Robert J. Korst

Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer

PURPOSE Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy

BACKGROUND The risks of complications in patients undergoing thoracotomy after neoadjuvant therapy for nonsmall cell lung cancer remain controversial. We reviewed our experience to define it further. METHODS All patients undergoing thoracotomy after induction chemotherapy from 1993 through 1999 were reviewed. Univariate and multivariate methods for logistic regression model were used to identify predictors of adverse events. RESULTS Induction chemotherapy included mitomycin, vinblastine, and cisplatin (179 patients), carboplatin and paclitaxel (152 patients), and other combinations (139 patients). Eighty-five patients (18%) received preoperative radiation. Operations were pneumonectomy (97 patients), lobectomy (297 patients), lesser resection (18 patients), and exploration only (58 patients). Total mortality was 7 of 297 (2.4%) and 11 of 97 (11.3%) for all lobectomies and pneumonectomies, respectively, but mortality was 11 of 46 (23.9%) for right pneumonectomy. Complications developed in 179 patients (38%). By multiple regression analysis, right pneumonectomy (p = 0.02), blood loss (p = 0.01), and forced expiratory volume in one second (percent predicted) (p = 0.01) predicted complications. No factor emerged to explain this high right pneumonectomy mortality rate. CONCLUSIONS Pulmonary resection after neoadjuvant therapy is associated with acceptable overall morbidity and mortality. However, right pneumonectomy is associated with a significantly increased risk and should be performed only in selected patients.

Proposed Revision Of The Staging Classification For Esophageal Cancer

OBJECTIVES This study analyzed survival with respect to lymph node involvement to develop a new staging system for patients with esophageal cancer that accurately reflects prognosis. METHODS The records of patients undergoing resection of primary esophageal cancer from 1989 to 1993 were reviewed. The data collected included patient age and sex, tumor histologic characteristics and location, the use of preoperative or postoperative radiation and chemotherapy, the type of resection, the depth of tumor invasion, the number and location of benign and malignant lymph nodes in the resected specimen, the disease status at last follow-up, and the first site of relapse. With an anatomically specific lymph node map, tumors designated in the current American Joint Committee on Cancer system as M1 because of extensive lymph node metastases were reclassified as N2, reserving the M1 category for visceral metastases. Survival was analyzed by the Kaplan-Meier method, and prognostic factors were assessed by log-rank and Cox regression analyses. RESULTS There were 216 patients (159 men, 57 women) with a median age of 63.5 years. Adenocarcinoma of the distal esophagus or gastroesophageal junction was the most common tumor (127 patients, 59%) and Ivor Lewis esophagogastrectomy was the most frequently performed operation. Both lymph node location (N1 versus N2) and number (0 vs 1 to 3 vs 4 or more) significantly influenced survival. CONCLUSIONS A new staging system that adds an N2 M0 descriptor and reclassifies stage groupings reflects prognosis more accurately than does the current American Joint Committee on Cancer staging system. The number of positive lymph nodes is also an important stratification factor.

An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer

BACKGROUND The 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) imaging is an advance over computed tomography alone in the staging of untreated nonsmall cell lung cancer (NSCLC). Aside from one 9-patient study, there are no data comparing FDG-PET imaging with surgical staging of NSCLC after induction therapy. METHODS We reviewed our institutional experience with FDG-PET imaging followed by surgical staging of nonsmall cell lung cancer after induction therapy. A nuclear physician blinded to surgical findings reviewed the FDG-PET scans and assigned a clinical TNM stage. A thoracic surgeon assigned a pathologic TNM stage. Then the clinical TNM stage and the pathologic TNM stage were compared. RESULTS Fifty-six patients (30 males and 26 females; median, age 60) with nonsmall cell lung cancer underwent chemotherapy (40 patients), chemoradiation (11 patients), or radiation alone (5 patients) followed by PET and operations. PET had a positive predictive value of 98% for detecting residual viable disease in the primary tumor. PET over-staged nodal status in 33% of patients, under staged nodal status in 15%, and was correct in 52%. PET correctly classified all patients with M1 disease. CONCLUSIONS Positron emission tomography after induction therapy accurately detects residual viable primary tumor, but not the involvement of mediastinal lymph nodes.

Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma

BACKGROUND The histologic criteria defining bronchioloalveolar carcinoma (BAC) were recently revised, but it is unclear whether these criteria predict clinical behavior. This study determined the outcome of resected BAC in relationship to clinical and radiologic disease pattern, and pathologic features. METHODS Between 1989 and 2000, 100 consecutive surgically treated patients with adenocarcinomas exhibiting various degrees of BAC features were retrospectively studied. Histology was reviewed; tumors were classified as pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features. Clinical and radiologic pattern were classified as unifocal, multifocal, or pneumonic. Demographic data, tumor stage, and outcome were recorded. Survival was analyzed by the Kaplan-Meier method, and prognostic factors were determined by the log-rank test. RESULTS Patient median age was 65, and 74% of the patients were female. Pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features occurred in 47, 21, and 32 patients, respectively. Unifocal disease occurred in 64 patients, multifocal in 29, and pneumonic in 7. Seventy-one patients had stage I/II tumors, 22 had stage III/IV, and 7 patients had Stage X tumors. Overall 5-year survival was 74%. There was no significant difference in survival among the three histologic subtypes. The pneumonic pattern had significantly worse survival compared with unifocal and multifocal patterns. Pathologic stage predicted survival, with 5-year survivals for I/II and III/IV of 83.7% and 59.6%, respectively. CONCLUSIONS Clinical pattern and pathologic stage, but not the degree of invasion on histologic examination predict survival. Multifocal disease is associated with excellent long-term survival after resection. The favorable survival of stage III/IV BAC indicates that the current staging system does not fully describe this disease in patients undergoing resection because of its distinct tumor behavior.

Thoracic esophageal perforations: a decade of experience

BACKGROUND Perforation of the thoracic esophagus is a formidable challenge. Treatment and outcome are largely determined by the time to presentation. We reviewed our experience with esophageal perforations to determine the overall mortality and whether the time to presentation should influence management strategy. METHODS A retrospective chart review was performed on all patients treated for perforation of the thoracic esophagus from 1990 to 2001. There were 26 patients (14 men and 12 women; median age, 62 years; range, 36 to 89 years). Fourteen patients presented within 24 hours (early), and 12 patients presented after 24 hours (delayed). Nine of the 12 patients in the delayed group presented after 72 hours. The causes of the perforations were as follows: instrumentation (19 patients), Boerhaaves syndrome (2 patients), intraoperative injury (1 patient), and other (4 patients). In the early group, 3 patients were treated conservatively, 10 patients underwent primary repair, and 1 patient required esophagectomy for carcinoma. In the delayed group, 3 patients were treated conservatively, 6 underwent successful repair of the perforation, 1 had a T-tube placement through the perforation and eventually required an esophagectomy, and 2 had an esophagectomy as primary surgical treatment. RESULTS Hospital mortality was 3.8% (1 of 26) and morbidity was 38% (10 of 26). Persistent leaks occurred in 3 patients, 2 after primary repair and 1 after T-tube drainage. All patients selected for conservative management successfully healed their perforation. CONCLUSIONS Primary repair can be carried out in most cases of thoracic esophageal perforation regardless of time to presentation, with a low mortality rate. A small but carefully selected group of patients may be treated successfully without operation. Esophagectomy should be reserved for patients with carcinoma or extensive necrosis of the esophagus.

Long-Term Results of Combined-Modality Therapy in Resectable Non–Small-Cell Lung Cancer

PURPOSE Assessment of long-term results of combined-modality therapy for resectable non-small-cell lung cancer is hampered by insufficient follow-up and small patient numbers. To evaluate this, we reviewed our collective experience. PATIENTS AND METHODS This study was a retrospective chart review recording demographics, tumor stage, treatment, and outcome of consecutive patients undergoing surgery. Survival was analyzed by Kaplan-Meier, and prognostic factors were analyzed by log-rank and Cox regression. RESULTS From January 1993 to December 1999, 470 patients were treated, with follow-up in 446: 27 stage I, 55 stage II, 316 stage III, 43 stage IV (solitary M1), and five uncertain. Chemotherapy was mitomycin/vinblastine/cisplatin (174 patients [39.0%]), carboplatin/paclitaxel (148 [33.2%]), and other combination (124 [27.8%]); 75 patients (16.8%) received induction radiation. Resection was complete in 77.4%, incomplete in 8.3%, attempted but with gross residual disease afterward in 1.8%, and not performed in 12.6%. Pathologic complete response occurred in 20 patients (4.5%). With median follow-up of 31.0 months for patients still alive, median and 3-year survival for pathologic stages 0, I, II, III, and IV were more than 90 months, 73%; 42 months, 52%; 23 months, 35%; 16 months, 28%; and 16 months, 23% (P <.001). In a multivariate analysis, age, complete resection, pathologic stage, and pneumonectomy, but not induction regimen, significantly influenced survival. CONCLUSION Although pathologic complete response outside the protocol setting is low, survival of this large patient cohort is comparable to that of patients in published combined-modality trials. Survival is significantly influenced by patient age, complete resection, pathologic stage, and pneumonectomy. These results can help guide standard clinical practice and emphasize the need for novel induction regimens.

Lobectomy improves ventilatory function in selected patients with severe COPD

BACKGROUND Patients often undergo limited resection instead of lobectomy for non-small cell lung cancer because of a low preoperative forced expiratory volume in 1 second (FEV1). Our goal is to define criteria that will preoperatively identify a group of patients who will not lose further function after lobectomy. METHODS Patients who underwent lobectomy with a preoperative FEV1 of less than 80% of predicted were retrospectively identified. Data collected included preoperative and postoperative pulmonary function tests, age, sex, the lobe resected, and preoperative ventilation-perfusion scan result. RESULTS Thirty-two patients were included in this study. The median preoperative FEV1 was 60% of predicted (1.65 L) and the mean change in FEV1 was a loss of 7.8% after lobectomy. The patients were divided into two groups. Group 1 (n = 13) had a preoperative FEV1 of less than or equal to 60% of predicted (median, 49%; 1.35 L) combined with an FEV1 to forced vital capacity ratio of less than or equal to 0.6. Group 2 (n = 19) includes all other patients (median preoperative FEV1, 69% of predicted; 1.87 L). The mean changes in FEV1 after lobectomy were +3.7% and -15.7% for groups 1 and 2, respectively (p < 0.005). A chronic obstructive pulmonary disease index was defined and then calculated for each patient. The relationship between this index and the change in FEV1 after lobectomy for all 32 patients appears linear (r = -0.43; p = 0.015). CONCLUSIONS Patients with a very low preoperative FEV1 and FEV1 to forced vital capacity ratio are less likely to lose ventilatory function after lobectomy and may actually improve it.

Extent of chest wall invasion and survival in patients with lung cancer

BACKGROUND The long-term survival after operation of patients with lung cancer involving the chest wall is known to be related to regional nodal involvement and completeness of resection, but it is not known whether the depth of chest wall involvement or the type of resection (extrapleural or en bloc) affects either the rate of local recurrence or survival. METHODS We retrospectively reviewed the Memorial Sloan-Kettering Cancer Center experience between 1974 and 1993 of 334 patients undergoing surgical exploration for lung cancer involving the chest wall or parietal pleura. RESULTS Of 334 patients who underwent exploration, 175 had apparently complete (R0) resections, 94 had incomplete (R1 or R2) resections, and 65 underwent exploration without resection. The overall 5-year survival of R0 patients was 32%, of R1 or R2 patients 4%, and of patients undergoing exploration without resection 0%. In the patients undergoing R0 resections, the extent of chest wall involvement was limited to the parietal pleura in 80 patients, and extended into the ribs or soft tissues in 95. The 5-year survival of R0 patients with T3 N0 M0 disease was 49%, T3 N1 M0 disease 27%, and T3 N2 M0 disease 15% (p < 0.0003). Independent of lymph node involvement, a survival advantage was observed in R0 patients if the chest wall involvement was limited to parietal pleura only, rather than invading into the chest wall musculature or ribs. CONCLUSIONS Survival of patients with lung cancer invading the chest wall after resection with curative intent is highly dependent on the extent of nodal involvement and the completeness of resection, and much less so on the depth of chest wall invasion.

Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules

OBJECTIVES A single randomized trial established lobectomy as the standard of care for the surgical treatment of early-stage non-small cell lung cancer. Recent advances in imaging/staging modalities and detection of smaller tumors have once again rekindled interest in sublobar resection for early-stage disease. The objective of this study was to compare lung cancer survival in patients with non-small cell lung cancer with a diameter of 30 mm or less with clinical stage 1 disease who underwent lobectomy or sublobar resection. METHODS We identified 347 patients diagnosed with lung cancer who underwent lobectomy (n = 294) or sublobar resection (n = 53) for non-small cell lung cancer manifesting as a solid nodule in the International Early Lung Cancer Action Program from 1993 to 2011. Differences in the distribution of the presurgical covariates between sublobar resection and lobectomy were assessed using unadjusted P values determined by logistic regression analysis. Propensity scoring was performed using the same covariates. Differences in the distribution of the same covariates between sublobar resection and lobectomy were assessed using adjusted P values determined by logistic regression analysis with adjustment for the propensity scores. Lung cancer-specific survival was determined by the Kaplan-Meier method. Cox survival regression analysis was used to compare sublobar resection with lobectomy, adjusted for the propensity scores, surgical, and pathology findings, when adjusted and stratified by propensity quintiles. RESULTS Among 347 patients, 10-year Kaplan-Meier for 53 patients treated by sublobar resection compared with 294 patients treated by lobectomy was 85% (95% confidence interval, 80-91) versus 86% (confidence interval, 75-96) (P = .86). Cox survival analysis showed no significant difference between sublobar resection and lobectomy when adjusted for propensity scores or when using propensity quintiles (P = .62 and P = .79, respectively). For those with cancers 20 mm or less in diameter, the 10-year rates were 88% (95% confidence interval, 82-93) versus 84% (95% confidence interval, 73-96) (P = .45), and Cox survival analysis showed no significant difference between sublobar resection and lobectomy using either approach (P = .42 and P = .52, respectively). CONCLUSIONS Sublobar resection and lobectomy have equivalent survival for patients with clinical stage IA non-small cell lung cancer in the context of computed tomography screening for lung cancer.