What is the clinical benefit of neoadjuvant chemotherapy for patients with stage III operable NSCLC?

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What is the clinical benefit of neoadjuvant chemotherapy for patients with stage III operable NSCLC?


Jutta's info icon.png Defining operable and inoperable disease in stage III

The management of Stage III NSCLC has been divided into sections dependent on whether the disease is considered operable or inoperable at the time of diagnosis.

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Stage III NSCLC encompasses a broad spectrum of disease extent from tumour involving a single nodal station identified only postoperatively despite extensive pre-operative staging to involvement of multiple contralateral mediastinal nodes and supraclavicular nodes appreciated on clinical examination. In patients with clinically equivocal involvement, pathological confirmation of nodal status should be made if it will influence management options.

The decision as to operability should be made in a multidisciplinary setting.

Patients with Stage III NSCLC may be deemed inoperable because of patient factors (the patient’s respiratory function or co-morbidities may preclude operative intervention or the patient may choose not to proceed with surgery) or tumour factors (the extent or location of gross disease might make surgical resection technically impossible, for example left sided tumours with mediastinal nodes to the right of the aorta, N3 nodal involvement and most T4 tumours).

In the absence of other factors precluding surgery, patients with N1 disease should be considered for surgery. Patients with confirmed N2 disease should not be treated by surgery as the sole modality, but resectable cases may be considered for a multimodality approach. There is no consensus on the distinction between resectable and unresectable N2 disease. Factors influencing assessment of resectability include nodal size, number of stations involved, extracapsular extension and involvement of the recurrent laryngeal nerve.

The clinical rationale for neoadjuvant chemotherapy includes:

(i) availability of clinical and/or pathological assessment of treatment response to indicate the likelihood of systemic disease control

(ii) tumour regression to improve the chances of successful tumour resection, and

(iii) increased chemotherapy delivery rate as chemotherapy would be better tolerated before rather than after major surgery.

Conversely, major disadvantages of neoadjuvant chemotherapy are:

(i) chemotherapy-induced accelerated tumour cell repopulation, and

(ii) delay in performing a potentially curative operation thus risking metastatic spread if the chemotherapy is ineffective.

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Neoadjuvant chemotherapy and surgery versus surgery alone

A recent high-quality, individual patient data-based meta-analysis of 2,385 patients in 15 trials compared chemotherapy and subsequent surgery with surgery alone.[1] The median follow-up period was 6 years for all patients. The patients were mostly men (80%) with a median age of 62 years (IQR 55-68) and good performance status (88%). Patients had predominantly squamous (50%) rather than adenocarcinoma histology (29%). Most patients had clinical stage IB-IIIA NSCLC (93%), and 22.2% patients had stage III disease.

The primary objective of this analysis was overall survival. A clear survival benefit of neoadjuvant chemotherapy was observed (HR 0.87, 95% CI 0.78-0.96; p=0.007). This benefit represented a 13% reduction in the relative risk of death, and translated to a 5% absolute improvement in survival at 5 years from 40% to 45% for all patients. As listed below, the effect of neoadjuvant chemotherapy on survival occurred irrespective of a large number of clinical factors. Consequently, this overall HR of 0.87 was applied to the survival of control group patients, and thus survival at 5 years for stage III patients receiving neoadjuvant chemotherapy improved from 20% to 25%. However, 98% of the stage III patients were stage IIIA, and comprised 21.6% of the total number of patients. Therefore, study results for stage III NSCLC can only be confidently applied to stage IIIA patients.

List of clinical factors that did not influence the effect of neoadjuvant chemotherapy on survival:

(i) age;

(ii) age group (<60, 60-64, 65-69, ≥70);

(iii) histology (adenocarcinoma or squamous);

(iv) performance status (0, 1, 2+);

(v) whether the chemotherapy was given pre-operatively, or both pre-operatively and post-operatively;

(vi) the number of pre-operative chemotherapy cycles (2 or 3);

(vii) the type of chemotherapy regimen (platinum plus second generation chemotherapy, platinum plus third generation chemotherapy, or non-platinum chemotherapy);

(viii) the number of chemotherapy agents (non-platinum single agent regimen [i.e. docetaxel], doublet regimen, or triplet regimen);

(ix) the chemotherapy regimen and the number of chemotherapy agents (non-platinum single agent regimen, platinum second generation [doublet], or platinum second generation [triplet]);

(x) whether the regimen was cisplatin-based or carboplatin-based;

(xi) whether post-operative radiotherapy given or not.

Deferring surgery because of neoadjuvant chemotherapy did not appear to produce an excess of early mortality. This meta-analysis did not identify deleterious effects of neoadjuvant chemotherapy on survival within either 30 days of surgery or 6 months of randomisation (OR 0.88, 95% CI 0.67-1.14, p=0.33; heterogeneity p=0.60). Administering neoadjuvant chemotherapy may have a practical advantage over adjuvant chemotherapy. In 10 of 15 trials in this meta-analysis, the mean compliance rate for neoadjuvant chemotherapy was 85% (range 71-100%),[1] which contrasts with the lower mean compliance rate of 62% (range 41-98%) for adjuvant chemotherapy.[2]

No evidence was found, for or against, to indicate that neoadjuvant chemotherapy improved the likelihood of complete resection by making tumours more operable. Indeed, an effect of neoadjuvant chemotherapy on complete resection rates could not be reliably estimated either because of possible variations in the classification of extent of complete resection or heterogeneity of the effect between trials, especially as the complete resection rate for control patients varied considerably. Furthermore, there was no clear effect of neoadjuvant chemotherapy on time to locoregional recurrence (HR 0.88, 95% CI 0.73–1.07; p=0.20; heterogeneity p=0.89).

As secondary outcomes, neoadjuvant chemotherapy conferred a clear benefit both on recurrence-free survival (HR 0.85, 95% CI 0.76–0.94, p=0.002; heterogeneity p=0.41) and time to distant recurrence (HR 0.69, 95% CI 0.58–0.82; p<0.001; heterogeneity p=0.40). The recurrence-free survival at 5 years improved from 30% to 36%. The time to distant recurrence at 5 years improved from 60% to 70%. This 10% absolute benefit of neoadjuvant chemotherapy on distant recurrence rate at 5 years was greater than the 5% absolute benefit at 5 years for adjuvant chemotherapy, and suggests that neoadjuvant chemotherapy may have greater potential to eradicate micrometastases. Moreover, there was a difference in effect by chemotherapy scheduling (p=0.05) for time to distant recurrence. A substantially greater relative benefit existed for those responding patients who also received adjuvant chemotherapy (HR 0.53, 95% CI 0.39–0.73, p<0.001) than for those who received neoadjuvant chemotherapy alone (HR 0.78, 95% CI 0.63–0.96, p=0.02).

The value of adding neoadjuvant radiotherapy to neoadjuvant chemotherapy and surgery was investigated recently using a randomised trial design. In a study of 232 patients with pathologically proven stage IIIA/N2 NSCLC, Pless et al (2015) allocated 117 patients to receive chemoradiotherapy and 115 patients to receive chemotherapy.[3] The primary endpoint was event-free survival. There was no significant difference in the median event-free survival between the two groups, and median overall survival also did not differ significantly. Hence, radiotherapy did not add any benefit to induction chemotherapy followed by surgery. The authors suggested that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 NSCLC.

In a recent systematic review and meta-analysis, Xu et al (2015) aimed to determine (i) the survival benefit of multimodality therapy including surgery to stage IIIA/N2 NSCLC patients and (ii) if neoadjuvant chemoradiotherapy was superior to neoadjuvant chemotherapy in stage IIIA/N2 NSCLC patients.[4] Seven trials involving 1049 patients were included in this study. There was no significant difference in OS or PFS in stage IIIA/N2 NSCLC patients who received neoadjuvant chemotherapy or chemoradiotherapy before surgery compared to those who received neoadjuvant chemotherapy or chemoradiotherapy before radical radiotherapy. These data lend further support to the notion that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 NSCLC.

Until the recent report of the NSCLC Meta-analysis Collaborative Group, which was based on individual patient data, reliable evidence had not been available to show a consistently beneficial survival effect of neoadjuvant chemotherapy in stage III NSCLC.[1]

The earlier systematic review and literature-based meta-analysis had been based on a relatively small number of trials and patients: seven randomised controlled trials and 988 patients. Neoadjuvant chemotherapy was found to increase survival with a HR of 0.82 (95% CI, 0.69 - 0.97; p=0.022). There was no evidence of statistical heterogeneity, and when this HR was applied across all stages of disease, it gave an equivalent absolute survival benefit of 6%, increasing overall survival from 14% to 20% at 5 years. However, this analysis had been unable to establish if stage III NSCLC patients benefit more or less from neoadjuvant chemotherapy.[5] An indirect comparison meta-analysis had been performed to obtain the relative hazards on survival of postoperative to preoperative chemotherapy administration in patients with resectable NSCLC.[6] Stage III patients were not analysed separately and in the final analysis, there were no evident differences in overall and disease-free survival in the timing of chemotherapy administration.[6] A subgroup meta-analysis was performed within a literature-based meta-analysis to understand the possible survival benefits of neoadjuvant chemotherapy in stage III NSCLC patients.[7] The quality of evidence in this study was low with a substantial risk of bias.

Finally, other recent but low-quality and biased studies do not weigh against the strength of evidence provided by the NSCLC Meta-analysis Collaborative Group.[1]

Katakami et al (2012)[8] performed a randomised controlled trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy in 60 patients with stage IIIA-pN2 NSCLC by. This study was too small because slow accrual had led to early closure. No statistically significant difference between treatment arms was found. Chen et al (2013)[9] reported on a study of 356 NSCLC patients (including 122 patients with stage IIIA disease) who were randomised to surgery alone or neoadjuvant chemotherapy then surgery. No effect of neoadjuvant chemotherapy was detected in patients with stage IIIA disease. Unfortunately, critical data were missing in this study, preventing a reliable assessment of outcomes to be made. Horita et al (2013)[10] performed a meta-analysis of aggregated patient data from 16 randomised controlled trials of a total of 2,385 patients, which included 1,447 stage IIIA patients. A meta-analysis was also performed for the seven studies that evaluated only patients with stage III NSCLC. For 1,447 patients and 1,068 deaths, the pooled HR for OS was 0.77 (95% CI, 0.68-0.87; p < 0.001). In this group of stage III disease studies, the heterogeneity was low and was not significant (I2 = 17%; p for x2 = 0.300 [<0.01]). However, the heterogeneity between the pooled HR for studies only with stage III patients and those without stage limitation was high and significant (I2 = 69%; p for x2 = 0.073 [<0.01]). In addition, in the remaining group of nine studies without stage limitation, moderate heterogeneity was found, and was significant (I2 = 47%; p for x2 = 0.059 [<0.01]). Furthermore, in this meta-analysis evaluating only patients with stage III NSCLC, three of the seven studies contributed the majority both of patients (1,217) and deaths (903), but these studies were of poor quality using the Chalmers score.

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Evidence summary and recommendations

Evidence summary Level References
In patients with clinical stage IIIA disease treated by surgery, neoadjuvant chemotherapy reduces the relative risk of death by 13%, and improves absolute 5 year survival rates from 20 to 25%.

Last reviewed December 2015

I [1]
Evidence-based recommendationQuestion mark transparent.png Grade
It is recommended to consider pre-operative administration of 2-3 cycles of platinum doublet-based, third-generation chemotherapy as a treatment option in good performance status patients with operable clinical stage IIIA non-small cell lung cancer.

Last reviewed December 2015


Practice pointQuestion mark transparent.png

Patients whose tumours respond to preoperative chemotherapy may derive additional survival benefit from postoperative chemotherapy.
Last reviewed December 2015

Practice pointQuestion mark transparent.png

Patients with resectable stage III non-small cell lung cancer, who are being considered for preoperative chemotherapy and surgery or surgery and postoperative chemotherapy, should have their treatment plan reviewed in a lung cancer-specific multidisciplinary meeting. The recommended treatment plan may need to be individualized to take account of such patient-specific factors as treatment preference, availability and timing of surgery, and geographically remote location.
Last reviewed December 2015

Neoadjuvant and adjuvant chemotherapy and the MDT

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  1. 1.0 1.1 1.2 1.3 1.4 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 Feb 24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24576776.
  2. NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A, Burdett S, Higgins JP, Johnson DH, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010 Apr 10;375(9722):1267-77 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20338627.
  3. Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015 Aug 11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26275735.
  4. Xu YP, Li B, Xu XL, Mao WM. Is There a Survival Benefit in Patients With Stage IIIA (N2) Non-small Cell Lung Cancer Receiving Neoadjuvant Chemotherapy and/or Radiotherapy Prior to Surgical Resection: A Systematic Review and Meta-analysis. Medicine (Baltimore) 2015 Jun;94(23):e879 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26061306.
  5. Burdett SS, Stewart LA, Rydzewska L. Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev 2007 Jul 18;(3):CD006157 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17636828.
  6. 6.0 6.1 Lim E, Harris G, Patel A, Adachi I, Edmonds L, Song F. Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials. J Thorac Oncol 2009 Nov;4(11):1380-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19861907.
  7. Song WA, Zhou NK, Wang W, Chu XY, Liang CY, Tian XD, et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 2010 Apr;5(4):510-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20107424.
  8. Katakami N, Tada H, Mitsudomi T, Kudoh S, Senba H, Matsui K, 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 Jun 6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22674529.
  9. Chen Z, Luo Q, Jian H, Zhou Z, Cheng B, Lu S, et al. Long-term results of a randomized controlled trial evaluating preoperative chemotherapy in resectable non-small cell lung cancer. Onco Targets Ther 2013;6:645-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23776338.
  10. Horita N, Miyazawa N, Morita S, Kojima R, Kimura N, Kaneko T, et al. Preoperative chemotherapy is effective for stage III resectable non--small-cell lung cancer: metaanalysis of 16 trials. Clin Lung Cancer 2013 Sep;14(5):488-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23664722.

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Further resources

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