Adjuvant and neoadjuvant chemotherapy in NSCLC: a paradigm shift

doi:10.1016/S0169-5002(05)81568-5

Lung Cancer

Volume 50, Supplement 2, December 2005, Pages S9-S16

https://doi.org/10.1016/S0169-5002(05)81568-5 Get rights and content

Summary

The role of adjuvant chemotherapy in patients with early-stage non-small cell lung cancer (NSCLC) remained controversial for many years. Although a positive impact on overall survival was long suggested for cisplatin-based chemotherapy, early randomized clinical trials failed to confirm a clear survival benefit. Recently, the results from 4 large randomized trials, IALT, JBR.10, CALGB 9633, and ANITA indicate a significant survival benefit with adjuvant chemotherapy for patients with IB through IIIA NSCLC, and the results of these trials support the adoption of chemotherapy in addition to surgery as a new standard of care. Neoadjuvant chemotherapy is potentially better tolerated compared to post-surgical adjuvant chemotherapy, though definitive survival benefits with this approach have yet to be shown. The current status of adjuvant and neoadjuvant chemotherapy for patients with early-stage NSCLC will be discussed.

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Cited by (22)

Is there a place for surgical management in stage IIIA N2 non-small cell lung cancer?
2015, Revue des Maladies Respiratoires
Le cancer bronchique non à petites cellules (CBNPC) demeure un problème de santé majeur, avec une survie globale à 5 ans des stades IIIA de l’ordre de 25 %. La prise en charge chirurgicale des CBNPC de stade IIIA demeure cependant controversée. Nous avons donc évalué les différentes stratégies de prise en charge des CBNPC de stade IIIA-N2.
De janvier 1990 à décembre 2013, les essais contrôlés randomisés évaluant la survie des patients traités par chimiothérapie d’induction suivie d’une résection chirurgicale vs chirurgie seule, et ceux évaluant la survie des patients traités par radio- ou chimiothérapie d’induction suivie d’une résection chirurgicale vs la combinaison chimiothérapie d’induction + radiothérapie pour le stade IIIA-N2 ont été analysés.
On retrouve une augmentation significative de la survie globale de 16 % dans le groupe chimiothérapie d’induction suivie d’un traitement chirurgical par rapport à la chirurgie seule. Cependant, il n’existait pas de différence significative en termes de survie entre le groupe chimiothérapie d’induction suivie d’un traitement chirurgical et le groupe chimiothérapie d’induction suivie d’une radiothérapie.
Les preuves scientifiques disponibles actuellement ne permettent pas de remettre en question de manière définitive la place de la chirurgie dans les CBNPC de stade IIIA-N2.
Non-small cell lung cancer (NSCLC) remains a major health problem, with a 5-year overall survival of 25%. Surgical management of stage IIIA NSCLC is still controversial. We conduct a systematic analysis of the different management strategies for stage IIIA-N2 NSCLC.
We analyzed randomized control trials published between January 1990 to December 2013, comparing induction chemotherapy followed by surgery vs. surgery alone, and those comparing induction chemo or radiotherapy followed by surgery vs. induction chemotherapy followed by radiotherapy for stage IIIA-N2 NSCLC.
A 16% significant increase in overall survival was found in favor of induction chemotherapy followed by surgery vs. surgery alone. However, there was no significant difference in overall survival between induction chemo- or radiotherapy followed by surgery and induction chemotherapy followed by radiotherapy.
Current scientific data do not permit the exclusion of surgery as an option in the management of stage IIIA-N2 NSCLC.
Surgical treatment for locally advanced lung cancer
2014, Revue des Maladies Respiratoires Actualites
La chirurgie reste la meilleure chance de guérison à terme du cancer bronchique primitif. Elle ne peut être proposée qu’aux patients dont l’extension locale autorise une exérèse radicale. L’amélioration de certaines techniques d’assistance circulatoire, d’ostéosynthèse ou de remplacement prothétique permettent à l’heure actuelle d’envisager une exérèse radicale y compris en cas d’atteinte localement avancée. Nous revoyons ici ces différentes techniques pour chaque structure potentiellement envahie et commentons le risque opératoire et le bénéfice à terme. Le stade N2 anime une controverse. Si certains estiment que la chirurgie doit se limiter aux patients dont le stade N a été diminué sous chimiothérapie d’induction, il existe également des arguments en faveur de l’exérèse systématique chez les patients inopérables. L’attitude vis-à-vis de la pneumonectomie doit être nuancée ; elle peut être proposée à des patients rigoureusement sélectionnés, y compris après chimiothérapie d’induction.
Surgery is the best chance for cure of primary lung cancer. This treatment is limited to patients fit for a radical en-bloc extended resection. Surgical techniques such as cardiocirculatory bypass, osteosynthesis or prosthesis enable to plan for a radical resection of lung cancer and its nearby extension to thoracic organs in patients with high T-low N disease. We discuss the risk-benefit rationale of the different surgical options defined by extension. Surgery for N2 disease is still debated; while some authors strongly recommend to limit surgery to patients whose N-stage has been downstaged by induction therapy, there are arguments in favour of routine resection in all operable patients. Pneumonectomy can be justified in carefully selected patients, even after induction therapy.
Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: An updated meta-analysis of 13 randomized control trials
2010, Journal of Thoracic Oncology
Citation Excerpt :
Therefore, future studies should avoid this. Also, our study could not answer whether neoadjuvant chemotherapy is more beneficial than postoperative adjuvant chemotherapy,43 which has been taken as a standard treatment for most of operable patients.44,45 In summary, this is an updated meta-analysis of 13 eligible RCTs on neoadjuvant chemotherapy in operable NSCLC patients.
The survival effectiveness of neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC) is still unclear based on the study of most up-to-date literatures. This article contributes to this problem by conducting an updated meta-analysis.
Based on Burdett et al's (J Thorac Oncol 2006;1:611–621) systematic review, this meta-analysis was conducted. Articles were searched electrically. The possible survival benefit of neoadjuvant chemotherapy was assessed by hazard ratio (HR) in terms of overall survival. A subgroup meta-analysis with only stage III NSCLC was also conducted. The software of Review Manager was used for data management.
Thirteen randomized control trials, 6 of which were new ones, were included into this meta-analysis. The overall survival of NSCLC patients in neoadjuvant chemotherapy arm were improved significantly, comparing with those in surgery-alone arm (combined HR = 0.84; 95% confidence interval, 0.77–0.92; p = 0.0001). When only patients with stage III NSCLC were considered, the result was similar (combined HR = 0.84; 95% confidence interval, 0.75–0.95; p = 0.005).
Neoadjuvant chemotherapy, as an addition of surgery, would significantly improve the overall survival of operable NSCLC patients, including patients with stage III NSCLC.
Selective pulmonary artery perfusion for the treatment of primary lung cancer: Improved drug exposure of the lung
2009, Lung Cancer
Citation Excerpt :
Seventy percent of these patients is presented in a non-surgical stage at the moment of initial diagnosis and is treated by intravenous chemotherapy and or radiotherapy resulting in a 5-year survival of less than 15% [2]. Furthermore, (neo-)adjuvant intravenous chemotherapy results in a 5-year survival benefit of only 4–14% in patients eligible for surgery in stage III NSCLC [3]. However, the current standard treatment for stage III NSCLC is combined chemoradiotherapy [4,5].
Selective pulmonary artery perfusion (SPAP) is an experimental drug infusion method for the treatment of lung cancer that aims to achieve more effective T(umour) and lymph N(ode) down-staging. The aim of this experiment was to compare drug uptake of gemcitabine and carboplatin during SPAP and intravenous infusion (IV).
SPAP was performed in 12 pigs using clinically applied doses of gemcitabine (1.25 g/m², n = 4) and carboplatin (AUC 5, n = 4) and a combination of both (n = 4). All animals underwent catheterisation of the left pulmonary artery and furthermore a left thoracotomy and lumbotomy for tissue sampling. After 2 min of SPAP, 30 min of blood flow occlusion was performed in order to delay drug washout from the lung. Two additional groups were infused intravenously (IV) using the same dose of gemcitabine (n = 4) and carboplatin (n = 4). Peak concentrations and area under the curve (AUC) were compared with t-tests.
Significantly higher pulmonary gemcitabine peak concentrations (p ≤ 0.017) and AUC (p ≤ 0.020) were observed after SPAP gemcitabine and gemcitabine/carboplatin compared to IV while no differences were shown between serum, renal and lymph tissue. Furthermore, SPAP carboplatin and gemcitabine/carboplatin also resulted in significantly higher pulmonary carboplatin peak concentrations (p ≤ 0.018) compared to IV while AUC was significantly higher after SPAP gemcitabine/carboplatin (p = 0.045). SPAP carboplatin resulted in significantly higher lymph concentrations at 10 min compared to IV carboplatin (p = 0.04).
SPAP with gemcitabine and carboplatin resulted in significantly improved drug exposure of the lung compared to IV. Equivalent serum concentrations and a trend towards higher mediastinal lymph node concentrations were achieved for carboplatin.
Selective pulmonary artery perfusion (SPAP) is an experimental drug infusion method for the treatment of lung cancer that aims to achieve more effective T(umour) and lymph N(ode) down-staging. The aim of this experiment was to compare drug uptake of gemcitabine and carboplatin during SPAP and intravenous infusion (IV). In conclusion, SPAP with carboplatin and gemcitabine or the combination of both showed a superior uptake profile into the lung while systemic exposure was equivalent compared to IV. Mediastinal lymph node concentrations are comparable with IV or tended to be higher after SPAP with carboplatin.
Genomic prognostic models in early-stage lung cancer
2009, Clinical Lung Cancer
Patients with early-stage lung cancer demonstrate significant recurrence rates and lower-than-expected survival rates after surgical resection, indicating that our current staging methods do not adequately predict outcome. Since the last revision of the TNM staging system, a number of genomic models have been proposed which more accurately predict prognosis in patients with early-stage lung cancer. A variety of prognostic genomic models based on gene-expression profiling and quantitative polymerase chain reaction (PCR) are able to stratify patients with early-stage lung cancer into high- and low-risk groups with respect to disease-free and overall survival. In the future, clinical application of these models may ultimately dictate both the use of adjuvant therapy as well as the choice of surgical procedure in patients with early-stage lung cancer. An effort to develop a robust genomic model for use in the clinical setting should be prompted by encouraging results obtained by the use of a quantitative PCR-based genomic signature in the field of breast oncology.
Pneumonectomy After Chemotherapy: Morbidity, Mortality, and Long-Term Outcome
2008, Annals of Thoracic Surgery
Results of pneumonectomy after chemotherapy are controversial, and the procedure is often considered as potentially dangerous.
Records of patients who underwent pneumonectomy after chemotherapy for non-small cell lung cancer in a single institution in a 6-year period were reviewed retrospectively.
One hundred eighteen patients had pneumonectomy after chemotherapy. Indications for preoperative chemotherapy were N2 disease, 74; potentially resectable T4 disease, 17; doubtful resectability, 18; stage IV disease (nodule on another ipsilateral lobe), 4; and participation in a randomized trial on induction chemotherapy in initial stages, 5. Chemotherapy protocols were platinum-based. Imaging reevaluation showed complete, partial, minor response, and disease stability in 0, 24, 39, and 55 patients, respectively. Operative mortality was 5.9% (7 of 118), consisting of 4 of 54 after pneumonectomy, and 3 of 64 after left pneumonectomy. Bronchopleural fistula caused one death. No factor among those evaluated (sex, age, comorbidities, forced expiratory volume in 1 second, symptoms, side and location of tumor; indication for operation, number of cycles, and response to chemotherapy; extent of resection, TNM status, pathologic stage) predicted postoperative death. Median and overall 5-year survival was 22 months and 23.7%, respectively. At univariate analysis, pathologic stage, T status, and the occurrence of postoperative complications influenced 5-year survival. At multivariate analysis, T status (p = 0.0054), the occurrence of postoperative complications (p = 0.0015), and clinical response to induction chemotherapy (p = 0.028) were identified as independent predictors of 5-year survival.
Pneumonectomy after chemotherapy has acceptable mortality. Long-term results are encouraging.

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Adjuvant and neoadjuvant chemotherapy in NSCLC: a paradigm shift

Summary

Chest

Ann Thorac Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg.

Lung Cancer

Lung Cancer

Lung Cancer

Adjuvant chemotherapy in completely resected non-small cell lung cancer

J Clin Oncol

Sites of recurrence in resected stage I non-small-cell lung cancer: a guide for future studies

J Clin Oncol

Cancer recurrence after resection: T1 NO non-small cell lung cancer. Lung Cancer Study Group

Ann Thorac Surg

Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC(R) is a predictor for relapse: A preliminary report

WorLd J Surg Oncol

Immunocytological detection of bone marrow micrometastasis in operable non-small cell lung cancer

Cancer Res

Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer

Ann Thorac Surg

Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials

Br Med J

Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial

Eur J Cardiothorac Surg