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Little Things Make Big Things Happen: Angiolymphatic Invasion and Tumor Necrosis Prognosticate the Outcome of Locally Advanced Non-Small Cell Lung Cancer Treated With a Prior Induction Therapy
Abstract
Size, invasion of thoracic structures, and ipsilateral mediastinal lymph node involvement (pN2) are well-known prognostic factors that configure the staging of resectable, locally advanced non-small cell lung cancer (LA-NSCLC). The prognostic impact of angiolymphatic invasion (ALI) and tumor necrosis (TN) has been barely explored in LA-NSCLC treated with prior induction therapies.
We retrospectively reviewed 47 resected LA-NSCLCs treated with a prior platin-based chemotherapy or chemoradiation. The impact of ALI, TN, and other pathologic features on survival was analyzed.
ALI was presented in 23.4% of cases and TN in 29.8%. Disease-free and overall survival decreased when ALI, TN, or pN2 was present. The incidence of ALI was lower in LA-NSCLC with a good response to induction.
Our series is the first to report the prognostic impact of ALI and TN in induction-treated LA-NSCLC. The presence of ALI and TN should be included in the pathologic reports.
Copyright© by the American Society for Clinical Pathology.
... [22][23][24] With the mechanisms above, patients of locally advanced NSCLC could obtain better long-term survival in induction chemotherapy group than those who only treated by CCRT only. Marquez-Medina et al [25] reported that for patients treated by induction chemotherapy, the lower presence of angiolymphatic invasion and tumor necrosis were associated with a good survival. Further analysis should be conducted to improve the prognosis of patients with locally advanced NSCLC. ...
Background:
The efficacy and toxicity of induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced nonsmall cell lung cancer (NSCLC) is unclear, we performed a systematic review and meta-analysis of published papers to quantitatively evaluate the potential benefit of induction chemotherapy.
Methods:
Eligible studies of induction chemotherapy and chemoradiotherapy were retrieved through extensive searches of the PubMed, Science Direct, Embase, and Cochrane library databases from 1994 to 2015. We excluded studies that using non-English. Our primary endpoint was overall survival (OS), secondary end point was toxicity.
Results:
Two studies of induction chemotherapy followed by CCRT versus CCRT alone and 5 studies of induction chemotherapy followed by CCRT versus CCRT followed by consolidation chemotherapy published in the same period were selected and analyzed. Our results showed that there was significant benefit of induction chemotherapy plus CCRT compared to CCRT alone on 5-year OS without 1, 2, 3, and 4 years OS. Our analysis also indicated that induction chemotherapy was as effect as consolidation chemotherapy for patients who received CCRT on overall response and OS. Treatment-related toxicity was similar between the 2 group; however, leucopenia was significant decreased in patients treated by induction chemotherapy (odds ratio [OR] = 0.43; 95% confidence interval [CI], 0.30-0.62; P < 0.00001).
Conclusion:
Five year OS could be improved when induction chemotherapy was added into CCRT for patients of NSCLC. Except low rate of leucopenia, induction chemotherapy was no difference compared to consolidation chemotherapy in patients with NSCLC treated by CCRT.
Background:
The incidence of vascular and lymphatic emboli in a specimen of resected non-small cell lung cancer is variable according to different authors' experience as well as prognostic significance in patients treated by surgery. We aimed at evaluating these factors in an unselected population of patients with primary pulmonary adenocarcinoma treated by major surgical resection.
Methods:
Clinical and pathology records of all patients treated by lobectomy or pneumonectomy and nodal dissection for pulmonary adenocarcinoma between June 2001 and June 2006 were retrospectively reviewed. Impact on survival of age, sex, tobacco use, history of chronic obstructive pulmonary disease, extent of resection, pathologic stage, and presence of vascular and lymphatic emboli was studied by univariate analysis and multivariate analysis (for factors significantly associated with survival at univariate analysis).
Results:
Five hundred three patients underwent lobectomy or pneumonectomy with nodal dissection for pathologically proven lung adenocarcinoma. There were 355 men and 148 women; mean age was 61.1 years, and 181 patients were 65 years old or older; 87% were current or former smokers; 90.3% had pulmonary lobectomy; and 9.7% had pneumonectomy. Pathologic stages were I, II, and III/IV in 45%, 17.9%, and 37.1%, respectively. Vascular emboli and lymphatic emboli were found in 183 of 503 patients (36.4%) and 149 of 503 (29.6%), respectively. Overall 5-year survival for the whole population was 50.7%. At univariate analysis, age more than 65 years (p=0.0019), chronic obstructive pulmonary disease (p=0.042), extent of resection (p=0.047), pathologic stage (p<0.0000001), T size (p=0.0020), T and N variables (p=0.0000016 and p<0.0000001, respectively), presence of vascular emboli (p=0.026), and presence of lymphatic emboli (p=0.000021) were associated with worse prognosis. At multivariate analysis, age more than 65 years (p=0.0047, relative risk 1.5), stage I versus II versus III versus IV (p=0.00000032), and presence of lymphatic emboli (p=0.05, relative risk 1.34) were identified as independent negative prognostic factors.
Conclusions:
In an unselected population of patients with pulmonary adenocarcinoma treated by lobectomy or pneumonectomy, the presence of lymphatic emboli is an independent negative prognostic factor.
Patients with breast cancer with a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a better prognosis than patients with residual disease. The aim of the current study was to identify predictors of pCR.
This retrospective study included 388 patients treated with anthracycline-based NAC. Clinicopathological parameters were compared between the patients with and without pCR in breast and axilla.
Treatment consisted of FAC/FEC in 230 patients (59%), TAC in 39 (10%) patients and AC followed by docetaxel in 119 (31%). In all, 36 (9.3%) patients had pCR. In univariate analysis, age, tumor size, lymph node involvement, tumor grade (p = 0.077, n = 265), ER and HER-2 status (n = 213), lymphovascular invasion (LVI), type of chemotherapy and taxane-containing chemotherapy were associated with pCR. In multivariate analysis, ER negativity (p = 0.003), the absence of LVI (p = 0.009) and taxane-containing NAC (p = 0.026) were found to be significant indicators of pCR. Median follow-up time was 69 months. Progression-free survival was significantly improved in patients achieving pCR (p = 0.001).
pCR is associated with a better outcome regardless of clinical and pathological parameters in breast cancer patients who receive NAC. The probability of pCR was higher in ER-negative, LVI-negative tumors and in patients treated with sequential taxane-containing chemotherapy.
To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non-small-cell lung cancer.
In this phase III trial, 624 patients with stage IA (tumor size > 2 cm), IB, II, or T3N1 were randomly assigned to surgery alone (212 patients), three cycles of preoperative paclitaxel-carboplatin followed by surgery (201 patients), or surgery followed by three cycles of adjuvant paclitaxel-carboplatin (211 patients). The primary end point was disease-free survival.
In the preoperative arm, 97% of patients started the planned chemotherapy, and radiologic response rate was 53.3%. In the adjuvant arm, 66.2% started the planned chemotherapy. Ninety-four percent of patients underwent surgery; surgical procedures and postoperative mortality were similar across the three arms. Patients in the preoperative arm had a nonsignificant trend toward longer disease-free survival than those assigned to surgery alone (5-year disease-free survival 38.3% v 34.1%; hazard ratio [HR] for progression or death, 0.92; P = .176). Five-year disease-free survival rates were 36.6% in the adjuvant arm versus 34.1% in the surgery arm (HR 0.96; P = .74).
In early-stage patients, no statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment.
The International Staging Committee (ISC) of the International Association for the Study of Lung Cancer (IASLC) collected 68,463 patients with nonsmall cell lung cancer and 13,032 patients with small cell lung cancer, registered or diagnosed from 1990 to 2000, whose records had adequate information for analyzing the tumor, node, metastasis (TNM) classification. The T, N, and M descriptors were analyzed, and recommendations for changes in the seventh edition of the TNM classification were proposed based on differences in survival. For the T component, tumor size was found to have prognostic relevance, and its analysis led to recommendations to subclassify T1 tumors into T1a (< or = 2 cm) and T1b (>2 - < or = 3 cm) and T2 tumors into T2a (>3 - < or = 5 cm) and T2b (>5 - < or = 7 cm), and to reclassify T2 tumors > 7 cm into T3. Furthermore, with additional nodules in the same lobe as the primary tumors, T4 tumors would be reclassified as T3; with additional nodules in another ipsilateral lobe, M1 as T4; and with pleural dissemination, T4 as M1. There were no changes in the N category. In the M category, M1 was recommended to be subclassified into M1a (contralateral lung nodules and pleural dissemination) and M1b (distant metastasis). The proposed changes for the new stage grouping were to upstage T2bN0M0 from stage IB to stage IIA, and to downstage T2aN1M0 from stage IIB to stage IIA and T4N0-N1M0 from stage IIIB to stage IIIA. The proposed changes better differentiate tumors of different prognoses.
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Background: Identification of pathologic features able to predict outcomes in resected stage I non-small cell lung cancer (NSCLC) may help to further stratify patients into risk groups, allowing for further refinement of adjuvant treatment recommendations. We performed a systematic review and meta-analysis to evaluate whether the presence of lymphovacular invasion (LVI) is associated with disease outcome in stage I NSCLC patients. Methods: A systematic search of the literature was performed (1990 to December 2012; Medline/Embase) using search terms related to lymphovascular invasion, lung cancer and prognosis. Studies were considered eligible if they reported the outcome of lung cancer in patients with LVI compared to those without. Pooled Hazard Ratios (HR) were estimated with a random effects model. Two different endpoints were independently analyzed: recurrence-free survival (RFS) and overall survival (OS). We analyzed both unadjusted and adjusted effect estimates, for a total of four separate meta-analyses. Several studies presented multiple results (i.e. adjusted and unadjusted and/or recurrence-free and overall survival) and were therefore included in more than one pooled analysis. Results: Of 2,878 titles identified, 20 articles met the inclusion criteria. Of these, 5 studies were excluded from the analysis due to duplication of results (n=4) and lack of data to calculate HR (n=1). The unadjusted models consisted of 808 (RFS) and 1675 (OS) patients, while the adjusted models consisted of 1,545 (RFS) and 2,601 (OS). The unadjusted pooled effect of LVI was significantly associated with worse both RFS (HR: 4.71, 95% Confidence Interval (CI): 3.08-7.21), and OS (HR: 3.05, 95% CI: 2.34-3.98). Adjusting for potential confounders yielded the same results with both RFS (HR: 2.49, 95% CI: 1.6-3.89), and OS (HR: 1.80, 95% CI: 1.44-2.25) being significantly worse for patients exhibiting LVI in their pathologic specimens. Conclusions: The present study indicates that LVI is an adverse prognostic factor in patients with surgically managed stage I lung cancer. Based on these results, the use of LVI as a stratifying factor in future prospective lung cancer trials seems to be justifiable.
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Background: The prognosis of patients with stage III non-small cell lung cancer (NSCLC) who achieved pathological complete response or downstaging following neoadjuvant chemotherapy is better than those with residual metastatic lymph node (LN). However, the prognostic significance of the number of residual metastatic LNs remains unclear. Methods: From January 2001 to January 2006, 42 consecutive patients with stage IIIAN2 (22 patients) and IIIB without pleural effusion (20 patients) were treated with neoadjuvant chemotherapy. Thirty four of 42 patients were pathologically staged by mediastinoscopy. Neoadjuvant chemotherapy consisted of 3 cycles of platinum based doublet (21 patients with gemcitabine, 15 with paclitaxel, and 6 with docetaxel). Results: After neoadjuvant chemotherapy, pathological complete response and downstaging was achieved in one patient and 24 patients, respectively. No pathological LN metastasis was present in 9 patients (21.4%), and LN metastasis was present in 33 patients (78.6%). With a median follow up of 23 months, the 2-year disease free survival (DFS) rate of patients without residual LN metastasis was statistically better than that of patients with residual LN metastasis (46% and 18% in patients with residual LN, p=0.03). Among 33 patients with residual LN metastasis, age (p=0.01), pathological downstaging (p=0.09) and number of residual metastatic LNs (median 14 months in LN =4 vs median 5 months in LN =5; p=0.01) were significant predictors of DFS in univariate analysis. In multivariate analysis, number of residual metastatic LNs was an independent predictor of DFS among patients with residual LN metastasis, irrespective of pathological downstaging. Conclusions: The number of residual metastatic lymph nodes following neoadjuvant chemotharpy is an independent predictor of DFS in patients with stage III NSCLC.
No significant financial relationships to disclose.
Controversy remains over the appropriate postoperative management for patients with stage Ia non-small cell lung cancer who underwent complete surgical resection as a result of a heterogeneous prognosis. We aimed to identify the predictive factors for recurrence in these patients to aid in the decision making.
We reviewed 344 patients with stage Ia non-small cell lung cancer to analyze the associations between recurrence-free survival and the following clinicopathologic variables: age, gender, smoking history, family history, preoperative serum carcinoembryonic antigen level, type of surgical resection, tumor location, tumor histology, lymphovascular invasion, tumor differentiation, and pathologic T status.
Cox multivariate survival analysis revealed that central tumor location (P = .019), stage T1b (P = .006), high histologic grade (including large cell carcinoma, solid predominant, micropapillary predominant, and invasive mucinous adenocarcinoma, P = .007), poor differentiation (P = .022), and lymphovascular invasion (P = .035) were independently associated with recurrence-free survival. A nomogram for predicting the probability of 3-year recurrence-free survival was developed using the 5 variables. This model shows good calibration, reasonable discrimination (concordance index = 0.733), and small overfitting (2.6%) demonstrated by bootstrapping.
We developed a clinicopathologic prediction model for postoperative recurrence in stage Ia non-small cell lung cancer. This model can help with the selection of appropriate postoperative therapeutic strategies for these patients.
We aimed to assess the prognostic significance of microscopic vessel invasion (MVI) and visceral pleural invasion (VPI) in non-small cell lung cancer (NSCLC).
VPI is included in the current tumor-node-metastasis (TNM) classification in NSCLC; however, MVI is not incorporated in TNM classification.
From August 1992 to December 2009, 2657 consecutive patients with pathological T1-4N0-2M0 NSCLC underwent complete resection. In addition to conventional staging factors, we evaluated MVI histologically and analyzed its significance in NSCLC recurrence prognosis. The recurrence-free period in several NSCLC subgroups was analyzed using the Kaplan-Meier method and Cox regression analysis.
The proportion of patients with a 5-year recurrence-free period was 52.6% and 87.5%, respectively, in those with and without MVI (P < 0.001). Multivariate analysis showed that MVI, similarly to VPI, was found to be an independently significant predictor of recurrence [hazard ratio (HR): 2.78]. In particular, MVI and VPI were the 2 strongest significant independent predictors of recurrence in 1601 patients with pathological stage I disease treated without adjuvant chemotherapy (HR: 2.74 and 1.84, respectively). In each T subgroup analysis, evident and significant separation of the recurrence-free proportion curves were observed among the 3 groups (VPI and MVI absent, VPI or MVI present, and VPI and MVI present).
This study demonstrated that MVI was a significant independent risk factor for recurrence in patients with a resected T1-4N0-2M0 NSCLC. Further data on MVI prognostic impact should be collected for the next revision of the TNM staging system.
Background:
Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy.
Methods:
We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat.
Findings:
The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup.
Interpretation:
The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy.
Funding:
UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.
Lymphovascular invasion (LVI) is considered a high-risk pathologic feature in resected non-small cell carcinoma (NSCLC). The ability to stratify stage I patients into risk groups may permit refinement of adjuvant treatment recommendations. We performed a systematic review and meta-analysis to evaluate whether the presence of LVI is associated with disease outcome in stage I NSCLC patients.
A systematic search of the literature was performed (1990 to December 2012 in MEDLINE/EMBASE). Two reviewers independently assessed the quality of the articles and extracted data. Pooled hazard ratios (HRs) and 95% confidence intervals (CI) were estimated with a random effects model. Two end points were independently analyzed: recurrence-free survival (RFS) and overall survival (OS). We analyzed unadjusted and adjusted effect estimates, resulting in four separate meta-analyses.
We identified 20 published studies that reported the comparative survival of stage I patients with and without LVI. The unadjusted pooled effect of LVI was significantly associated with worse RFS (HR, 3.63; 95% CI, 1.62 to 8.14) and OS (HR, 2.38; 95% CI, 1.72 to 3.30). Adjusting for potential confounders yielded similar results, with RFS (HR, 2.52; 95% CI, 1.73 to 3.65) and OS (HR, 1.81; 95% CI, 1.53 to 2.14) both significantly worse for patients exhibiting LVI.
The present study indicates that LVI is a strong prognostic indicator for poor outcome for patients with surgically managed stage I lung cancer. Future prospective lung cancer trials with well-defined methods for evaluating LVI are necessary to validate these results.
Although lobectomy is the standard surgical procedure for operable non-small cell lung cancer (NSCLC), sublobar resection also has been undertaken for various reasons. The aim of this study was to identify risk factors of locoregional recurrence and poor disease-specific survival in patients with clinical stage IA NSCLC undergoing sublobar resection.
We retrospectively reviewed 328 patients with clinical stage IA NSCLC who underwent segmentectomy or wedge resection. Demographic, clinical, and pathologic factors were analyzed using the log-rank test as univariate analyses, and all factors were entered into a Cox proportional hazards regression model for multivariate analyses to identify independent predictors of locoregional recurrence and poor disease-specific survival.
The 5- and 10-year locoregional recurrence-free probabilities were 84.8% and 83.6%, respectively, and the 5- and 10-year disease-specific survivals were 83.6% and 73.6%, respectively. Four independent predictors of locoregional recurrence were identified: wedge resection (hazard ratio [HR], 5.787), microscopic positive surgical margin (HR, 3.888), visceral pleural invasion (HR, 2.272), and lymphatic permeation (HR, 3.824). Independent predictors of poor disease-specific survival were identified as follows: smoking status (Brinkman Index; HR, 1.001), wedge resection (HR, 3.183), microscopic positive surgical margin (HR, 3.211), visceral pleural invasion (HR, 2.553), and lymphatic permeation (HR, 3.223). All 4 predictors of locoregional recurrence also were identified as independent predictors of poor disease-specific survival.
Segmentectomy should be the surgical procedure of first choice in patients with clinical stage IA NSCLC who are being considered for sublobar resection. Patients having tumors presenting with no suspicious of pleural involvement would be suitable candidates for sublobar resection.
To define subgroups at high risk of local recurrence (LR) after surgery for non-small cell lung cancer using a recursive partitioning analysis (RPA).
This Institutional Review Board-approved study included patients who underwent upfront surgery for I-IIIA non-small cell lung cancer at Duke Cancer Institute (primary set) or at other participating institutions (validation set). The 2 data sets were analyzed separately and identically. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered an LR. Recursive partitioning was used to build regression trees for the prediction of local recurrence-free survival (LRFS) from standard clinical and pathological factors. LRFS distributions were estimated with the Kaplan-Meier method.
The 1411 patients in the primary set had a 5-year LRFS rate of 77% (95% confidence interval [CI], 0.74-0.81), and the 889 patients in the validation set had a 5-year LRFS rate of 76% (95% CI, 0.72-0.80). The RPA of the primary data set identified 3 terminal nodes based on stage and histology. These nodes and their 5-year LRFS rates were as follows: (1) stage I/adenocarcinoma, 87% (95% CI, 0.83-0.90); (2) stage I/squamous or large cell, 72% (95% CI, 0.65-0.79); and (3) stage II-IIIA, 62% (95% CI, 0.55-0.69). The validation RPA identified 3 terminal nodes based on lymphovascular invasion (LVI) and stage: (1) no LVI/stage IA, 82% (95% CI, 0.76-0.88); (2) no LVI/stage IB-IIIA, 73% (95% CI, 0.69-0.80); and (3) LVI, 58% (95% CI, 0.47-0.69).
The risk of LR was similar in the primary and validation patient data sets. There was discordance between the 2 data sets regarding the clinical factors that best segregate patients into risk groups.
Objective:
The aim of this study was to assess the influence of lymphatic and vascular invasion on overall survival in patients with surgically resected non-small cell lung cancer (NSCLC) without lymph node and distant metastases.
Methods:
From January 1999 to December 2009, a total of 190 NSCLC patients with node-negative pT1-pT4 disease underwent radical resection with lymphadenectomy. Pathologic reports were reclassified to the TNM-7 version, and the influence of lymphatic and vascular invasion on overall survival was examined using Kaplan-Meier and adjusted Cox proportional hazards analyses.
Results:
Lymphatic invasion was present in 34 (17.9%) and vascular invasion in 28 (14.7%) of 190 cases. Lymphatic and vascular invasions were correlated with higher Union for International Cancer Control stages (P = .056 and P = .011, respectively) and poor differentiated tumors (P = .051 and P = .012, respectively). There was no difference between pT1a and pT1b tumors in the presence of lymphatic (P = .912) or vascular (P = .134) invasion. Survival analyses revealed lymphatic (P < .001) and vascular (P = .008) invasion as statistically significant for the entire study population. Multivariable Cox analysis adjusted for age, Union for International Cancer Control stage, and lymphatic and vascular invasion confirmed lymphatic, but not vascular, invasion as an independent prognostic factor (P < .001; hazard ratio, 3.002; 95% confidence interval, 1.780-5.061). Especially in early stages, lymphatic invasion was associated with poorer overall survival in pT1a (P < .001), pT1b (P = .019), and pT2a (P = .028) tumors.
Conclusions:
Lymphatic invasion represents an independent risk factor for node-negative NSCLC. Its implications on therapy decision making should be further evaluated, especially in early stages.
Background:
We investigated blood vessel invasion (BVI) as a possible negative prognostic factor in patients with stage I non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification.
Methods:
Between 1999 and 2007, a total of 694 consecutive patients with pathological stage I NSCLC underwent complete resection with systematic lymph node dissection at Tokyo Medical University Hospital. All sections of the specimens were stained by Elastica van Gieson to visualize elastic fibers and were examined to determine the prognostic symptoms of BVI. We statistically analyzed the association between BVI and clinicopathologic factors, as well as clinical outcomes.
Results:
BVI was detected in 201 patients with stage I NSCLC (29.0%). The 5-year overall survival (OS) rates of the non-BVI and BVI patients were 90.5% and 66.0%, respectively (p < 0.0001). BVI was found to be a significant independent prognostic factor by multivariate survival analysis in stage IA and stage IB NSCLC (HR 2.591, p < 0.001; HR 2.347, p = 0.009, respectively). The 5-year OS rate of patients with BVI was significantly worse than that of patients without BVI in the T1a (94.5% vs 87.5%, p < 0.0001), T1b (82.7% vs 65.9%, p < 0.0001), and T2a (90.9% vs 61.8%, p < 0.0001) subgroups.
Conclusion:
We identified the presence of BVI as an independent poor prognostic factor in patients with stage I NSCLC. In the future revision of the TNM staging system, the routine use of elastic fiber stains in pathological evaluations of lung cancer for BVI determination might be recommended, and tumors with BVI should be upstaged to the higher current T staging.
The prognostic value of vascular microinvasion (VMI) in non-small cell lung cancer (NSCLC) has been a matter of discussion in recent decades. The last T N M classification does not take VMI into account, but many points remain questionable.
A retrospective study was performed of patients undergoing operations for NSCLC during a 20-year period. Lymphatic VMI (LVMI) was classified as group (G) 1, blood VMI (BVMI) as G2, LVMI and BVMI as G3, and no VMI as G4. The demographic, pathologic, T N M characteristics, and long-term survival of each group were analyzed.
A total of 3,868 patients (G1, 334; G2, 642; G3, 172; G4, 2,720), mean age 61.9 ± 10.1 years, underwent different types of resection, with complete lymphadenectomy in 88.5%. Adenocarcinomas were more frequent in G1 and G3, and squamous cell carcinomas in G2. In G2, more N1 tumors needed more extensive resections. G1 was equally distributed regardless of tumor size, but G2 prevalence increased with augmenting size. Nodules in the same lobe were significantly more frequent in LVMI than in BVMI. After exclusion of patients with R1 and R2 resections, multivariate analysis confirmed that LVMI and BVMI were independent prognostic factors as well as age, sex, type of resection, T extension, and N involvement.
VMI is generally associated with a poorer prognosis. LVMI is less frequent than BVMI but has lower survival rates. The benefit of adjuvant therapy in VMI patients needs to be evaluated.
Persistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III-N2 non-small cell lung cancer patients. This population has high rates of local-regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients.
In all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local-regional failure, distant failure, and overall survival.
All patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p=0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p=0.003). However, additional postoperative chemotherapy had no affect on local-regional failure.
Aggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery.
The American College of Surgery Oncology Group Z0030 study was a prospective randomized study that showed that mediastinal lymph node sampling (MLNS) offered similar results to mediastinal lymph node dissection (MLND) in patients with non-small cell lung cancer (NSCLC). However, that study only randomized patients after thorough samplings that were negative on frozen section in several N2 and N1 nodal stations. The purpose of this study was to evaluate the effect of MLND to the more common practice of ruling out N2 disease preoperatively and then resection without sending lymph nodes for frozen section.
This is a retrospective study of patients clinically staged as N0 with NSCLC. The incidence of pathologic N2 disease reported by the Society of Thoracic Surgeons (STS) database was considered to represent MLNS and it was compared with our patients who underwent complete MLND.
Between January 2002 and December 2009, 1,358 patients clinically staged as N0 underwent lobectomy or segmentectomy and MLND (not MLNS). Our incidence of pathologic N2 disease in 1,107 patients who underwent lobectomy was 10.6% compared with 9.4% in the 24,896 STS lobectomy patients (p=0.196). Our incidence of pathologic N2 disease in 251 patients who underwent segmentectomy was 13.0% compared with 5.3% in the 2,150 STS segmentectomy patients (p<0.001).
When complete MLND is performed in patients during pulmonary resection who are clinically node negative (have benign N2 nodes after selective endobronchial or esophageal ultrasound or mediastinoscopy) without using intraoperative frozen section of N2 or N1, more patients are pathologically staged with N2 disease; thus, more are considered for adjuvant chemotherapy. The impact on survival in these patients is unproven.
Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy resulted in improved outcome, and to determine predictive factors for pCR.
Eligible patients with stage-IB or -II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique phase-III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen.
Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival was 80.0% compared with 55.8% in the non-pCR group (p = 0.0007). In multivariate analyses, pCR was a favorable prognostic factor of overall survival (relative risk = 0.34; 95% confidence interval = 0.18-0.64) in addition to squamous-cell carcinoma, weight loss less than or equal to 5%, and stage-IB disease. Five-year disease-free survival was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p < 0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (odds ratio [OR] = 4.30; 95% confidence interval = 1.90-9.72).
Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in stage-IB-II NSCLC. Our study is the largest published series evaluating pCRs after preoperative chemotherapy. The only factor predictive of pCR was squamous-cell carcinoma. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen.
The appropriate therapeutic strategy and postoperative management for patients with stage IA non-small-cell lung cancer (NSCLC) still remain a matter of debate because of the prognostic heterogeneity of this population, including the risk of cancer recurrence. The objective of the current study was to identify the clinicopathological factors that affect overall prognosis and cancer recurrence of stage IA NSCLC.
We reviewed the data of 532 patients in whom complete resection of stage IA NSCLC had been performed. Overall survival and recurrence-free proportion (RFP) were estimated using the Kaplan-Meier method. RFP was estimated from the date of the primary tumor resection to the date of the first recurrence or last follow-up. We performed univariate and multivariate analyses to determine the independent prognostic factors.
On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histological differentiation (hazard ratio [HR] = 1.925), blood-vessel invasion (HR = 1.712), and lymph-vessel invasion (HR = 1.751). On subgroup analyses combining these risk factors, the 5-year RFP was 91.3% for patients with no risk factors, 79.5% for those with either poorly differentiated carcinoma or vascular invasion, (p < 0.001 for both), and 62.9% for those with both poorly differentiated carcinoma and vascular invasion (p = 0.068).
These results indicated that vascular invasion and tumor differentiation have a significant impact on the prediction of cancer recurrence in patients with stage IA NSCLC. Patients with these predictive factors of recurrence may be good candidates for adjuvant chemotherapy.
Lymphovascular space invasion (LVI) is an established negative prognostic factor and an indication for postoperative radiation therapy in many malignancies. The purpose of this study was to evaluate LVI in patients with early-stage non-small-cell lung cancer, undergoing surgical resection.
All patients who underwent initial surgery for pT1-3N0-2 non-small-cell lung cancer at Duke University Medical Center from 1995 to 2008 were identified. A multivariate ordinal regression was used to assess the relationship between LVI and pathologic hilar and/or mediastinal lymph node (LN) involvement. A multivariate Cox regression analysis was used to evaluate the relationship of LVI and other clinical and pathologic factors on local failure (LF), freedom from distant metastasis (FFDM), and overall survival (OS). Kaplan-Meier methods were used to generate estimates of LF, FFDM, and OS in patients with and without LVI.
One thousand five hundred and fifty-nine patients were identified. LVI was independently associated with the presence of regional LN involvement (p < 0.001) along with lobar (versus sublobar) resections (p < 0.001), and an open thoracotomy (versus video-assisted thoracoscopic surgery). LVI was not independently associated with LF on multivariate analysis (hazard ratio [HR] = 1.23, p = 0.25), but was associated with a lower FFDM (HR 1.52, p = 0.005) and OS (HR 1.26, p = 0.015). In addition, multivariate analysis showed that LVI was strongly associated with increased risk of developing distant metastases (HR = 1.75, p = 0.006) and death (HR = 1.53, p = 0.003) in adenocarcinomas but not in squamous carcinomas.
LVI is associated with an increased risk of harboring regional LN involvement. LVI is also an adverse prognostic factor for the development of distant metastases and long-term survival.
Angiolymphatic invasion (ALI), representing lymphatic invasion (Ly) and intratumoral vascular invasion (V), is considered to be a useful prognostic factor for pathological stage I non-small cell lung carcinoma (NSCLC). However, the types of tumor for which prognoses are most influenced by ALI positivity have not previously been discussed, nor has the question of whether these findings should influence postoperative therapeutic decision-making after complete resection. The present study investigated 195 cases of stage I NSCLC treated by potentially curative surgical resection of the primary tumor and systematic lymphadenectomy. ALI-positive (ALI(+)) results were found in 31.8% of tumors, and 5.1% exhibited both Ly(+) and V(+). Five-year recurrence-free survival was significantly lower in ALI(+) cases (50.6%) than in ALI(-) cases (85.9%; p<0.0001, log-rank test). In particular, 5-year recurrence-free survival rate was only 10.0% for Ly(+)V(+) cases. ALI(+) correlated with high age, male sex, tumor size (>2.0 cm), elevated preoperative serum carcinoembryonic antigen level (≥5.0 ng/mL), high maximum standard uptake value (SUVmax) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) (≥5.0), pleural invasion, and histological classification of non-adenocarcinoma (ADC). According to histopathological subset analyses, ALI(+) was associated with shorter recurrence-free survival than ALI(-) only among ADC patients (p<0.0001, log-rank test), and not among non-ADC patients (p=0.7710). High preoperative serum CEA level, high SUVmax on FDG-PET, pleural invasion, Ly(+), and V(+) were significant risk factors for recurrence in univariate Cox survival analysis among stage I ADC patients. Importantly, Ly(+) and V(+) were identified as independent risk factors for recurrence by multivariate analysis. Histopathological detection of ALI as a risk factor for recurrence should be considered for inclusion in the staging criteria and as additional information for determining postoperative adjuvant treatment of stage I NSCLC, particularly among ADC patients, but not among non-ADC patients.
Long-term survival after R0 resection for non-small cell lung cancer (NSCLC) is less than 50%. The majority of mortality after resection is related to tumor recurrence. The purpose of this study was to identify independent perioperative and pathologic variables that are associated with NSCLC recurrence after complete surgical resection.
A retrospective examination was performed of a prospectively maintained database of patients who underwent resection for NSCLC from July 1999 to August 2008 at a single institution. Clinicopathologic variables were evaluated for their influence on time to recurrence. Cox's proportional regression hazard model examined the association of recurrence in NSCLC.
A total of 1,143 patients met inclusion criteria and had complete follow-up information. Of these patients, 378 (33.1%) had recurrence of the primary cancer. Median follow-up was 24 months (range, 3-134 months). Preoperative tumor maximum standardized uptake value (SUVmax) greater than 5 was associated with increased risk of recurrence (hazard ratio [HR], 1.81; p=0.01). Preoperative radiation was independently associated with recurrence (HR, 1.98; p=0.05) as well as the presence of pathologic stage II and stage III disease (stage II: HR, 2.53; p=0.05; stage III: HR, 6.49; p=0.006). Subgroup analysis found that sublobar resection was also associated with locoregional recurrence after resection (HR, 4.17; p=0.02) and lymphovascular invasion of distant recurrence (HR, 4.21; p=0.002).
In the largest series reported to date on postresectional recurrence of NSCLC, SUVmax greater than 5, increasing pathologic stage, and the administration of preoperative radiation were independently associated with NSCLC recurrence after resection. Sublobar resection was independently associated with locoregional recurrence, and lymphovascular invasion was associated with distant recurrence.
We evaluated the ability of histopathologic response criteria to predict overall survival (OS) and disease-free survival (DFS) in patients with surgically resected non-small cell lung cancer (NSCLC) treated with or without neoadjuvant chemotherapy.
Tissue specimens from 358 patients with NSCLC were evaluated by pathologists blinded to the patient treatment and outcome. The surgical specimens were reviewed for various histopathologic features in the tumor including percentage of residual viable tumor cells, necrosis, and fibrosis. The relationship between the histopathologic findings and OS was assessed.
The percentage of residual viable tumor cells and surgical pathologic stage were associated with OS and DFS in 192 patients with NSCLC receiving neoadjuvant chemotherapy in multivariate analysis (p = 0.005 and p = 0.01, respectively). There was no association of OS or DFS with percentage of viable tumor cells in 166 patients with NSCLC who did not receive neoadjuvant chemotherapy (p = 0.31 and p = 0.45, respectively). Long-term OS and DFS were significantly prolonged in patients who had ≤10% viable tumor compared with patients with >10% viable tumor cells (5 years OS, 85% versus 40%, p < 0.0001 and 5 years DFS, 78% versus 35%, p < 0.001).
The percentages of residual viable tumor cells predict OS and DFS in patients with resected NSCLC after neoadjuvant chemotherapy even when controlled for pathologic stage. Histopathologic assessment of resected specimens after neoadjuvant chemotherapy could potentially have a role in addition to pathologic stage in assessing prognosis, chemotherapy response, and the need for additional adjuvant therapies.
Patients achieving a mediastinal pathologic complete response with neoadjuvant chemotherapy have improved outcomes compared with patients with persistent N2 disease. How to best manage this latter group of patients is unknown, prompting a review of our institutional experience.
All patients who initiated neoadjuvant therapy for non-small-cell lung cancer from 1995 to 2008 were evaluated. The patients were excluded if they had received preoperative radiotherapy, had had a mediastinal pathologic complete response, or had evidence of disease progression after neoadjuvant chemotherapy. The clinical endpoints were calculated using the Kaplan-Meier product-limit method and compared using a log-rank test.
A total of 28 patients were identified. The median follow-up period was 24 months. Several neoadjuvant chemotherapy regimens were used, most commonly carboplatin with vinorelbine (36%) or paclitaxel (32%). A partial response to chemotherapy was noted in 23 (82%) and stable disease was noted in 5 (18%) on postchemotherapy imaging. Resection was performed in 22 of 28 patients, consisting of lobectomy in 14, pneumonectomy in 2, and wedge/segmentectomy in 6 (21/22 R0, 1/22 R1). There were no postoperative deaths. Postoperative therapy (radiotherapy and/or additional chemotherapy) was administered to 12 patients (55%). The remaining 6 patients generally received definitive radiotherapy with or without additional chemotherapy. The overall and disease-free survival rate at 1, 3, and 5 years was 75%, 37%, and 37% and 50%, 23%, and 19%, respectively. The survival rate at 5 years was similar between patients undergoing resection (34%) and those receiving definitive radiotherapy with or without chemotherapy (40%; P = .73).
Disease-free and overall survival was sufficiently high to warrant aggressive local therapy (surgery or radiotherapy) in patients with persistent N2 disease after neoadjuvant chemotherapy.
In stage IA non-small cell lung cancer (NSCLC), lobectomy and mediastinal lymph node dissection is considered the standard treatment. However, 20% to 30% of patients have cancer recurrences. The purpose of this study was to determine the patterns and risk factors for recurrence in patients with stage IA NSCLC.
We retrospectively reviewed the medical records of 201 patients who had confirmed stage IA NSCLC by lobectomy and complete lymph node dissection.
There were 131 male patients with a mean age of 60.68±9.26 years. The median follow-up period was 41.4 months. Recurrences were reported in 16 patients. One hundred fourteen and 87 patients were T1a (≤2 cm) and T1b (>2 cm to ≤3 cm), respectively. The pathologic results were as follows: adenocarcinomas and bronchioloalveolar carcinomas (n=134); squamous cell carcinomas (n=57); and other diagnoses (n=10). Tumor necrosis and lymphatic invasion were significant adverse risk factors for recurrence based on univariate analysis. Multivariate analysis showed that tumor necrosis was the only significant risk factor to predict cancer recurrence (hazard ratio, 4.336; p=0.032). The 5-year overall survival was 94.8% for necrosis-negative patients and 86.2% for necrosis-positive patients (p=0.04). The 5-year disease-free survival was 92.1% for necrosis-negative patients and 78.9% for necrosis-positive patients (p=0.016).
Tumor necrosis was shown to be an adverse risk factor for survival and recurrence in patients with stage IA NSCLC. Thus, close observation and individualized adjuvant therapy might be helpful for patients with stage IA NSCLC with tumor necrosis.
A radical resection is considered to be the most effective treatment for resectable non-small cell lung cancer. However, even when resected in early stages (T1aN0, T1bN0) up to 20% of patients will experience recurrence. The aim of this retrospective study was to evaluate the prognostic influence of lymphatic vessel invasion (LVI) in stage IA adenocarcinoma patients.
From January 1983 to June 2003, a total of 229 consecutive patients with pT1a or T1b N0 M0 lung adenocarcinoma who had undergone radical resection and lymph node dissection were retrospectively reviewed. Sections stained by the hematoxylin-eosin and the Elastica van Gieson method were examined for the presence of LVI. The overall survival was estimated using the Kaplan-Meier method, log-rank test, and the Cox proportional hazards analysis.
The median follow-up was 81 months. A total of 143 patients (62%) were able to be diagnosed with regard to the presence of LVI, while information was not provided for 86 patients (38%), who were therefore excluded from the study. LVI was noted in 22 of the evaluable patients (15%) and was not seen in the other 121 patients (85%). The 5-year overall survival rate of the LVI-negative group and the LVI-positive group was 94.5 and 70.9%, respectively (P = .003). A multivariate analysis revealed LVI to be an independent predictive factor (hazard ratio: 0.202; P = .001).
LVI is an independent poor prognostic factor in patients with pathologic stage IA adenocarcinoma. The T1a and T1b patients with LVI both might benefit from adjuvant chemotherapy.
In the current study, we analyze the impact of pathologic variables (angiolymphatic invasion, visceral pleural invasion, and tumor inflammation) upon survival outcomes after segmentectomy or lobectomy for stage I non-small cell lung cancer.
A retrospective review was made of 524 patients undergoing resection of stage I non-small cell lung cancer through either lobectomy (n = 285) or anatomic segmentectomy (n = 239). Primary outcome variables include recurrence-free and overall survival. Statistical comparisons were performed with the t test and Fisher's exact test. Recurrence-free and overall survival was estimated utilizing the Kaplan-Maier method, with statistical significance being assessed by the log rank test.
The incidence of angiolymphatic invasion, visceral pleural invasion, and degree of tumor inflammation, as well as morbidity, mortality, and length of stay were similar between segmentectomy and lobectomy. The presence of angiolymphatic invasion or visceral pleural invasion was associated with a significant decrease in recurrence-free survival (p < 0.01) and overall survival (p < 0.01). There was a trend for decreased recurrence with increasing tumor inflammation (mild versus severe, p = 0.066). There was no difference in rates of local recurrence (5.6% versus 7.9%, p = 0.59) or survival (p = 0.455) between segmentectomy and lobectomy, respectively.
Angiolymphatic and visceral pleural invasion appear to be strong adverse prognostic factors after anatomic resection by segmentectomy or lobectomy for stage I non-small cell lung cancer. Overall survival is not affected by the extent of anatomical surgical resection. These data may have implications regarding the role of adjuvant systemic therapy after surgical resection for tumors with these pathologic characteristics.
The aim of this study was to assess the significance of microscopic vascular invasion (MVI) in a population of resected patients with early-stage non-small cell lung cancer (NSCLC), along with an analysis of the effect of the combination of MVI and tumor size for the T-size categories T1a-T2b according to the 2009 7th edition of the tumor, node, metastasis (TNM) classification.
From January 1993 to August 2008, 746 patients with pT1-T2N0 NSCLC received resection at our institution. MVI was ascertained using histopathological and immunohistochemical techniques.
MVI was observed in 257 patients (34%). Prevalence was higher in adenocarcinoma (ADK) than in squamous cell carcinoma (p = 0.002). A significant correlation was found between MVI and ADK (p = 0.03), increased tumor dimension (p = 0.05), and the presence of tumor-infiltrating lymphocytes (p = 0.02). The presence of MVI was associated with a reduced 5-year survival overall (p = 0.003) and in ADK (p = 0.0002). In a multivariate survival analysis, MVI was an indicator of poor survival overall (p = 0.003) and in ADK (p = 0.0005). In each T category (T1a-T2b) of the 2009 TNM staging system, survival of MVI+ patients was significantly lower than the corresponding MVI- patients; T1a and T1b MVI+ patients had a survival similar to MVI- T2 patients.
The finding of MVI in pT1-T2N0 NSCLC is frequent. MVI correlates with adenocarcinoma histotype, increased tumor dimensions, and tumor-infiltrating lymphocytes. The presence of MVI is an independent negative prognostic factor. In our experience, MVI was a stronger prognostic indicator than T size in T1a-T2b categories according to the 2009 TNM staging system.
This study investigated poor prognostic factors in patients with stage IB non-small cell lung cancer (NSCLC) according to the seventh edition of the TNM classification.
Between July 1992 and December 2004, 1,204 consecutive patients with stage I NSCLC diagnosed based on the sixth edition TNM classification underwent complete resection with systematic node dissection. Of these patients, 434 were reclassified as stage IB according to the seventh edition TNM classification. Univariate analyses were performed using the log-rank test to select prognostic factors. The Cox proportional hazards regression model was used for multivariate analyses to identify independent factors indicating an unfavorable prognosis.
On multivariate analyses, two variables were independent significant factors indicating an unfavorable prognosis: presence of intratumoral vascular invasion and presence of visceral pleural invasion. According to subgroup analyses combining these two risk factors, 5-year disease-specific survival probabilities were 93%, 83%, and 73% for patients with zero, one, or two risk factors, respectively. The 5-year disease-specific survival of patients without risk factors was not statistically different from that of patients with stage IA cancer. In addition, the 5-year disease-specific survival curve of patients with two risk factors lay beneath that of patients with T2b or T3N0M0, stage II cancer, and there were no statistically significant differences between them.
We identified the presence of intratumoral vascular invasion and the presence of visceral pleural invasion as independent poor prognostic factors in patients with stage IB NSCLC. When these two factors are combined, higher- and lower-risk subgroups can be identified, which will help to personalize adjuvant chemotherapy.
The seventh edition of TNM classification for non-small cell lung cancer (NSCLC) has been approved. Vascular invasion has been reported as being a strong risk factor; therefore, we reviewed the impact of vascular invasion on new TNM classification.
We reviewed patients with completely resected NSCLC without lymph node metastasis treated at our institute between January 1993 and December 2003. Vascular invasion was examined using Victoria blue-van Gieson stains performed in maximum cut sections of tumor. Correlation between vascular invasion and other clinicopathologic factors, such as age, sex, histology, serum carcinoembryonic antigen (CEA) levels, smoking habitation, and T descriptors, were assessed. In addition, we evaluated the impact of vascular invasion on survival.
A total of 826 patients were analyzed. Median age was 65 years (range, 32-86). Thirty-two percent of patients were > 70 years, 44% were women, 78% had adenocarcinoma, 41% were never smokers, 39% smoked > 30 pack-years, and 31% had elevated serum CEA levels. Vascular invasion was detected in 279 patients (33.8%) and more was observed in patients who were male, did not have adenocarcinoma, were smokers, and had elevated CEA levels. Positive vascular invasion was significantly correlated with worse prognosis compared with negative (5-year survival, 90.5% vs 71.0%, P < .001). This trend was observed in each subgroup of T1a (92.9% vs 72.5%, P < .001), T1b (89.7% vs 77.2%, P = .015), and T2a (86.3% vs 65.6%, P < .001).
Vascular invasion was a strong prognostic factor in the revised TNM classification. Further investigation is warranted to generalize these findings.
Vascular invasion is thought to be a fundamental step in hematogenous metastasis. The aim of this study was to assess whether the qualitative evaluation of vascular invasion according to its location (intratumoral or extratumoral) could provide an appropriate means of predicting the prognostic outcome and potential patterns of recurrence in non-small cell lung cancer.
We reviewed the cases of 1000 consecutive patients in whom complete resection of non-small cell lung cancer had been performed. Sections stained by the Victoria blue van Gieson method were examined for the presence of vascular invasion and the evaluation of its location (v0: absence, n = 540; v1: intratumoral, n = 428; v2: extratumoral, n = 32). Survival was estimated using the Kaplan-Meier method. To determine independent prognostic factors, univariate and multivariate analyses were conducted.
The study cohort included 605 men and 395 women, with a mean age of 66 years (range, 20-90 years). The 5-year overall survival rate of the vascular invasion-negative group and the vascular invasion-positive group was 82.5% and 55.1%, respectively (p < 0.001), and the 5-year overall survival rates of the v1 group and v2 groups were 55.9% and 44.0%, respectively (p = 0.010). Multivariate analysis showed that location of the vascular invasion (v0-1 versus v2) (p = 0.049), age (p = 0.030), tumor size (p = 0.004), lymph node metastasis (p < 0.001), and pleural invasion (p < 0.001) were significant prognostic factors. The proportion of patients who developed distant metastasis was significantly higher in the v2 group than in the v1 group (p = 0.026).
Evaluation of vascular invasion location was a statistically significant predictor of prognosis and potential recurrence patterns.
The purpose of this study was to evaluate the risk of late recurrence in patients who had undergone complete resection for non-small cell lung cancer (NSCLC) and remained recurrence-free for > or = 5 years.
Between 1993 and 2002, 1,358 patients with NSCLC underwent complete primary tumor resection and systematic lymph node dissection. Of these, 819 patients remained recurrence-free for 5 years. Recurrence-free probability was estimated from the benchmark of 5 years after primary tumor resection to the date of first recurrence or last follow-up, using the Kaplan-Meier method. Multivariate Cox regression was used to test the relationship of recurrence-free probability to various clinicopathologic factors.
Of the 819 patients who were free of recurrence at 5 years, 87 (11%) developed a subsequent recurrence. The recurrence-free probabilities at 3 years and 5 years from the point of 5 years after primary tumor resection were 92% and 87%, respectively. The 5-year recurrence-free probabilities from the point of 5 years after primary tumor resection were 81% for patients with intratumoral vascular invasion (P < .001), and 89%, 84%, and 65% for patients with N0, N1, and N2 cancers, respectively (P < .001). Multivariate Cox analysis demonstrated that intratumoral vascular invasion and nodal involvement significantly influenced recurrence 5 years after complete resection (P = .030, P = .022, respectively).
Patients with NSCLC with selected tumor characteristics have a significant risk of late recurrence. Therefore, 5 years might not be a sufficient amount of time to declare that NSCLC has been cured.
Many studies focus on bronchial microscopic residual disease (R1) after resection for lung cancer, although R1 also concerns vascular and soft tissues. Our purpose was to study the R1 prognosis at different resection margins and to compare it with the prognosis for those having complete resection (R0).
We reviewed the clinical records of 4,026 patients from two centers who underwent surgery in view of cure. Despite perioperative frozen section, 216 patients (5.4%) proved R1 and were classified into seven types according to R1 anatomic site: bronchus, peribronchus, great vessels and atrium, mediastinum and pericardium, chest wall, lung tissue, and lymph nodes. Patients who were classified as R0 and R1 were compared, and R1 patients were further studied according to R1 margins.
Frequency of R1 increased with the T and N values and type of resection (lobectomies, 3.3% [70 of 2,041 patients]; pneumonectomies, 8.8% [126 of 1,308 patients]; p < 10(-6)). Five-year survival rates for R1 patients were lower than those for R0 patients (20% versus 46%; p < 10(-6)), and were not modified by the degree of T and N involvement or adjuvant therapy, but were better in bronchial and peribronchial (48.4% of R1 patients) than in extrabronchial R1 (26.3% versus 15.6%; p = 0.023). Multivariate analysis confirmed R1 to be an independent factor of poor prognosis (p = 0.0008), after N, T, and age.
Long-term survival is possible in case of an R1 margin, but 5-year survival rates are jeopardized. Poor efficacy of adjuvant therapy and global outcome indicate advanced disease or reflect tumor cell aggressiveness, rather than surgical insufficiency, when prevention of R1 margins is guided by frozen-section examination and scrupulously respected.
Lung adenocarcinomas 2 cm or less in diameter were studied to develop histologic criteria predicting the outcome.
We reviewed 510 consecutive lung adenocarcinomas 2 cm or less in diameter and assessed three histologic parameters to implement a histologic scoring system: lymphovascular invasion, maximum diameter of the nonbronchioloalveolar carcinoma (BAC) component, and percentage of the solid, cribriform, and/or papillary component in the entire tumor volume (%solid/cribriform/papillary). One point was given to each of lymphovascular invasion-positive, non-BAC >10 mm and %solid/cribriform/papillary > or =30%, and by the sum of these points, a score of 0 to 3 was assigned for each tumor. We also evaluated minimally invasive adenocarcinomas comprising non-BAC < or =5 mm, Sakurai grades 1 and 2.
Five-year disease-free survival rates of 287 patients with a histologic score of 0, 69 with a score of 1, 64 with a score of 2, and 90 with a score of 3 were 98.9%, 92.4%, 78.4%, and 54.0%, respectively. The 510 tumors included 129 noninvasive and 127 minimally invasive adenocarcinomas. None of these tumors recurred. In remaining 254 patients with overtly invasive adenocarcinomas, 5-year disease-free survival rates in 51 with a histologic score of 0, 49 with a score of 1, 64 with a score of 2, and 90 with a score of 3 were 95.9%, 89.2%, 79.4%, and 54.2%, respectively.
The histologic scoring system comprising lymphovascular invasion-positive, non-BAC >10 mm and %solid/cribriform/papillary > or =30% is able to predict the outcome of lung adenocarcinomas 2 cm or less in diameter not only in all cases but also in overtly invasive adenocarcinomas. Minimally invasive adenocarcinomas did not recur in this large series.
For more than 50 years, small cell lung cancer (SCLC) has been staged mainly as either limited or extensive stage disease. Small published series of resected SCLC have suggested that the tumor, node, metastases (TNM) pathologic staging correlates with the survival of resected patients. Recent analysis of the 8088 cases of SCLC in the International Association for the Study of Lung Cancer (IASLC) database demonstrated the usefulness of clinical TNM staging in this malignancy. The IASLC data bank contains an unprecedented number of resected SCLC cases with pathologic staging information. This analysis was undertaken to examine the impact of the TNM system on the pathologic staging of SCLC and to assess the new IASLC proposals in this subtype of lung cancer.
Using the IASLC database, survival analyses were performed for resected patients with SCLC. Prognostic groups were compared, and the new IASLC TNM proposals were applied to this population and to the Surveillance, Epidemiology, and End Results (SEER) database.
The IASLC database contained 349 cases of resected SCLC where pathologic TNM staging was available. Survival after resection correlated with both T and N category with nodal status having a stronger influence on survival. Stage groupings using the 6th edition of TNM clearly identify patient subgroups with different prognoses. The IASLC proposals for the 7th edition of TNM classification also apply to this population and to the SEER database.
This analysis further strengthens our previous recommendation to use TNM staging for all SCLC cases.
We investigated the impact of new biological prognostic factors is in 28 patients receiving a median of two courses of cisplatin-based chemotherapy with (n = 14) or without (n = 14) radiation and operation for stage IIIB (T4) non-small cell lung cancer (NSCLC). After induction therapy, 5 patients had a complete and 21 a partial response; 2 had a stable disease. A complete resection was made in 26 patients (93%). Five patients (18%) had their primary tumour and involved vestiges completely sterilized. In the remaining 23, the majority of the tumours showed abnormalities in the p53 gene expression (56%), harboured proliferating cells (91%) and induced angiogenesis (91%). Peritumoural blood and lymphatic vessel invasion (PBLVI) by tumour emboli was observed in 6 tumours. With a median follow-up of 25 months, overall 3-year survival was 48%; disease-free survival (DFS) has not been reached yet. The only significant factor influencing DFS in multivariate analysis was PBLVI by tumour cells; PBLVI-positive patients had a significantly higher likelihood ratio (P = 0.000001) of developing metastasis than their PBLVI-negative counterparts. This study documents the prognostic implication of PBLVI by tumour cells in T4 NSCLC.
The prognosis of patients with stage III non-small-cell lung cancer (NSCLC) who achieve a pathological complete response or downstaging following neoadjuvant therapies are better than the prognosis of patients with residual metastatic lymph nodes (LN). However, the prognostic significance of the number of residual metastatic LNs remains unclear. From January 2001 to January 2006, 42 consecutive patients with stage IIIAN2 (22 patients) and IIIB without pleural effusion (20 patients) were treated with neoadjuvant chemotherapy. Thirty-four (81.0%) of the 42 patients were pathologically staged by mediastinoscopy. Neoadjuvant chemotherapy consisted of 3 cycles of platinum-based doublet (21 patients with gemcitabine, 15 with paclitaxel, and 6 with docetaxel). After neoadjuvant chemotherapy, a pathological complete response was achieved in one patient and downstaging was achieved in 24 patients. Pathological LN metastasis was absent in 9 patients (21.4%) and present in 33 patients (78.6%). With a median follow-up of 23 months, the 2-year disease-free survival (DFS) rate of patients without residual LN metastasis was statistically better than that of patients with residual LN metastasis (46% vs. 18% respectively, P=0.03). Among 33 patients with residual LN metastasis, age (P=0.01), pathological downstaging (P=0.098) and the number of residual metastatic LNs (median 14 months in 1-4 LN vs. median 5 months in LN > or =5; P=0.011) were significant predictors of DFS in univariate analysis. In multivariate analysis, the number of residual metastatic LNs was an independent predictor of DFS among patients with residual LN metastasis, irrespective of pathological downstaging. The number of residual metastatic lymph nodes following neoadjuvant chemotherapy is an independent predictor of DFS in patients with stage III NSCLC.
Operative management of patients with persistent N2 disease after induction therapy is still debated.
One hundred fifty-three consecutive patients underwent pneumonectomy from January 1999 until July 2005; 28 patients (18.3%) had persistent N2 disease after induction therapy (group 1), 32 patients (20.9%) had pathologic stage N0 or N1 after induction therapy (group 2), and 93 patients (60.8%) with pathologic N2 disease underwent immediate surgery (group 3). Short-term end points were operative mortality at 30 and 90 days and major complications. Long-term end points were 5-year survival and disease-free survival rates.
Demographics of the three groups were similar (age, sex, side of operation, type of chemotherapy, smoking status, and comorbidity such as coronary artery disease, diabetes, and chronic obstructive pulmonary disease). Thirty-day postoperative mortality was 10.7% in group 1, 3.1% in group 2 (p = 0.257), and 4.3% in group 3 (p = 0.201); 90-day postoperative mortality was 10.7% in group 1, 12.5% in group 2 (p = 0.577), and 9.7% in group 3 (p = 0.558). Incidence of major postoperative complications was similar. Five-year survival rate was 32.2% (median, 28 months; 95% confidence interval, 7 to 43) in group 1, 34.8% (median, 27 months; 95% confidence interval, 7 to 47) in group 2 (p = 0.685), and 12.4% (median, 15 months; 95% confidence interval, 11 to 19) in group 3 (p = 0.127). No statistical difference was found in terms of 5-year event-free survival, or regarding the side of pneumonectomy.
Our results suggest that pneumonectomy is justified in patients with persistent N2 disease after induction chemotherapy.
The revised TNM staging system for lung cancer
- Rami-Porta
Factors associated with the development of brain metastases: analysis of 975 patients with early stage nonsmall cell lung cancer
- J L Hubbs
- J A Boyd
- D Hollis
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