Bernard J. Park

Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.

A new lung adenocarcinoma classification is being proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan–Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33–89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n=1) and minimally invasive adenocarcinoma (n=8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant (n=29), papillary predominant (n=143) and acinar predominant (n=232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n=13), colloid predominant (n=9), solid predominant (n=67) and micropapillary predominant (n=12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (P<0.001). Among the clinicopathological factors, stage 1B versus 1A (P<0.001), male sex (P<0.008), high histological grade (P<0.001), vascular invasion (P=0.002) and necrosis (P<0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P=0.04) and invasive tumor size adjusted by the percentage of lepidic growth (P<0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P=0.038), male gender (P=0.007), tumor invasive size (P=0.026) and necrosis (P=0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas.

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.

Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP)

AbstractBackground: Primary peritoneal mesothelioma is a locally aggressive disease that is difficult to treat or even palliate. Continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin (CDDP) allows uniform, high regional delivery of chemotherapeutics and hyperthermia to the peritoneal surface for the treatment of peritoneal tumors. This article summarizes the results of 18 patients with peritoneal mesothelioma treated with CHPP. Methods: From June 1993 through April 1998, 18 patients with primary peritoneal mesothelioma (13 male, 5 female; median age, 51 years) underwent surgical exploration and tumor debulking followed by a 90-minute CHPP with CDDP and hyperthermia as part of three consecutive phase I trials conducted at the National Cancer Institute. Seventeen of 18 patients had malignant peritoneal mesothelioma, 13 with associated ascites. One patient had a symptomatic, multiply recurrent, benign, cystic peritoneal mesothelioma. Three patients who had a recurrence after a prolonged progression-free interval (>6 months) after CHPP underwent re-treatment. CHPP parameters included median cisplatin dose of 530 mg (range, 187–816), perfusate volume 6.0 liter (range, 4–9), flow 1.5 liter/min (range, 1–2), intraperitoneal temperature 41°C (range, 38.7–43.2), and central temperature 38.6°C (range, 36.8–39.7). Results: Median follow-up after CHPP is 19 months (range, 2–56) with no operative or treatment-related mortality. Overall operative morbidity was 24% and included two patients with superficial wound infection and one patient each with atrial fibrillation, pancreatitis, fascial dehiscence, ileus, line sepsis, and clostridium difficile colitis. The major treatment-related toxicity was systemic renal toxicity at doses above what was defined as the maximum tolerated dose of cisplatin. Nine of 10 patients had resolution of their ascites postoperatively. Three patients who developed recurrent ascites (27, 22, and 10 months after initial treatment) were re-treated and had resolution of their ascites with ongoing responses at 24, 6, and 4 months after the second perfusion. The median progression-free survival was 26 months, and the overall 2-year survival was 80%. The median overall survival has not been reached. Conclusions: CHPP with cisplatin can be performed safely with no mortality and minimal morbidity. In selected patients, successful palliation in the abdomen and long-term survival, compared with historical controls, can be achieved with aggressive surgical debulking and CHPP. Re-treatment after initial response can result in a second long-term response.

Prevalence and Mortality of Acute Lung Injury and ARDS After Lung Resection

STUDY OBJECTIVES To describe the frequency and outcome of patients with acute lung injury (ALI) and ARDS who require mechanical ventilation (MV) after lung resection, and to analyze preoperative and perioperative variables associated with mortality. METHODS We retrospectively reviewed the case records of all patients who underwent lung resection and acquired ALI and/or ARDS and required invasive MV and ICU admission at a tertiary-care cancer center from January 1, 2002, to December 31, 2004. Preoperative and perioperative information including ICU-specific variables and outcome data were analyzed. Data are presented as median (range). RESULTS During the study period, 2,039 patients underwent a total of 2,192 lung resections. ALI/ARDS developed in 50 patients (2.45%). The prevalence of ALI/ARDS by procedure was as follows: pneumonectomy, 7.9% (10 cases in 126 procedures); lobectomy/bilobectomy, 2.96% (31 cases in 1,047 procedures); and sublobar resection, 0.88% (9 cases in 1,019 procedures). There were 28 men (56%) and 22 women (44%). Median age was 68.5 years (range, 44 to 88 days). Median time of presentation to the ICU with ALI/ARDS following surgery was 4 days (range, 1 to 22 days). Median ICU length of stay was 10 days (range, 2 to 43 days), and median hospital LOS was 26.5 days (range, 6 to 93 days). During hospitalization, 20 of the 50 patients (40%) died: 16 in the ICU and 4 after ICU discharge. The mortality rate was highest after pneumonectomy (50%), followed by lobectomy (42%) and sublobar resections (22%). Although increased age was associated with a higher ICU mortality, none of the preoperative and perioperative variables were significantly associated with hospital mortality. There was a marginally significant association between mortality and time of presentation to the ICU after surgery (p = 0.06). CONCLUSIONS Our results confirm that ALI/ARDS after lung resection is associated with a high mortality in patients who require invasive MV and ICU care.

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.

Cost Comparison of Robotic, Video-assisted Thoracic Surgery and Thoracotomy Approaches to Pulmonary Lobectomy

The financial impact of employing minimally invasive techniques for lobectomy compared with traditional open thoracotomy was assessed. A retrospective review was conducted using ICD9 codes for thoracotomy, video-assisted thoracic surgery (VATS), and robotic VATS lobectomy to determine total average costs associated with the resultant hospital stay. The difference in total average costs was calculated for each group. Robotic VATS lobectomy had higher associated costs than VATS only, primarily attributed to increased costs of the first hospital day, but was still less costly than thoracotomy. The average cost of VATS is substantially less than thoracotomy primarily because of a decreased length of stay. The cost of robotic assistance for VATS is still less than thoracotomy, but greater than VATS alone.

Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations.

Background: Patients with stage IV lung adenocarcinoma and epidermal growth factor receptor (EGFR) mutation derive clinical benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). Whether treatment with TKI improves outcomes in patients with resected lung adenocarcinoma and EGFR mutation is unknown. Methods: Data were analyzed from a surgical database of patients with resected lung adenocarcinoma harboring EGFR exon 19 or 21 mutations. In a multivariate analysis, we evaluated the impact of treatment with adjuvant TKI. Results: The cohort consists of 167 patients with completely resected stages I to III lung adenocarcinoma. Ninety-three patients (56%) had exon 19 del, 74 patients (44%) had exon 21 mutations, and 56 patients (33%) received perioperative TKI. In a multivariate analysis controlling for sex, stage, type of surgery, and adjuvant platinum chemotherapy, the 2-year disease-free survival (DFS) was 89% for patients treated with adjuvant TKI compared with 72% in control group (hazard ratio = 0.53; 95% confidence interval: 0.28–1.03; p = 0.06). The 2-year overall survival was 96% with adjuvant EGFR TKI and 90% in the group that did not receive TKI (hazard ratio: 0.62; 95% confidence interval: 0.26–1.51; p = 0.296). Conclusions: Compared with patients who did not receive adjuvant TKI, we observed a trend toward improvement in DFS among individuals with resected stages I to III lung adenocarcinomas harboring mutations in EGFR exon 19 or 21 who received these agents as adjuvant therapy. Based on these data, 320 patients are needed for a randomized trial to prospectively validate this DFS benefit.

Genomic and Mutational Profiling to Assess Clonal Relationships Between Multiple Non–Small Cell Lung Cancers

Purpose: In cases of multiple non–small cell lung cancer, clinicians must decide whether patients have independent tumors or metastases and tailor treatment accordingly. Decisions are currently made using the Martini and Melamed criteria, which are mostly based on tumor location and histologic type. New genomic tools could improve the ability to assess tumor clonality. Experimental Design: We obtained fresh-frozen tumors specimens from patients who underwent surgery on at least two occasions for presumptively independent NSCLC. We did array comparative genomic hybridization (aCGH), mutational profiling of select genes, and detailed clinicopathologic review. Results: We analyzed a total of 42 tumors from 20 patients (6 patients with synchronous tumors, 14 patients with metachronous tumors, 24 potential tumor pair comparisons); 22 tumor pairs were evaluable by aCGH. Surprisingly, classification based on genomic profiling contradicted the clinicopathologic diagnosis in four (18%) of the comparisons, identifying independent primaries in one case diagnosed as metastasis and metastases in three cases diagnosed as independent primaries. Matching somatic point mutations were observed in these latter three cases. Another four tumor pairings were assigned an “equivocal” result based on aCGH; however, matching somatic point mutations were also found in these tumor pairs. None of the tumor pairs deemed independent primaries by aCGH harbored matching mutations. Conclusion: Genomic analysis can help distinguish clonal tumors from independent primaries. The development of rapid, inexpensive, and reliable molecular tools may allow for refinement of clinicopathologic criteria currently used in this setting. (Clin Cancer Res 2009;15(16):5184–90)

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.