Nabil P. Rizk

Optimum lymphadenectomy for esophageal cancer.

Objective:Using Worldwide Esophageal Cancer Collaboration data, we sought to (1) characterize the relationship between survival and extent of lymphadenectomy, and (2) from this, define optimum lymphadenectomy. Summary Background Data:What constitutes optimum lymphadenectomy to maximize survival is controversial because of variable goals, analytic methodology, and generalizability of the underpinning data. Methods:A total of 4627 patients who had esophagectomy alone for esophageal cancer were identified from the Worldwide Esophageal Cancer Collaboration database. Patient-specific risk-adjusted survival was estimated using random survival forests. Risk-adjusted 5-year survival was averaged for each number of lymph nodes resected and its relation to cancer characteristics explored. Optimum number of nodes that should be resected to maximize 5-year survival was determined by random forest multivariable regression. Results:For pN0M0 moderately and poorly differentiated cancers, and all node-positive (pN+) cancers, 5-year survival improved with increasing extent of lymphadenectomy. In pN0M0 cancers, no optimum lymphadenectomy was defined for pTis; optimum lymphadenectomy was 10 to 12 nodes for pT1, 15 to 22 for pT2, and 31 to 42 for pT3/T4, depending on histopathologic cell type. In pN+M0 cancers and 1 to 6 nodes positive, optimum lymphadenectomy was 10 for pT1, 15 for pT2, and 29 to 50 for pT3/T4. Conclusions:Greater extent of lymphadenectomy was associated with increased survival for all patients with esophageal cancer except at the extremes (TisN0M0 and ≥7 regional lymph nodes positive for cancer) and well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 for pT2, and ≥30 for pT3/T4 is recommended.

Adenocarcinoma of the gastroesophageal junction: influence of esophageal resection margin and operative approach on outcome.

Objective:To determine whether the length of esophageal resection or the operative approach influences outcome for patients with adenocarcinoma of the gastroesophageal junction (GEJ). Summary Background Data:While R0 resection remains the mainstay of curative treatment of patients with GEJ cancer, the optimal length of esophageal resection remains controversial. Methods:Patients with Siewert I, II, or III adenocarcinoma who underwent complete gross resection without neoadjuvant therapy were identified from a prospectively maintained database. Proximal margin lengths were recorded ex vivo as the distance from the gross tumor edge to the esophageal transection line. Operative approaches were grouped into gastrectomy (limited esophagectomy) or esophagectomy (extended esophagectomy). Results:From 1985 through 2003, 505 patients underwent R0/R1 gastrectomy (n = 153) or esophagectomy (n = 352) without neoadjuvant treatment. There were no differences in R1 resection rate, number of nodes examined or operative mortality between gastrectomy and esophagectomy. Univariate analysis found >3.8 cm to be the ex vivo proximal margin length (approximately 5 cm in situ) most predictive of improved survival. Multivariable analysis in patients who underwent R0 resection with ≥15 lymph nodes examined (n = 275) found the number of positive lymph nodes, T stage, tumor grade, and ex vivo proximal margin length >3.8 cm to be independent prognostic factors. Subset analysis found that the benefit associated with >3.8 cm margin was limited to patients with T2 or greater tumors and ≤6 positive lymph nodes. Conclusions:In patients not receiving neoadjuvant therapy, the goal for patients with adenocarcinoma of the GEJ should be R0 resection including at least 15 lymph nodes, preferably with 5 cm of grossly normal in situ proximal esophagus for those with ≤6 positive lymph nodes. The operative approach may be individualized to achieve these goals.

American Joint Committee on Cancer Staging System Does Not Accurately Predict Survival in Patients Receiving Multimodality Therapy for Esophageal Adenocarcinoma

PURPOSE In patients with adenocarcinoma of the esophagus who receive preoperative chemoradiotherapy (CRT), American Joint Committee on Cancer (AJCC) stage, pathologic complete response (pCR), and estimated treatment response are various means used to stratify patients prognostically after surgery. However, none of these methods has been formally evaluated. The purpose of this study was to establish prognostic pathologic variables after CRT. PATIENTS AND METHODS A retrospective review was performed of patients with esophageal adenocarcinoma who received CRT before esophagectomy. Data collected included demographics, CRT details, pathologic findings, and survival. Statistical methods included recursive partitioning and Kaplan-Meier analyses. RESULTS Two hundred seventy-six patients were appropriate for this analysis. Kaplan-Meier analysis indicates that the current AJCC system poorly distinguishes between stages 0 to IIA (P = .52), IIB to III (P = .87), and IVA to IVB (P = .30). The presence of a pCR conferred improved survival over residual disease (P = .01). Recursive partitioning analysis indicates that involved lymph nodes and metastatic disease are the best predictors of survival and that depth of invasion and degree of treatment response are less predictive. CONCLUSION The current AJCC staging system is not a good predictor of survival after CRT. Although patients with a pCR do have improved long-term survival relative to patients with residual disease, this method places too much emphasis on residual depth of invasion and fails to identify patients with residual disease who have good long-term survival. Recursive partitioning analysis more accurately identifies nodal disease and metastatic disease as the most important prognostic variables. Degree of treatment response is less prognostic than nodal involvement.

Prognostic Factors for Recurrence After Pulmonary Resection of Colorectal Cancer Metastases

BACKGROUND This study was undertaken to review a large series of resections of colorectal pulmonary metastases in the era of modern chemotherapy. METHODS A retrospective chart review of prospectively maintained thoracic surgery databases identified 378 patients who underwent pulmonary resection for colorectal cancer metastases with curative intent from 1998 to 2007. RESULTS The primary site of disease was rectum (52%), left colon (26%), right colon (16%), and unknown (6%). Before thoracic recurrence, 166 patients (44%) had previously undergone resection of extrathoracic metastases. Median disease-free interval (DFI) was 24 months from the time of the primary operation. The number of metastatic deposits resected was one in 60%, two in 20%, three in 10%, and four or more in 10%. Chemotherapy was administered to 87 patients (23%) before resection and to 169 patients (45%) after resection. Three-year recurrence-free survival was 28%, and 3-year overall survival was 78%. Multivariable analysis revealed age younger than 65 years, female sex, DFI less than 1 year, and number of metastases greater than three as independent predictors of recurrence. Of 44 patients with three or more lesions and less than 1 year DFI, none was cured by operation. By contrast, recurrence-free survival was 49% at 3 years for those with one lesion and DFI greater than 1 year. CONCLUSIONS Age younger than 65 years, female sex, DFI less than 1 year, and number of metastases greater than three predict recurrence. Medical management alone should be considered standard for patients who have both three or more pulmonary metastases and less than 1 year DFI.

Impact of Micropapillary Histologic Subtype in Selecting Limited Resection vs Lobectomy for Lung Adenocarcinoma of 2cm or Smaller

BACKGROUND We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (≤2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO). METHODS Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Greys test. All statistical tests were two-sided. RESULTS Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5-year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP ≥ 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP ≥ 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10). CONCLUSIONS Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR.

Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas

Introduction: Tumor invasion in lung adenocarcinoma is defined as infiltration of stroma, blood vessels, or pleura. Based on observation of tumor spread through air spaces (STAS), we considered whether this could represent new patterns of invasion and investigated whether it correlated with locoregional versus distant recurrence according to limited resection versus lobectomy. Methods: We reviewed resected small (less than or equal to 2 cm) stage I lung adenocarcinomas (n = 411; 1995–2006). Tumor STAS was defined as tumor cells—micropapillary structures, solid nests, or single cells—spreading within air spaces in the lung parenchyma beyond the edge of the main tumor. Competing risks methods were used to estimate risk of disease recurrence and its associations with clinicopathological risk factors. Results: STAS was observed in 155 cases (38%). In the limited resection group (n = 120), the risk of any recurrence was significantly higher in patients with STAS-positive tumors than that of patients with STAS-negative tumors (5-year cumulative incidence of recurrence, 42.6% versus 10.9%; P < 0.001); the presence of STAS correlated with higher risk of distant (P = 0.035) and locoregional recurrence (P = 0.001). However, in the lobectomy group (n = 291), the presence of STAS was not associated with either any (P = 0.50) or distant recurrence (P = 0.76). In a multivariate analysis, the presence of tumor STAS remained independently associated with the risk of developing recurrence (hazard ratio, 3.08; P = 0.014). Conclusion: The presence of STAS is a significant risk factor of recurrence in small lung adenocarcinomas treated with limited resection. These findings support our proposal that STAS should formally be recognized as a pattern of invasion in lung adenocarcinoma.

Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer

Purpose:Endoscopic biopsy after chemoradiation therapy (CRT) for esophageal cancer has been used to determine response to treatment. We wanted to determine if endoscopic biopsy can accurately establish evidence of local pathologic complete response (pCR) in patients undergoing CRT. Methods:We queried a prospectively maintained database for patients seen at Memorial Sloan-Kettering Cancer Center from 1996 to the present who underwent, (1) CRT for local-regionally advanced esophageal cancer, (2) post-CRT endoscopic biopsy, and (3) esophagectomy. Data points included pathology of post-CRT endoscopy and surgical specimens, tumor histology, and survival. Correlations were analyzed by the &khgr;2 test and one-way analysis of variance. Survival comparisons were assessed using the Kaplan-Meier method and log-rank analysis. Results:One hundred fifty-six patients were identified. Over 80% of patients received cisplatin-based chemotherapy and 5040 cGy of radiation. One hundred eighteen patients had no tumor identified on endoscopic biopsy. A negative biopsy at endoscopy was a poor predictor of pCR (negative predictive value: 31%), with 69% having local disease at esophagectomy. A positive biopsy was predictive of residual disease (positive predictive value: 95%). Negative endoscopic biopsy better predicted a pCR for squamous cell carcinomas versus adenocarcinomas (P[r] < 0.001). Nodal status of surgical specimens was not correlated with post-treatment endoscopic findings. Survival was equivalent after surgery in patients with a negative endoscopic biopsy versus patients with positive pathology. Conclusion:A negative endoscopic biopsy is not a useful predictor of a pCR after CRT, final nodal status, or overall survival.

Video-assisted thoracoscopic surgery (VATS) lobectomy: catastrophic intraoperative complications.

OBJECTIVE Large case series have demonstrated that video-assisted thoracoscopic surgery (VATS) lobectomy is feasible and safe. However, catastrophic intraoperative complications during VATS lobectomy requiring thoracotomy can be overlooked and are not reported in the current literature. We reviewed our experience to determine the frequency, management, and outcome of these complications. METHODS A systematic review of a prospective database was performed after institutional review board approval. All patients who underwent VATS lobectomy or a combination of any VATS procedure plus a thoracotomy were identified. A catastrophic complication was defined as an event that resulted in an additional unplanned major surgical procedure other than the planned lobectomy. RESULTS From 2002 to 2010, a total of 633 VATS lobectomies were performed and 610 patients had any VATS procedure plus a thoracotomy. Thirteen catastrophic complications were identified in 12 (1%) patients. We included all cases in which a VATS was performed as well as a thoractomy since this would include conversions as well. These cases included 3 main pulmonary arterial and 1 main pulmonary venous transection requiring reanastomosis, 3 unplanned pneumonectomies, 1 unplanned bilobectomy, 1 tracheoesophageal fistula, 1 membranous airway injury to the bronchus intermedius, 1 complete staple line disruption of the inferior pulmonary vein injury to the azygos/superior vena cava junction, and 1 splenectomy. There were no intraoperative deaths. CONCLUSIONS Catastrophic intraoperative complications of VATS lobectomy are uncommon. However, awareness of the possibility of such injuries is critical to avoid them, and development of specific management strategies is necessary to limit morbidity should they occur.

Predictors of Outcomes after Surgical Treatment of Synchronous Primary Lung Cancers

Introduction: Distinguishing synchronous primary lung cancers (SPLCs) from advanced disease is important because prognosis and treatments are very different and a surgical approach to SPLC may result in survival similar to solitary cancers. Determining this distinction with certainty, however, is challenging. We reviewed our experience with surgical resection of presumed SPLC to analyze outcomes and identify factors associated with prolonged survival. Patients and Methods: A retrospective review identified patients treated for presumptive SPLC. Cases were defined using modified criteria set forth by Martini and Melamed and histologic subtyping. Survival was estimated using the Kaplan-Meier method, and factors associated with survival were evaluated using a log-rank test or Cox proportional hazards model for categorical and continuous variables, respectively. Results: From January 1995 to July 2006, 175 patients met study criteria and underwent complete resection. Tumors were more often in different lobes of an ipsilateral chest (55 of 175, 31%) or contralateral lesions (45 of 175, 26%). More than half (104 of 175, 59%) of the patients underwent a single operation. Median follow-up was 50.3 months (4.8-164.7); median overall survival (OS) for the group was 67.4 months (46.4-80.0) with a 3-year OS of 64%. On multivariable analysis controlling for stage, only female gender was a significant predictor of better OS (p = 0.001). Conclusions: An aggressive surgical approach to patients with apparent SPLC can result in survival that is comparable with patients with single lung cancers of similar stage. The Martini and Melamed criteria and histologic subtyping can identify appropriate patients for resection. Female gender was associated with superior OS.

Predictive Value of Initial PET-SUVmax in Patients with Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma

Introduction: We have previously shown that in early clinical stage esophageal adenocarcinoma, a positron emission tomography standardized uptake values (PET SUVmax) of <4.5 is associated with earlier pathologic stage and predicts better survival. In this study, we analyze the impact of the pretreatment PET SUVmax in patients with locally advanced esophageal adenocarcinoma who undergo preoperative chemoradiotherapy. Methods: We performed a retrospective analysis, selecting patients with adenocarcinoma of the esophagus who had a pretreatment PET scan and who received chemoradiotherapy before esophagectomy. Data recorded included demographics, PET SUVmax, treatment details, pathologic details, and survival data. Comparison of categorical variables was done by &khgr;2 analysis, continuous variables by t test, survival analysis by the Kaplan-Meier method, and comparisons of survival using the log-rank test. Results: Between January 1996 and September 2007, 189 patients were appropriate for this analysis. The initial PET SUVmax was <4.5 in 28 patients and ≥4.5 in 161 patients. The two groups were similar with regards to demographics and treatment details. Patients in the low SUV group were less likely to show evidence of treatment response after chemoradiotherapy, including a higher likelihood of residual nodal disease and a lower likelihood of a pathologic complete response and estimated treatment response. However, both groups had similar survival. Conclusions: Although the initial PET SUVmax does not predict survival in patients with locally advanced esophageal adenocarcinoma who receive preoperative chemoradiotherapy, patients with a high initial SUVmax respond better to preoperative therapy. These results can be used to better select esophageal cancer patients for combined modality treatment.