemotherapy 31 28% 17 Surgery alone 31 16
Felip 2010[26] European Chemotherapy 201 53.50% Surgery alone 212
Open in a new tab

OS = overall survival, PFS = progression-free survival.

3.2. Chemotherapy or radiotherapy

Nine studies assessed the results of overall survival,[22,25–27,30,32,35–37] 1035 patients who received chemotherapy or radiotherapy before surgery did not prolong the OS compared with 1038 patients who received surgery alone (hazard ratio [HR] 1.13, 95% CI 1.00–1·28, P = 0.05, Fig. 2A). However, chemotherapy did contribute to progression-free survival (PFS, HR 1.13, 95% CI 1.04–1.36, P = 0.01, Fig. 2B). The pathological response was about 22–65%, Hamouda, W, etc[28] compared the radiotherapy and chemotherapy, no significant difference was found between the 2 groups (HR 0.40, 95% CI 0.14–1·18, P = 0.10), Berghmans, T, etc[22] compared to 2 neoadjuvant chemotherapy (gemcitabine–vinorelbine–cisplatin, GVP VS mitomycin–ifosfamide–cisplatin, MIP), objective response rates to induction CT were 65%(GVP) and 60% (MIP)(P = .55), while GVP was associated with more hematological toxicity, mainly thrombopenia (P = .03). Scagliotti, G. V, etc[37] also found chemotherapy increased the grade 3 or 4 adverse (HR 5.59, 95% CI 2.94 to 10·63, P < 0.0001).

Figure 2.

Figure 2.

Open in a new tab

Forest plot for overall survival (A) and progression-free survival (B) for chemotherapy neoadjuvant comparing surgery alone.

3.3. Chemoradiotherapy

As shown in Figure 3, 1192 patients received chemoradiotherapy and 864 patients received chemotherapy or radiotherapy, chemoradiotherapy prolonged the OS compared with chemotherapy (HR 0.52, 95% CI 0.29 to 0.95, P = .03, Fig. 3A), PFS was also found a significant difference between chemoradiotherapy and chemotherapy (HR 0.58, 95% CI 0.37 to 0.92, P = .02, Fig. 3B). Chemoradiotherapy increased the response rate by 68% (HR 1.68, 95% CI 1.33–2·12, P < .0001, Fig. 3C), and grade 3 and 4 adverse effects were no difference between the 2 groups (HR 5.90, 95% CI 0.88 to 39.60, P = .007, Fig. 3D).

Figure 3.

Figure 3.

Open in a new tab

Forest plot for overall survival (A), progression-free survival (B), pathological response rate (C), and grade 3–4 adverse (D) for neoadjuvant chemoradiotherapy comparing chemotherapy or radiation.

3.4. Immunotherapy

Compared with other therapy, 93 patients who received immunotherapy did prolong the OS (HR 1.56, 95% CI 1.08–2·25, P = .02, Fig. 4A), 1 study indicated immunotherapy was a benefit for PFS (HR 0.39, 95% CI 0.24–0.64, P = .0002, Fig. 4B). Immunotherapy increased the pathological response by 2.79 folds(HR 2.79, 95% CI 1.71–4·54, P < .0001, Fig. 4C), with no significant effects on grade 3 and 4 adverse (HR 0.71, 95% CI 0.19–2·64, P = .61, Fig. 4D).

Figure 4.

Figure 4.

Open in a new tab

Forest plot for overall survival (A), progression-free survival (B), pathological response rate (C), and grade 3-4 adverse (D) for neoadjuvant immunotherapy comparing chemotherapy or radiation.

3.5. Publication bias

Funnel figures were used to evaluate the publication bias for OS, no obvious bias was found as the figure was fundamental symmetry in the chemotherapy or radiotherapy group (Fig. 5A), chemoradiotherapy group (Fig. 5B), and immunotherapy group (Fig. 5C).

Figure 5.

Figure 5.

Open in a new tab

Funnel plots evaluating possible publication bias.

4. Discussion

Our meta-analysis summarizes the efficacy and safety outcomes of the currently published trials. A comprehensive search and systematic analysis of adjuvant therapy for nonsmall cell lung cancer were conducted in this paper. Results indicated that the neoadjuvant no matter chemotherapy, radiotherapy, chemoradiotherapy, or immunotherapy did not alter the OS, PFS was benefited from neoadjuvant in the immunotherapy group, but it was noted only 1 study investigated the PFS in this group, the sample size was small,[43] data showed chemoradiotherapy and immunotherapy were contributing to the pathological response (Figs. 3C and 4C), which may reduce tumor stage and increase the chance of complete resection, on the other hand, we found the sever complications were associated with chemoradiotherapy (Fig. 3D). The choice of treatment requires a trade-off between survival benefits and the risk of complications.

Previous studies showed that the use of neoadjuvant chemotherapy before surgery could give additional benefits for NSCLC patients with mediastinal involvement compared to surgery alone, however, the survival benefit after long-term follow-up was not observed, some other studies supported chemotherapy offered a significant 5-year overall survival advantage,[22,27,28,32,37,44] we noted that there are a variety of chemotherapy options, gemcitabine-cisplatin, paclitaxel-carboplatin, gemcitabine-vinorelbine-cisplatin, mitomycin-ifosfamide-cisplatin, etc were optional, these regimens were mainly platinum-based chemotherapy. Both gemcitabine-vinorelbine-cisplatin (GVP) and mitomycin-ifosfamide-cisplatin (MIP) neoadjuvant chemotherapy regimens shared similar efficacy in patients with NSCLC, costs were significantly higher for GVP regimens.[22] The advantages of neoadjuvant chemotherapy may be limited due to the progress of anesthesia and surgery, 2 of included studies indicated neoadjuvant chemotherapy favored better OS, and 1 suggested perioperative chemotherapy consisted of cyclophosphamide (500 mg per square meter of the body-surface area given intravenously on day 1), etoposide (100 mg per square meter of the body-surface area given intravenously on days 1, 2, and 3), and cisplatin (100 mg per square meter of the body-surface area given intravenously on day 1), the other suggested 3 cycles of gemcitabine 1250 mg per square meter of the body-surface area on days 1 and 8 every 3 weeks plus cisplatin 75 mg per square meter of the body-surface area on day 1 every 3 weeks.[36,37] Radiotherapy alone was rarely applied for neoadjuvant therapy; the OS benefit was limited.[28]

Studies have focused on the combined application of radiotherapy and chemotherapy,[19,20,29,31,33,38,39,41] however, the pooled results were not satisfactory (Fig. 3A, B). The advent of novel irradiation techniques, such as 3-dimensional conformal radiation therapy (3D-CRT), intensity-modulated RT (IMRT), and volumetric-modulated arc therapy (VMAT), may improve clinical outcomes in some situations,[45] our meta-analysis indicated clinical response was better in chemoradiotherapy, meanwhile, adverse effects were more common (Figs. 3C and 3D). Docetaxel plus cisplatin with concurrent radiation at a dose of 40 to 46 Gy used for induction chemoradiotherapy was verified by Toyooka, S, et al that it could prolong patients’ overall survival and disease-free survival than the chemotherapy group (OS, P = .0020; PFS, P = .015).[39]

Our data indicated immunotherapy favored better OS and PFS than chemotherapy (Figs. 4A and 4B), the response rate was also higher in the immunotherapy group (Fig. 4C), and the adverse effect was not increased (Fig. 4D). Over the last decade, there has been an acceleration in the emergence of new inhibitors approved in NSCLC immunotherapy, since the first epidermal growth factor receptor inhibitor developed in 1990, dozens of new drugs have been developed.[46] Nowadays, ipilimumab, nivolumab, and erlotinib were commonly applied in the clinic, data showed immunotherapy alone may be sufficient for neoadjuvant.[24,34,43] Carcinogenesis is initiated when an irreversible and heritable mutation occurs in one of the key proteins that control many vital cell functions, various genes such as MET, NTRK, ROS1, ALK, etc. were potential oncogenes, and drugs aimed to inhibit the activity of these genes were developed,[46] individual immunotherapy will be possible soon.

Several limitations should be noted in this meta-analysis. First, subgroup analysis was not performed, neoadjuvant may exert different effect in distinct stage NSCLC, the role of neoadjuvant may be more vital for stage III NSCLC than stage I NSCLC; Second, studies from different country may achieved various results, racial and regional differences may lead to different efficacy of neoadjuvant; Third, differences in surgical techniques may lead to differences in patient survival, and advances in surgical techniques may vary in the selection of surgical patients; Forth, NSCLC consist of squamous cell carcinoma, adenocarcinoma, and large cell lung cancer, this study did not focus on the response of different pathological types of lung cancer to neoadjuvant therapy; Fifth, adjuvant was applied for some patients, this study did not investigate the effect of adjuvant therapy on outcome; Sixth, the effect of neoadjuvant therapy on surgery-related data and complications was not analyzed; Seventh, the sample size of some studies is too small, the reliability of pooled results may be affected. Despite these shortcomings, this study is the most systematic meta-analysis to date, and we look forward to the results of more high-level clinical trials for further analysis.

5. Conclusion

In conclusion, our data showed the combination of chemotherapy and radiation show an advantage for prolonging OS and PFS, immunotherapy may be the best choice for neoadjuvant (Fig. 6).

Figure 6.

Figure 6.

Open in a new tab

The pathological responses and adverse effects were indicated, the pathological response was about 22–65% for the radiotherapy or chemotherapy, chemoradiotherapy increased the response rate by 1.68 folds, and immunotherapy increased the pathological response by 2.79 folds. III–IV adverse effects occurred in 15/58 in the radiotherapy or chemotherapy group, 30/58 in the chemoradiotherapy group, and 17/160 in the immunotherapy group.

Author contributions

Project development: Yirong Hu; data collection or management: Yirong Hu and Yi Liu; data analysis and interpretation: Yi Liu and Chong Zhao; manuscript writing: Yi Liu and Chong Zhao; manuscript editing: Qiuliang Lu; and study supervision: Yirong Hu.

Abbreviations:

CI =
confidence interval
GVP =
gemcitabine–vinorelbine–cisplatin
HR =
hazard ratio
MIP =
mitomycin–ifosfamide–cisplatin
NSCLC =
non-small cell lung cancer
OR =
odds ratio
OS =
overall survival
PFS =
progression-free survival

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Liu Y, Zhao C, Lu Q, Hu Y. The optimal neoadjuvant regimen for nonsmall cell lung cancer: a meta-analysis. Medicine 2022;101:34(e30159).

Conflict of Interest Statement: All named authors have no conflicts of interest to declare.

Role of the funding source: None.

Ethical approval: All procedures performed in the included studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. This article does not contain any studies with human participants performed by any of the authors.

Informed consent: Informed consent was obtained from all individual participants in the included studies. For this study, formal consent was not required.

Contributor Information

Yi Liu, Email: 53897511@qq.com.

Chong Zhao, Email: 85354017@qq.com.

Qiuliang Lu, Email: 594904632@qq.com.

References

  • [1].Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33. [DOI] [PubMed] [Google Scholar]
  • [2].Montagne F, Guisier F, Venissac N, et al. The role of surgery in lung cancer treatment: present indications and future perspectives—state of the art. Cancers. 2021;13:3711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Xiong L, Lou Y, Bai H, et al. Efficacy of erlotinib as neoadjuvant regimen in EGFR-mutant locally advanced non-small cell lung cancer patients. J Int Med Res. 2020;48:300060519887275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Rizzo A, Cusmai A, Massafra R, et al. Pathological complete response to neoadjuvant chemoimmunotherapy for early triple-negative breast cancer: an updated meta-analysis. Cells. 2022;11:1857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Yeh JH, Yeh YS, Tsai HL, et al. Neoadjuvant chemoradiotherapy for locally advanced gastric cancer: where are we at? Cancers (Basel). 2022;14:3026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Kong F, Wang Z, Liao D, et al. Non-small cell lung cancer: challenge and improvement of immune drug resistance. Front Oncol. 2021;11:739191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Rodak O, Peris-Díaz MD, Olbromski M, et al. Current landscape of non-small cell lung cancer: epidemiology, histological classification, targeted therapies, and immunotherapy. Cancers. 2021;13:4705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Zhou Y, He M, Li R, et al. The safety and effectiveness of bevacizumab in the treatment of nonsquamous non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Biomed Res Int. 2021;2021:1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Galucio NCDR, Moysés DDA, Pina JRS, et al. Antiproliferative, genotoxic activities and quantification of extracts and cucurbitacin B obtained from Luffa operculata (L.) Cogn. Pharm Biol. 2013;51:1249–55. [Google Scholar]
  • [10].Neto RDAM, Santos CBR, Henriques SVC, et al. Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations. J Biomol Struct Dyn. 2020;40:2204–16. [DOI] [PubMed] [Google Scholar]
  • [11].Castro ALG, Cruz JN, Sodré DF, et al. Evaluation of the genotoxicity and mutagenicity of isoeleutherin and eleutherin isolated from Eleutherine plicata herb. using bioassays and in silico approaches. Arabian J Chem. 2021;14. [Google Scholar]
  • [12].Neves CJ, Da CKS, de Carvalho TAA, et al. Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia. J Biomol Struct Dyn. 2020;38:1425–34. [DOI] [PubMed] [Google Scholar]
  • [13].Souza DSJO, de Jesus PFC, Barbosa DMAA, et al. In silico analyses of toxicity of the major constituents of essential oils from two Ipomoea L. species. Toxicon. 2021;195:111–8. [DOI] [PubMed] [Google Scholar]
  • [14].Altorki NK, McGraw TE, Borczuk AC, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. Lancet Oncol. 2021;22:824–35. [DOI] [PubMed] [Google Scholar]
  • [15].Eichhorn F, Klotz LV, Kriegsmann M, et al. Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: first clinical experience. Lung Cancer. 2021;153:150–7. [DOI] [PubMed] [Google Scholar]
  • [16].Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21:1413–22. [DOI] [PubMed] [Google Scholar]
  • [17].NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383:1561–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Ren S, Xu A, Lin Y, et al. A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future. Transl Lung Cancer Res. 2021;10:3264–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Kumar R, Kumar HS, Paramanandhan M, et al. Neo-adjuvant chemotherapy followed by either continuous hyper-fractionated accelerated radiation therapy week-end less or conventional chemo-radiotherapy in locally advanced NSCLC-a randomised prospective single institute study. J Cancer Res Ther. 2020;16:860–6. [DOI] [PubMed] [Google Scholar]
  • [20].Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer. 2010;69:86–93. [DOI] [PubMed] [Google Scholar]
  • [21].Ulas EB, Dickhoff C, Schneiders FL, et al. Neoadjuvant immune checkpoint inhibitors in resectable non-small-cell lung cancer: a systematic review. ESMO Open. 2021;6:100244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Berghmans T, Lafitte JJ, Giner V, et al. Final results and pharmacoeconomic analysis of a trial comparing two neoadjuvant chemotherapy (CT) regimens followed by surgery in patients with resectable non-small cell lung cancer (NSCLC): a phase II randomised study by the European Lung Cancer Working Party. Lung Cancer. 2012;77:605–10. [DOI] [PubMed] [Google Scholar]
  • [23].Cascone T, William WJ, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med. 2021;27:504–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Chen WQ, Li P, Wang Q, et al. [A randomized controlled study of erlotinib versus pemetrexed combined with cisplatin in neoadjuvant therapy of stage IIIA EGFR-mutant lung adenocarcinoma]. Zhonghua Zhong Liu Za Zhi. 2018;40:133–7. [DOI] [PubMed] [Google Scholar]
  • [25].Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20:247–53. [DOI] [PubMed] [Google Scholar]
  • [26].Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010;28:3138–45. [DOI] [PubMed] [Google Scholar]
  • [27].Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007;369:1929–37. [DOI] [PubMed] [Google Scholar]
  • [28].Hamouda W, Dorgham Y, Yosry A, et al. Neoadjuvant chemotherapy in locally advanced non-small cell lung cancer. Gulf J Oncolog. 2007:55–64. [PubMed] [Google Scholar]
  • [29].Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer. 2012;118:6126–35. [DOI] [PubMed] [Google Scholar]
  • [30].Nagai K, Tsuchiya R, Mori T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg. 2003;125:254–60. [DOI] [PubMed] [Google Scholar]
  • [31].Pezzetta E, Stupp R, Zouhair A, et al. Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC. Eur J Cardiothorac Surg. 2005;27:1092–8. [DOI] [PubMed] [Google Scholar]
  • [32].Pisters KM, Vallieres E, Crowley JJ, et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol. 2010;28:1843–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049–56. [DOI] [PubMed] [Google Scholar]
  • [34].Ratto GB, Costa R, Maineri P, et al. Neo-adjuvant chemo/immunotherapy in the treatment of stage III (N2) non-small cell lung cancer: a phase I/II pilot study. Int J Immunopathol Pharmacol. 2011;24:1005–16. [DOI] [PubMed] [Google Scholar]
  • [35].Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330:153–8. [DOI] [PubMed] [Google Scholar]
  • [36].Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673–80. [DOI] [PubMed] [Google Scholar]
  • [37].Scagliotti GV, Pastorino U, Vansteenkiste JF, et al. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012;30:172–8. [DOI] [PubMed] [Google Scholar]
  • [38].Thomas M, Rube C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. 2008;9:636–48. [DOI] [PubMed] [Google Scholar]
  • [39].Toyooka S, Kiura K, Shien K, et al. Induction chemoradiotherapy is superior to induction chemotherapy for the survival of non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis. Interact Cardiovasc Thorac Surg. 2012;15:954–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Xiong L, Lou Y, Bai H, et al. Efficacy of erlotinib as neoadjuvant regimen in EGFR-mutant locally advanced non-small cell lung cancer patients. J Int Med Res. 2020;48:300060519887275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Yang CF, Gulack BC, Gu L, et al. Adding radiation to induction chemotherapy does not improve survival of patients with operable clinical N2 non-small cell lung cancer. J Thorac Cardiovasc Surg. 2015;150:1484–92; discussion 1492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Zhao X, Su Y, You J, et al. Combining antiangiogenic therapy with neoadjuvant chemotherapy increases treatment efficacy in stage IIIA (N2) non-small cell lung cancer without increasing adverse effects. Oncotarget. 2016;7:62619–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37:2235–45. [DOI] [PubMed] [Google Scholar]
  • [44].Zhang Y, Hu X, Liu D, et al. Effectiveness of neoadjuvant chemotherapy on the survival outcomes of patients with resectable non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Surg Oncol. 2021;38:101590. [DOI] [PubMed] [Google Scholar]
  • [45].Qiu B, Men Y, Wang J, et al. Dosimetry, efficacy, safety, and cost-effectiveness of proton therapy for non-small cell lung cancer. Cancers. 2021;13:4545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Rodak O, Peris-Díaz MD, Olbromski M, et al. Current landscape of non-small cell lung cancer: epidemiology, histological classification, targeted therapies, and immunotherapy. Cancers. 2021;13:4705. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Medicine are provided here courtesy of Wolters Kluwer Health

RESOURCES