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Induction Chemo-radiation (50Gy) Followed by Surgery for Stage IIIA-N2 Non-small Cell Lung Cancer
Abstract
Background:
The optimal therapeutic strategy for potentially resectable clinical (c-) stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. This phase II multi-institutional study (WJOG5308L) was designed to evaluate the feasibility of induction chemotherapy with concurrent thoracic radiotherapy (50 Gy) followed by surgery and postoperative consolidation chemotherapy in IIIA-N2 NSCLC.
Methods:
Patients with resectable c-stage IIIA-N2 were eligible, and pathological confirmation of N2 disease was mandatory. Patients received chemotherapy consisting of weekly carboplatin plus paclitaxel with concurrent radiotherapy (50 Gy in 25 fractions). Unless disease progression, patients underwent surgical resection, and thereafter received two courses of consolidation chemotherapy with carboplatin plus paclitaxel. The primary endpoint was the proportion of patients who achieved complete resection after induction chemo-radiotherapy (R0 rate).
Results:
From December 2011 to November 2013, 40 eligible patients were enrolled. All patients completed induction chemo-radiotherapy with an overall response rate of 58%, and 32 patients achieved complete resection (R0 rate, 80%) mostly with lobectomy (N =27). Twenty patients (50%) completed the study treatment including postoperative chemotherapy. After the median follow-up period of 38 months, the progression-free survival, overall survival and recurrence-free survival rates at 2 years were 63 %, 75 %, and 62%, respectively. The 30-day and 90-day mortality were 0%.
Conclusions:
Induction chemotherapy with concurrent radiotherapy (50 Gy) followed by surgery was a feasible and promising treatment option for resectable c-stage IIIA-N2 NSCLC.
... In this regard, the optimal treatment strategy for patients with potentially resectable locally advanced NSCLC is considered to be concurrent chemoradiotherapy followed by surgery. Some phase I and II studies demonstrated promising results for ICRT followed by surgery (18)(19)(20)(21)(22)(23)(24). However, some largescale multi-institutional clinical trials comparing definitive chemoradiotherapy to ICRT followed by surgery for Stage III patients showed that adding surgery had no benefit (25,26). ...
... The authors have no conflicts of interest to declare.Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective analysis was approved by the Institutional Review Board of Seirei Mikatahara General Hospital (approval number:[18][19][20][21][22][23][24][25][26][27][28][29][30]. ...
Background:
The optimal treatment for patients with resectable non-small cell lung cancer (NSCLC) involving adjacent organs (T3 or T4) and/or cN2 remains unclear. We investigated whether or not induction chemoradiotherapy (ICRT) followed by surgery improves the survival.
Methods:
We retrospectively analyzed 84 patients with NSCLC involving the adjacent organs and/or cN2 who underwent ICRT followed by surgery at our hospital from 2006 to 2018. Presurgical treatment consisted of 2 courses of platinum-doublet and concurrent radiotherapy (40-50 Gy) to the tumor and involved field.
Results:
All 84 patients completed ICRT. One patient died after completion of ICRT due to bacterial pneumonia. Radiological responses to ICRT were a complete response (CR), n=1; partial response (PR), n=48; stable disease (SD), n=32; and progressive disease (PD), n=2 (overall response rate: 58.3%). Eighty-one patients underwent radical surgery. The procedures included lobectomy, n=66; bilobectomy, n=7; pneumonectomy, n=6; and segmentectomy, n=2 (including 49 extended resections). Seventy-three patients (90%) underwent complete resection. The postoperative morbidity rate was 30%. The 30- and 90-day mortality rates were 1.2% and 2.4%, respectively. A pathological CR (Ef3) and major response (Ef2) were achieved in 17 (21.0%) and 38 (46.9%) patients, respectively; a minor response (Ef1) was observed in 26 (32%). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were 58.0% and 45.6%, respectively. The median survival time was 73.2 months. Based on the response to ICRT, patients with radiological CR or PR showed better 5-year OS than those with SD (63.7% vs. 40.0%, P=0.020). Patients with Ef3 or Ef2 demonstrated a much better 5-year OS than those with Ef1 (65.0% vs. 24.4%, P=0.005).
Conclusions:
ICRT followed by surgery for patients with NSCLC involving the adjacent organs and/or cN2 was feasible and improved the survival. A CR/PR or Ef2/Ef3 after ICRT led to a better prognosis.
... The authors highlighted bronchopleural fistula (BPF) as an adverse outcome reported in 3 patients, possibly due to the higher dose of thoracic radiotherapy used in this study before surgery. The use of bronchial stump coverage is suggested to try to reduce the risk of this complication [28]. ...
Purpose of Review
The treatment of stage III N2 non-small cell lung cancer (NSCLC) remains debated. There is an absence of a universally agreed definition of resectability for this heterogeneous group and a lack of trial data.
Recent Findings
We reviewed and compared current international guidelines and evidence surrounding management of stage III N2 NSCLC. The Irish and Australian guidelines advise subcategorising N2 disease into N2a (may be resectable) and N2b (never resectable). On the contrary, American and British guidelines avoid subcategorising N2 disease, emphasising importance of local MDT decisions. It is suggested that evidence for resection of stage III tumours is relatively weak, but that stage IIIA should generally be considered for resection, and stage IIIB is not recommended for resection. For resectable disease, surgery may be combined with neoadjuvant chemoimmunotherapy, or adjuvant chemotherapy followed by immunotherapy and radiotherapy in selected patients.
Summary
There is some evidence that technically resectable disease can be treated solely with radiotherapy with similar outcomes to resection. In the event of unresectable disease, chemoradiotherapy has been the traditional management option. However, recent studies with chemoradiotherapy alongside immunotherapy appear promising. There are many factors that influence the treatment pathway offered to patients with stage III N2 NSCLC, including patient factors, team expertise, and local resources. Therefore, the role of MDTs in defining resectability and formulating an individualised treatment plan is crucial.
... 10 Pathological response to preoperative treatment was evaluated according to the 'General rule for clinical and pathological record of lung cancer (7th edition) by the Japan Lung Cancer Society' as follows: therapeutic effect 0, no therapeutic effect; 1, residual viable cancer cells detected in '≥1/3' of resected tumour; 2, residual viable cancer cells detected in '<1/3' of resected tumour; 3, no residual viable cancer cells. 11 Evaluation tumour immune microenvironment PD-L1 expression on tumour cells and density of stromal CD8 + TILs were evaluated with IHC. 9,12-14 Serial 4-µm sections were cut from each formalin-fixed and paraffin-embedded tumour specimen. ...
Consolidation treatment with an anti-PD-L1 antibody, durvalumab, following concurrent chemo-radiotherapy (cCRT) has become a new standard of care for locally advanced non-small cell lung cancer (NSCLC). The rationale of PD-L1 blockade after cCRT is based on preclinical evidence suggesting that chemotherapy and radiotherapy up-regulate tumoural PD-L1 expression, which has not been shown in clinical studies.
To examine alteration in tumoural PD-L1 expression (tumour proportion score, TPS) and density of stromal CD8-positive tumour-infiltrating lymphocytes (CD8 + TILs) after cCRT, paired NSCLC samples obtained before and after cCRT were reviewed in comparison with those obtained before and after drug therapy.
PD-L1 expression was significantly up-regulated after cCRT (median TPS, 1.0 at baseline versus 48.0 after cCRT; P < 0.001), but not after drug therapy. There was no significant correlation between baseline TPS and post-cCRT TPS. CD8 + TIL density was significantly increased after cCRT (median, 10.6 versus 39.1; P < 0.001), and higher post-cCRT CD8 + TIL density was associated with a higher pathologic response and with a favourable survival (P = 0.019).
Tumoural PD-L1 expression was up-regulated after cCRT, which provides pathologic rationale for PD-L1 blockade following cCRT to improve prognosis. Stromal CD8 + TIL density was also increased after cCRT, and higher post-cCRT CD8 + TIL density was a favourable prognostic indicator.
... The role of surgery in the multimodality setting is intensively debated and different treatment recommendations have been proposed. However, more recent evidence suggests that in selected patient groups neoadjuvant treatment followed by surgery yields good long-term survival with limited morbidity (4). Despite the advances in mediastinal staging and imaging techniques, a number of these patients are treated by surgical resection initially, and are found to have N2 disease only at the final pathological examination (5). ...
Background
Surrogate endpoints for overall survival in patients with resectable non–small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study’s main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival.
Methods
A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non–small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard ratio [HR] for overall survival or event-free survival by pathological complete response or major pathological response status, yes vs no) and at the trial level using weighted least squares regressions (hazard ratio for overall survival or event-free survival vs pathological complete response, by treatment arm) were performed.
Results
In both meta-analyses, pathological complete response yielded favorable overall survival compared with no pathological complete response (frequentist, 20 studies and 6530 patients: HR = 0.49, 95% confidence interval = 0.42 to 0.57; Bayesian, 19 studies and 5988 patients: HR = 0.48, 95% probability interval = 0.43 to 0.55) and similarly for major pathological response (frequentist, 12 studies and 1193 patients: HR = 0.36, 95% confidence interval = 0.29 to 0.44; Bayesian, 11 studies and 1018 patients: HR = 0.33, 95% probability interval = 0.26 to 0.42). Across subgroups, estimates consistently showed better overall survival or event-free survival in pathological complete response or major pathological response compared with no pathological complete response or no major pathological response. Trial-level analyses showed a moderate to strong correlation between event-free survival and overall survival hazard ratios (R2 = 0.7159) but did not show a correlation between treatment effects on pathological complete response and overall survival or event-free survival.
Conclusion
There was a strong and consistent association between pathological response and survival and a moderate to strong correlation between event-free survival and overall survival following neoadjuvant therapy for patients with resectable non–small cell lung cancer.
Introduction
Increased efforts to optimize outcomes for early-stage non-small cell lung cancer (NSCLC) through the investigation of novel perioperative treatment strategies are ongoing. An emerging question is the role of pathological response and its association with long-term clinical outcomes after neoadjuvant therapy.
Methods
To investigate the association of pathological complete response (pCR) and event-free survival (EFS) and overall survival (OS), we performed a systematic review and meta-analysis identifying studies reporting on the prognostic impact of pCR after neoadjuvant chemotherapy or chemoradiotherapy. To evaluate this prognostic value, an aggregated data (AD) meta-analyses was conducted to estimate the pooled HRs of EFS and OS for pCR. Using reconstructed individual patient data (IPD), pooled Kaplan-Meier curves (KMCs) were obtained to estimate this association in a more granular fashion. Subgroup analyses were conducted to further explore the impacts of study-level characteristics.
Results
A total of 28 studies comprising 7011 patients were included in the AD meta-analysis, of which, IPD was available for 6274 patients from 24 studies. Results from our AD meta-analysis revealed a pooled pCR rate of 18% (95%CI 15%-21%), as well as significant improvements in OS (HR 0.50, 95% CI 0.45-0.56) and EFS (HR 0.46, 95% CI 0.37-0.57) based on pCR status. Our IPD analysis revealed a 5-year OS rate of 63% (95% CI 59.6, 67.4) for patients with a pCR, compared to 39% (95% CI 34.5, 44.5) for those without a pCR.
Conclusions
PCR after neoadjuvant chemo+/-radiotherapy is associated with significant improvements in recurrence and survival for patients with resectable NSCLC.
Introduction
We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center - Clinical Trials Information-195069).
Patients and Methods
Key inclusion criteria include 1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC and 2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy [carboplatin (area under the curve=2) and paclitaxel (40 mg/m²) on days 1, 8, 15, 22, and 29, with involved-field radiation therapy (dose 50 Gy) on days 1-25] and neoadjuvant immunotherapy [durvalumab (1500 mg) on days 1 and 29]. Surgical resection with mediastinal lymph node dissection is performed within 2-6 weeks after radiation therapy. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR: ≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a one-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.
Non-small cell lung cancer patients with N2 disease should be treated with induction therapy. The feasibility of potential surgery should be assessed prior to starting induction therapy. Surgical resection should only be considered for acceptable surgical candidates with single-station mediastinal nodal disease for whom lobectomy is technically feasible; other patients should receive definitive chemoradiation. Patients who do not progress after induction therapy and have some evidence of response should have the planned surgical resection. Prognosis is significantly better for patients whose mediastinal disease has been cleared, but proceeding with surgery if N2 disease persists after induction therapy is reasonable.
Objectives
Lung cancer patients have been reported to have a high incidence of venous thromboembolism (VTE) and a high recurrence rate of VTE. However, there are no detailed reports of VTE in lung cancer patients who underwent surgery after induction therapy. We examined the incidence and clinical features of VTE in these patients.Methods
We retrospectively evaluated 89 patients with non-small cell lung cancer who underwent surgery after induction therapy at our department between April 2009 and March 2018. The incidence of VTE, clinical features, and long-term prognosis were retrospectively examined.ResultsAmong the 89 patients, 4 (4.5%) developed VTE, and there was no significant difference in the background characteristics between patients with and without VTE. All four patients developed VTE during preoperative treatment. In the patients with VTE, anticoagulant therapy with oral anticoagulants was administered after heparinization, and the median duration of anticoagulant therapy was 18.7 months. There were no cases of symptomatic VTE recurrence after surgery, regardless of lung cancer recurrence. Although the overall survival (OS) showed no significant difference between patients with and without VTE, the disease-free survival was significantly shorter in patients with VTE than in those without it (median 6.3 vs. 71.6 months, p < 0.01).Conclusions
In induction cases, the incidence of VTE was 4.5%, and it can at least be stated that no symptomatic VTE developed or recurred after surgery. Patients with VTE in induction therapy had short progression-free survival and required careful follow-up after surgery.
Neoadjuvant Chemotherapy has been used for the stage III of non-small cell lung cancer (NSCLC) and has shown good clinical effects. However, the survival benefits of radiation therapy added in induction regimens remains controversial. We therefore conducted a meta-analysis of the published clinical trials to quantitatively evaluate the benefit of preoperative chemoradiotherapy. After searching the database of Pubmed, CNKI, EMBASE, ESMO, The Cochrane Library databases, The American Society of Clinical Oncology and Clinical Trials.gov. Trials were selected for meta-analysis if they provided an independent assessment of neoadjuvant chemoradiation and neoadjuvant chemotherapy, odds ratio(OR) for tumor downstaging, mediastinal lymph nodes pathological complete response and local control, hazard ratios (HRs) for 5-year survival and progression-free survival were pooled by the stata software version 12.0. Twelve studies involving 2,724 patients were identified, tumor downstaging (p = 0.01), mediastinal lymph nodes pathological complete responses (p = 0.028) and local control (P = 0.002) were achieved, when compared with neoadjuvant chemotherapy. The meta-analysis demonstrated neither 5-year survival nor progression-free-survival benefit in survival from adding radiation. In conclusion, the addition of radiotherapy into chemotherapy was not superior to neoadjuvant chemotherapy. The higher quality of trials need be investigated combining with the histopathological type and genotyping of lung cancer by clinicians.
Purpose:
Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2) non-small-cell lung cancer. Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2) disease and with selected IIIB disease. Here, we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction.
Patients and methods:
Patients with pathologically proven IIIA(N2) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy, which consisted of three cycles of cisplatin 50 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days, as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50 mg/m(2) on days 2 and 9, and concurrent vinorelbine 20 mg/m(2) on days 2 and 9. Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were randomly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery (arm B). The primary end point was overall survival (OS).
Results:
After 246 of 500 planned patients were enrolled, the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding, which left the study underpowered relative to its primary study end point. Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification, sixth edition. The median age was 59 years (range, 33 to 74 years). After induction, 161 (65.4%) of 246 patients with resectable tumors were randomly assigned; strata were tumor-node group, prophylactic cranial irradiation policy, and region. Patient characteristics were balanced between arms, in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost. In arm B, 81% underwent R0 resection. With a median follow-up after random assignment of 78 months, 5-year OS and progression-free survival (PFS) did not differ between arms. Results were OS rates of 44% for arm B and 40% for arm A (log-rank P = .34) and PFS rates of 32% for arm B and 35% for arm A (log-rank P = .75). OS at 5 years was 34.1% (95% CI, 27.6% to 40.8%) in all 246 patients, and 216 patients (87.8%) received definitive local treatment.
Conclusion:
The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group.
To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early stage disease and locally-advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally-advanced disease.
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.
A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.
Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.
Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.
The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy.
Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity.
Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity.
Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.
The majority of patients with stage T3, N1, M0 or T1-3, N2, M0 non-small cell lung cancer are considered inoperable, and receive radical radiotherapy. This randomised trial aimed to assess whether, in this group of inoperable patients, a policy of neo-adjuvant chemotherapy (with mitomycin, ifosfamide and cisplatin (MIC) or mitomycin, vinblastine and cisplatin (MVP)) followed, if feasible, by surgery (CT-S), would result in better outcomes than radical radiotherapy (RT). The trial closed due to poor accrual, with only 48 patients randomised in 3 years. Only 4 of the 24 patients in the CT-S group had a complete resection, and of these, the 2 patients who had a pneumonectomy both died 12 days after surgery. There was no evidence of an improved survival in the CT-S group (median survival 13.8 months, compared with 11.3 months for the RT group), but because the trial failed to recruit we were unable to reach any reliable conclusions about these two treatment options.
Background:
The role of surgical resection in patients with clinical stage IIIA-N2 positive (cIIIA-N2) lung cancer is controversial, partly because of the variability in short- and long-term outcomes. The objective of this study was to characterize the management of cIIIA-N2 lung cancer in The Society of Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD).
Methods:
The STS-GTSD was queried for patients who underwent operations for cIIIA-N2 lung cancer between 2002 and 2012. A subset of patients aged older than 65 years was linked to Medicare data.
Results:
Identified were 3,319 surgically managed, cIIIA-N2 patients, including 1,784 (54%) treated with upfront resection (treatment naïve upfront surgery group, and 1,535 (46%) with induction therapy. A positron emission tomography scan was documented in 93% of patients, and 51% of patients were coded in STS-GTSD as having undergone invasive mediastinal staging. Nodal overstaging (cN2→pN0/N1) was observed in 43% of upfront surgery patients. Lobectomy was performed in 69% of patients and pneumonectomy in 11%. Operative mortality was similar between patients treated with upfront surgery (1.9%) and induction therapy (2.5%, p = .2583). The unadjusted Kaplan-Meier estimate of 5-year survival of cIII-N2 patients treated with induction therapy then resection was 35%.
Conclusions:
STS surgeons achieve excellent short- and long-term results treating predominantly lobectomy-amenable cIIIA-N2 lung cancer. However, prevalent overstaging and abstention from induction therapy suggest "overcoding" of false positives on imaging or variable compliance with current guidelines for cIIIA-N2 lung cancer. Efforts are needed to improve clinical stage determination and guideline compliance in the GTSD for this cohort.
PURPOSETo assess the feasibility of concurrent chemotherapy and irradiation (chemoRT) followed by surgery in locally advanced non-small-cell lung cancer (NSCLC) in a cooperative group setting, and to estimate response, resection rates, relapse patterns, and survival for stage subsets IIIA(N2) versus IIIB.PATIENTS AND METHODS
Biopsy proof of either positive N2 nodes (IIIAN2) or of N3 nodes or T4 primary lesions (IIIB) was required. Induction was two cycles of cisplatin and etoposide plus concurrent chest RT to 45 Gy. Resection was attempted if response or stable disease occurred. A chemoRT boost was given if either unresectable disease or positive margins or nodes was found.RESULTSThe median follow-up time for 126 eligible patients [75 stage IIIA(N2) and 51 IIIB] was 2.4 years. The objective response rate to induction was 59%, and 29% were stable. Resectability was 85% for the IIIA(N2) group eligible for surgery and 80% for the IIIB group. Reversible grade 4 toxicity occurred in 13% of patients. There were ...
One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes.
We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771.
From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery.
Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer.
Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The management of potentially resectable stage III non-small cell lung carcinoma (NSCLC) is controversial. Options include induction chemotherapy or induction chemoradiation followed by resection, or chemoradiation without surgery. No trial has compared the outcomes of induction chemoradiation using different radiation doses. We reviewed our experience involving patients with clinical stage III disease treated with trimodality therapy involving two radiation strategies to determine the response rates, operative results, recurrence patterns, and long-term survival.
A retrospective review was made of consecutive stage III NSCLC patients treated from 2004 to 2011.
Fifty-two patients with clinical stage IIIa NSCLC were treated with trimodality therapy. Eighteen patients were treated to doses of 60 Gy or higher, and 34 to lower doses (45, 50, or 54 Gy). There were significantly more postoperative complications in the higher radiation group (p < 0.001). Pathologic complete response (50% versus 15%, p = 0.016) and mediastinal nodal clearance (75% versus 42%, p = 0.254) rates were also higher in the high-dose group. That did not, however, translate into better disease-free and overall survival rates. Importantly, long-term noncancer mortality was significantly higher after higher dose preoperative radiation therapy.
In this series of patients with clinical stage IIIa NSCLC treated with trimodality therapy, a higher dose of preoperative radiation therapy resulted in better response rates but that did not translate to better cancer-specific survival. Of significance, we observed a notably higher delayed noncancer mortality in the high-dose group.
Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on external-beam radiotherapy for patients with locally advanced non-small-cell lung cancer (NSCLC). Because of its relevance to the American Society of Clinical Oncology (ASCO) membership, ASCO endorsed the guideline after applying a set of procedures and a policy that are used to critically examine and endorse guidelines developed by other guideline development organizations.
The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO expert panel was convened and endorsed the guideline. The ASCO guideline approval body, the Clinical Practice Guideline Committee, approved the final endorsement.
The recommendations from the ASTRO guideline, published in Practical Radiation Oncology, are clear, thorough, and based on the most relevant scientific evidence. The ASCO Endorsement Panel endorsed the guideline and added qualifying statements.
For curative-intent treatment of locally advanced NSCLC, concurrent chemoradiotherapy improves local control and overall survival compared with sequential chemotherapy followed by radiation. The standard dose-fractionation of radiation is 60 Gy given in 2-Gy once-daily fractions over 6 weeks. There is no role for the routine use of induction therapy before chemoradiotherapy. Current data fail to support a clear role for consolidation therapy after chemoradiotherapy; however, consolidation therapy remains an option for patients who did not receive full systemic chemotherapy doses during radiotherapy. Important questions remain about the ideal concurrent chemotherapy regimen and optimal management of patients with resectable stage III disease.
© 2015 by American Society of Clinical Oncology.
The role of surgery in addition to chemotherapy and radiation for stage IIIA non-small-cell lung cancer (NSCLC) remains controversial. Because there are limited data on the benefit from surgery in this setting, we evaluated the use of combined modality therapy nationally and explored the outcomes with and without the addition of surgery.
Patient variables and treatment-related outcomes were abstracted for patients with clinical stage IIIA NSCLC from the National Cancer Database. Patients receiving chemotherapy and radiation were compared with those undergoing chemotherapy, radiation, and surgery (CRS) in any sequence.
Between 1998 and 2010, 61,339 patients underwent combined modality treatment for clinical stage IIIA NSCLC. Of these, 51,979 (84.7%) received chemotherapy and radiation while 9360 (15.3%) underwent CRS. Patients in the CRS group were younger, more likely female patients and Caucasians, and had smaller tumors and lower Charlson comorbidity scores. The 30-day surgical mortality was 200 of 8993 (2.2%). The median overall survival favored the CRS group in both unmatched (32.4 months versus 15.7 months, p < 0.001) and matched analysis based on patient characteristics (34.3 versus 18.4 months, p < 0.001).
There is significant heterogeneity in the treatment of stage IIIA NSCLC in the United States. Patients selected for surgery in addition to chemoradiation therapy seem to have better long-term survival.
Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients.
Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews.
For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival.
Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation.
Background:
This study sought to ascertain whether induction-concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC).
Methods:
Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m(2) and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible.
Results:
Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P = .187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P = .397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P = .001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P = .021).
Conclusions:
The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC.
This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC).
Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m(2) on days 1, 8)/carboplatin (AUC 5 on day 1); C, weekly paclitaxel (40 mg/m(2))/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m(2) on day 1)/carboplatin (AUC 5 on day 1).
The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C.
Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.
Locally advanced non-small cell lung cancers share a risk of both local and systemic recurrence and justifies a therapeutic strategy combining focal and systemic treatment. In resectable stage IIIA-N2 tumors, peri-operative chemotherapy significantly increases survival rates. Chemoradiotherapy, which is the standard treatment of non-resectable locally advanced tumors, may have a role as an induction treatment to reduce locoregional recurrence rates. In the present phase II trial, we aimed at comparing standard induction chemotherapy (arm A: cisplatin and gemcitabine) with 2 different regimens of induction chemoradiotherapy (total dose: 46 Gy) including third-generation cytotoxic agents (arm B: cisplatin and vinorelbine; arm C: carboplatin and paclitaxel) in patients with resectable stage IIIA-N2 NSCLC, using feasibility of the whole strategy, including surgery, as a primary endpoint. A total of 46 patients were included. Response rate was significantly higher after induction chemoradiotherapy vs. chemotherapy (87% vs. 57%, p=0.049). A total of 44 patients underwent operation. The feasibility rate of the proposed therapeutic strategy was 89% for the whole cohort, 93% in arm A (induction chemotherapy with cisplatin and gemcitabine), 88% in arm B (induction chemoradiotherapy with cisplatin and vinorelbine), and 87% in arm C (induction chemoradiotherapy with carboplatin and paclitaxel) (p=0.857). Overall median, 1-year, and 3-year survival were 30 months, 87%, and 43%, respectively. Induction chemoradiotherapy with modern treatment regimens is highly feasible and may show promises in the current and future developments of multimodal therapeutic strategies in locally advanced NSCLC.
Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection.
Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550.
202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy.
Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer.
National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
We have previously demonstrated that high-dose chemoradiotherapy followed by resection for patients selected on the basis of mediastinal sterilization was feasible and resulted in excellent outcomes. This study was designed to determine the ability to intensify our prior approach utilizing hyperfractionated radiation and more aggressive consolidative chemotherapy.
Patients with documented stage IIIA/B nonsmall-cell lung cancer, performance status 0 to 2, and adequate organ function were eligible. A phase I portion utilized escalating doses of carboplatin and vinorelbine, commencing with areas under the curve of 1 and 5 mg/m(2), respectively, and concurrent 69.6 Gy hyperfractionated radiotherapy. A phase II portion utilized the identical radiotherapy with carboplatin/vinorelbine at the maximum tolerated dose established in phase I. Patients for whom mediastinal nodal clearance was demonstrated underwent resection. All patients were to receive consolidation chemotherapy consisting of carboplatin/vinorelbine for three cycles, followed by docetaxel for three cycles. Prophylactic cranial irradiation was offered to patients after completion of therapy.
Forty-seven patients participated in the study (33 IIIA, 14 IIIB; 15 men, 32 women; median age, 56 years). The maximum tolerated dose for concurrent carboplatin/vinorelbine and hyperfractionated radiotherapy was established at areas under the curve of 1 and 10 mg/m(2), respectively. Twenty-eight patients completed trimodality treatment including surgery. Median survival time for the entire study cohort (n = 47) is 29.6 months, and it is 55.8 months for patients with mediastinal clearance who underwent resection (n = 28).
Surgical resection of locally advanced stage IIIA and IIIB nonsmall-cell lung cancer after induction hyperfractionated radiation and concurrent chemotherapy is safe and well tolerated. Whether this approach is superior to less aggressive therapy is uncertain and will require comparative studies.
The standard phase II trial problem is to decide whether or not to continue the testing of a new agent (or combination). Typically, one tests the null hypothesis HO: p = pO against the alternative HA: p = pA, where p is the probability of response. There is available a variety of two-stage phase II designs, including optimal designs according to various criteria. Practical considerations in the conduct of multicentre trials, however, make it difficult to follow designs precisely. We investigate several approaches to adapting stopping rules when the attained sample size is not the planned size. We find that a simple approach of testing HA: p = pA at the 0.02 level at the first stage and HO: p = pO at the 0.055 level at the second stage works well across a variety of powers, pOs and pAs.
Preoperative chemotherapy and radiation administered separately or in combination have been used in the treatment of locally advanced non-small cell lung cancer. To assess the postoperative morbidity and mortality associated with aggressive neoadjuvant therapy, we reviewed the records of 13 patients who underwent resection of locally advanced non-small cell lung cancer after two monthly cycles of infusional 5-fluorouracil, 640 to 800 mg/m2 (days 1 through 5); cisplatin, 20 mg/m2 (days 1 through 5); etoposide, 50 mg/m2 (days 1, 3, and 5); and concomitant radical thoracic irradiation (6,000 cGy) administered in 200-cGy daily fractions. Six patients underwent lobectomy with no mortality, whereas 7 pneumonectomies were associated with three deaths (43%). Culture-negative, diffuse pulmonary infiltrates developed 3 to 6 days after operation in 5 of 7 pneumonectomy patients and in 1 of 6 lobectomy patients. Two patients who had undergone pneumonectomy died of progressive adult respiratory distress syndrome. A third death resulted from a bronchopleural fistula that developed 30 days after pneumonectomy. Morbidity and mortality were not associated with preoperative pulmonary function test results, nutritional status, or intraoperative inspired oxygen fraction (p > 0.05 by chi 2 test). Only pneumonectomy correlated with increased morbidity and mortality (p < 0.05 by chi 2 test). We conclude that lobectomy may be performed safely after this combination of aggressive chemotherapy and high-dose radiation, but pneumonectomy is associated with unacceptable morbidity and mortality.
The main objectives of this study were (a) to ascertain the feasibility and toxicity of preoperative twice-daily radiation therapy and concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA (N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor response, resection rate, pathologic tumor downstaging, and survival.
Eligibility included biopsy-proven N2 lesion (stage IIIA) by mediastinoscopy, Karnofsky performance score > or = 70, and weight loss less than 5% in the 3 months before diagnosis. The treatment program consisted of two courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42 Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day; surgery on day 57; and one more course of postoperative chemotherapy and 12 to 18 Gy of concurrent twice-daily radiation.
Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15 women, age 38 to 77 years) were enrolled onto this prospective study. Forty of 42 patients tolerated the intended dose (42 Gy) of preoperative radiation and 37 of 39 resected patients received prescribed postoperative radiation. The intended dose of chemotherapy was given in 100%, 70%, and 60% of patients for the first, second, and third courses of chemotherapy. Marked dysphagia that required intravenous hydration was noted in 14% of patients (six of 42). Myelotoxicities included grade > or = 3 granulocytopenia in 23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile neutropenia that required hospital admission was noted in 9% of 113 chemotherapy courses. Surgical resection was performed in 93% of patients. Treatment-related mortality was noted in 7% of patients. The overall survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2,3, and 5 years, respectively, with a median follow-up time of 48 months. Pathologic examination of the surgical specimen showed a downward shift in tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (NO) in 24% (10 of 42), and to stage 0 (TONO) in 9.5%, for a total of 67%. The degree of tumor downstaging was also translated into a survival benefit: 5-year survival rates from the time of surgery were 79%, 42%, and 18% for postoperative tumor stages 0 and I, II, and III, respectively (P = .04).
Concurrent chemoradiotherapy using twice-daily radiation is an effective induction regimen that resulted in 67% tumor downstaging, and an encouraging 37% 5-year survival rate. The degree of tumor downstaging may be a useful intermediate end point for survival benefit in stage IIIA (N2) NSCLC.
To evaluate the feasibility and efficacy of an intensive multimodality approach with combination chemotherapy, hyperfractionated accelerated chemoradiotherapy, and definitive surgery in prognostically unfavorable subgroups of locally advanced non-small-cell lung cancer stages IIIA and IIIB (LAD-NSCLC).
Following staging, including mediastinoscopy, 94 patients with inoperable LAD-NSCLC were treated preoperatively with chemotherapy (three courses of split-dose cisplatin and etoposide [PE]) followed by concurrent chemoradiotherapy (one course of PE combined with 45 Gy hyperfractionated accelerated radiotherapy). After repeat mediastinoscopy, patients underwent surgery 4 weeks postradiation.
Of 94 consecutive patients (52 stage IIIA [> or = two lymph node levels involved] and 42 stage IIIB [no pleural effusion, no supraclavicular nodes]), 62 (66%) completed induction and underwent surgery. Complete resection (R0) was achieved in 50 (53% of all patients) and pathologic complete response (PCR) in 24 (26%). After a median follow-up of 43 months, the median survival time was 20 months for IIIA, 18 months for IIIB, and 42 months for R0 patients. Calculated survival rates at 4 years were 31%, 26%, and 46%. Two patients died of sepsis preoperatively and four died postoperatively of pleural empyema (n = 1), stump insufficiency (n = 2), and cardiac failure (n = 1). Other toxicities were acceptable-mainly hematologic during chemotherapy or chemoradiotherapy and esophagitis during chemoradiotherapy.
This intensive multimodality treatment is feasible and demonstrates high efficacy in prognostically unfavorable LAD-NSCLC subgroups with high R0 rates and improved long-term survival compared with historical controls
To compare the outcome of treatment of mediastinoscopy-verified N2 non-small-cell lung cancer treated with induction chemotherapy followed by either surgery or radiotherapy (RT), with both options followed by consolidation chemotherapy.
A randomized Phase III trial for Stage IIIA (T1-T3N2M0) non-small cell lung cancer was conducted by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group between April 1990 and April 1994. After documentation of N2 disease by mediastinoscopy or anterior mediastinotomy, patients received induction chemotherapy with cisplatin, vinblastine, and mitomycin-C. Mitomycin-C was later dropped from the induction regimen. Patients were then randomized to surgery or RT (64 Gy in 7 weeks) followed by cisplatin and vinblastine.
RTOG 89-01 accrued 75 patients, of whom 73 were eligible and analyzable. Twelve patients received induction chemotherapy but were not randomized to RT or surgery thereafter. Forty-five patients were randomized to postinduction RT or surgery. Of the analyzable patients, 90% had a Karnofsky performance score of 90-100, 18% had weight loss >5%, 37% had squamous cell histologic features, and 54% had bulky N2 disease. The distribution of bulky N2 disease was uniform among the treatment arms. The incidence of Grade 4 toxicity was 56% in patients receiving mitomycin-C and 29% in those who did not. Only 1 patient in each group had acute nonhematologic toxicity greater than Grade 3 (nausea and vomiting). No acute Grade 4 radiation toxicity developed. The incidences of long-term toxicity were equivalent across the arms. Three treatment-related deaths occurred: 2 patients in the surgical arms (one late pulmonary toxicity and one pulmonary embolus), and 1 patient in the radiation arm (radiation pneumonitis). Induction chemotherapy was completed in 78% of the patients. Complete resection was performed in 73% of 26 patients undergoing thoracotomy. Consolidation chemotherapy was completed in 75% of the patients. No statistically significant difference was found among the treatment arms. The overall progression-free survival rate was 53% at 1 year and 17% at 3 years. The median progression-free survival was 14 months. No difference in the 1-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between the surgery and RT arms. The median survival in the patients receiving induction chemotherapy only was 8.9 months. Mitomycin-C had no impact on survival (p = 0.75). No statistically significant difference was noted in the time to local failure between the surgical and RT arms.
The patient accrual to this trial made its results inconclusive, but several observations are notable. In this trial, histologic confirmation of N2 disease in the surgical and nonsurgical arms eliminated the usual biases from clinical staging. In this setting, local control and survival were essentially equal between the surgical and RT arms. The 3- and 5-year survival rates of nonsurgical therapy were comparable to published surgical trials of N2 disease.
Background:
Pulmonary resection after chemotherapy and concurrent full-dose radiotherapy (>59 Gy) has previously been associated with unacceptably high morbidity and mortality. Subsequently neoadjuvant therapy protocols have used reduced and potentially suboptimal radiotherapy doses of 45 Gy. We report a series of 40 patients with locally advanced non-small-cell lung cancer who successfully underwent pulmonary resection after receiving greater than 59 Gy radiation and concurrent chemotherapy. Operative results and midterm survival follow-up are presented.
Methods:
Data were reviewed from 40 consecutive patients who underwent lung resection after receiving high-dose radiotherapy and concurrent platinum-based chemotherapy between January 1994 and May 2000. The follow-up closing interval for this study was until August 2003 or time of death.
Results:
Preoperative stage was IIb (7 patients), IIIA (21 patients), IIIB (10 patients), and IV (2 patients with isolated brain metastasis). Thirteen patients exhibited Pancoast tumors. Median time from completion of induction therapy to surgery was 53 days. Twenty-nine lobectomies and 11 pneumonectomies (7 right, 4 left) were performed. There were no postoperative deaths. Intercostal muscle flaps were used prophylactically in all but one pneumonectomy patient. Seven patients required perioperative transfusions. Median intensive care unit (ICU) time averaged 2 days and the total length of stay was 6 days. One patient exhibited postpneumonectomy pulmonary edema and a bronchopleural fistula developed in another patient (not receiving an intercostal muscle flap). Thirty-four of 40 patients (85%; 95% CI: 70%-94%) were downstaged pathologically, 33 out of 40 patients (82.5%, 95% confidence interval [CI]: 67%-93%) indicated no residual lymphadenopathy, and 18 out of 40 patients (45%, 95% CI: 29%-61%) exhibited a complete pathologic response. Median follow-up was 2.8 years. The 1-, 2-, and 5-year overall survival rates were 92.4%, 66.7%, and 46.2%, respectively. Disease-free 1-, 2-, and 5-year survival rates were 73.0%, 67.2%, and 56.4%, respectively. Median disease-free survival has not been reached.
Conclusions:
Pulmonary resection may be performed safely after curative intent concurrent chemotherapy and radiotherapy to greater than 59 Gy. High pathologic complete response rates and sterilization of mediastinal lymph nodes were observed accompanied by highly favorable survival rates. This experience, though promising, will require confirmation in a prospective multiinstitutional clinical trial.
The treatment of stage III non-small-cell lung cancer has evolved over the last two decades, with combined-modality therapy the current standard of care. As a result, intermediate and long-term survival has improved for patients in this common stage category, compared to the poor outcomes achieved with the historical standard of once-daily radiation therapy alone. This review summarizes two decades of clinical research regarding bimodality and trimodality approaches for the heterogenous stage subsets within the stage III designation, discusses the rationale and status of prophylactic brain irradiation, and concludes with perspectives on progress and future directions. Chemotherapy plus radiotherapy given concurrently is the optimal treatment for the group of patients with advanced stage III disease. The potential role of a surgical resection following chemotherapy (with or without radiation) in this setting is still controversial. The only subsets for which trimodality treatments are clearly preferred include T4N0-1 disease and superior sulcus tumors. The other major stage III subgroup has a minimal disease burden with low tumor volume and/or microscopic N2 disease, thus technically could undergo a surgical resection upfront. Induction chemotherapy before surgery may yield a survival advantage, although the phase III trials in this area are not conclusive. Given the marked survival benefit from adjuvant chemotherapy after surgery in even earlier stages of non-small-cell lung cancer, the proper sequence of surgery and chemotherapy (before v after surgery) remains an important unresolved question in this subgroup. Furthermore, how to incorporate radiation therapy, as well as whether it should be given at all in this subset of patients, are other important issues actively under study in ongoing trials.
The purpose of this study is to assess the safety and efficacy of pulmonary resection after low and high dose neoadjuvant radiotherapy with concurrent chemotherapy.
A retrospective cohort study using an electronic prospective database from January 1998 to August 2004. All patients had N2, stage IIIa, nonsmall cell lung cancer, and received neoadjuvant carboplatinum-based chemotherapy with similar doses. In addition, some patients received high-dose chest radiation (HD) equal to or greater than 60 Gy and were compared with those who received low-dose radiation (LD) less than 60 Gy. All bronchial stumps were buttressed with an intercostal muscle.
There were 104 patients, 50 in the LD group and 54 patients in the HD group. Median dose of radiation was 45 Gy (range 35-50.4) in the LD group and 60 Gy (range 60-66.7) in the HD group. Complete pathologic response rate was 10% compared to 28% favoring the HD group (p = 0.04). Median length of stay for both groups was 4 days and the ICU was avoided in 74%. Major morbidity and mortality rates were similar: 8% compared to 9% and 2% compared to 3.7% for the low and high dose groups, respectively. Pneumonectomy was a significant risk factor for morbidity (OR = 17.0).
Pulmonary resection after preoperative chest radiation is safe even after 60 Gy or higher. Sixty or higher may afford an increase in complete pathologic response and it does not seem to increase morbidity or mortality. However, if pneumonectomy is known to be required we prefer to avoid neoadjuvant radiotherapy and use chemotherapy alone.
To improve the prognosis of cN2, N3 non-small cell lung cancer, we performed induction chemoradiotherapy (carboplatin-taxane chemotherapy and concurrent 50-Gy radiation) followed by surgery.
Patients with pathologically proven non-small cell lung cancer with bulky cN2, N3 disease were enrolled. Forty-one patients underwent an operation after chemoradiotherapy from January 2000 to April 2006. Either carboplatin-paclitaxel (n = 19) or carboplatin-docetaxel (n = 22) chemotherapy was randomly used. Two cycles of chemotherapy were performed with concurrent radiation (50 Gy). In all cases, conventional radiological reevaluations were performed; in the latest 21 cases, reevaluations with positron-emission tomography with fludeoxyglucose F 18 were also performed.
In all 41 cases, complete resections were performed, with no operative mortality. The histologically complete response rate, major response rate, and minor response rate were 17.1% (7/41), 56.1% (23/41), and 26.8% (11/41), respectively. The 5-year overall survival was 52.7%. There were no differences in survival between taxane groups. Both the complete response and the major response groups revealed a significantly better 5-year survivals than the minor response group (85.7%, P = .044, 52.4%, P = .01). Even with persistent N2 disease, the 5-year survival in the major response group (66%) was promising. With the combination of conventional computed tomography and positron-emission tomography with fludeoxyglucose F 18 for reevaluation, eligible patients could be selected for this protocol.
Surgery after chemoradiotherapy (carboplatin-taxane and 50-Gy radiation) for bulky cN2, N3 non-small cell lung cancer can be safely performed with promising results. Even with persistent N2 disease, the survival in the major response group was promising.
The seventh edition of the TNM Classification of Malignant Tumors is due to be published early in 2009. In preparation for this, the International Association for the Study of Lung Cancer established its Lung Cancer Staging Project in 1998. The recommendations of this committee for changes to the T, N, and M descriptors have been published. This report contains the proposals for the new stage groupings.
Data were contributed from 46 sources in more than 19 countries. Adequate data were available on 67,725 cases of non-small cell lung cancer treated by all modalities of care between 1990 and 2000. The recommendations for changes to the T, N, and M descriptors were incorporated into TNM subsets. Candidate stage groupings were developed on a training subset and tested in a validation subset.
The suggestions include additional cutoffs for tumor size, with tumors >7 cm moving from T2 to T3; reassigning the category given to additional pulmonary nodules in some locations; and reclassifying pleural effusion as an M descriptor. In addition, it is suggested that T2b N0 M0 cases be moved from stage IB to stage IIA, T2a N1 M0 cases from stage IIB to stage IIA, and T4 N0-1 M0 cases from stage IIIB to stage IIIA.
Such changes, if accepted, will involve a reassessment of existing treatment algorithms. However, they are based on an intensive and validated analysis of the largest database to date. The proposed changes would improve the alignment of TNM stage with prognosis and, in certain subsets, with treatment.
Preoperative chemotherapy improves survival in patients with stage III non-small-cell lung cancer (NSCLC) amenable to resection. We aimed to assess the additional effect of preoperative chemoradiation on tumour resection, pathological response, and survival in these patients.
Between Oct 1, 1995, and July 1, 2003, patients with stage IIIA-IIIB NSCLC and invasive mediastinal assessment from 26 participating institutions of the German Lung Cancer Cooperative Group (GLCCG) were randomly assigned to one of two treatment groups. The intervention group were scheduled to receive three cycles of cisplatin and etoposide, followed by twice-daily radiation with concurrent carboplatin and vindesine, and then surgical resection (those with positive resection margins or unresectable disease were offered further twice-daily radiotherapy). The control group were scheduled to receive three cycles of cisplatin and etoposide, followed by surgery, and then further radiotherapy. The primary endpoint was median progression-free survival (PFS) in patients eligible for treatment after randomisation. Secondary endpoints in patients eligible for treatment after randomisation were overall survival (OS) and the proportion of patients undergoing surgery. Secondary endpoints in patients with tumour resection were the proportion with negative resection margins, the proportion with complete resection, the proportion with histopathological response, and the proportion with mediastinal downstaging. Additionally, exploratory (not prespecified) post-hoc analyses in terms of PFS and OS were done on patients not amenable to resection and on further subgroups of patients undergoing resection. Analyses were by intention to treat. This trial is registered on the ClinicalTrials.gov website, number NCT 00176137.
558 patients were randomly assigned. 34 patients did not meet inclusion criteria and were excluded. Of 524 eligible patients, 142 of 264 (54%) in the interventional group and 154 of 260 (59%) in the control group underwent surgery; 98 of 264 (37%) and 84 of 260 (32%) underwent complete resection. In patients with complete resection, the proportion of those with mediastinal downstaging (45 of 98 [46%] and 24 of 84 [29%], p=0.02) and pathological response (59 of 98 [60%] and 17 of 84 [20%], p<0.0001) favoured the interventional group. However, there was no difference in PFS (primary endpoint) between treatment groups-either in eligible patients (median PFS 9.5 months, range 1.0-117.0 [95% CI 8.3-11.2] vs 10.0 months, range 1.0-111.0 [8.9-11.5], 5-year PFS 16% [11-21] vs 14% [10-19], hazard ratio (HR) 0.99 [0.81-1.19], p=0.87), in those undergoing tumour resection, or in patients with complete resection. In both groups, 35% of patients undergoing surgery received a pneumonectomy (50/142 vs 54/154). In patients receiving a pneumonectomy, treatment-related mortality increased in the interventional group compared with the control group (7/50 [14%] vs 3/54 [6%]).
In patients with stage III NSCLC amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival. After induction with chemoradiation, pneumonectomy should be avoided.
German Cancer Aid (Bonn, Germany).
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.
- Goldstraw P.
- Crowley J.
- Chansky K.