Philippe Nafteux

Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upper-half esophageal carcinoma

Objective:To determine the impact of esophagectomy with 3-field lymphadenectomy on staging, disease-free survival, and 5-year survival in patients with carcinoma of the esophagus and gastroesophageal junction (GEJ). Background:Esophagectomy with 3-field lymphadenectomy is mainly performed in Japan. Data from Western experience with 3-field lymphadenectomy are scarce and dealing with relatively small numbers. As a result, its role in the surgical practice of cancer of the esophagus and GEJ remains controversial. Methods:Between 1991 and 1999, primary surgery with 3-field lymphadenectomy was performed in 192 patients, of whom a cohort of 174 R0 resections was used for further analysis. Results:Hospital mortality of the whole series was 1.2%. Overall morbidity was 58%. Pulmonary complications occurred in 32.8%, cardiac dysrhythmias in 10.9%, and persistent recurrent nerve problems in 2.6%. pTNM staging was as follows: stage 0, 0.6%; stage I, 9.2%; stage II, 27.6%; stage III, 28.7%; and stage IV, 33.9%. Overall 3- and 5-year survival was 51% and 41.9%, respectively. The 3- and 5-year disease-free survival was 51.4% and 46.3%, respectively. Locoregional lymph node recurrence was 5.2%; no patient developed an isolated cervical lymph node recurrence. Five-year survival for node-negative patients was 80.2% versus 24.5% for node-positive patients. Five-year survival by stage was 100% in stages 0 and I, 59.1% in stage II, 36.8% in stage III, and 13.3% in stage IV. Twenty-three percent of the patients with adenocarcinoma (25.8% distal third and 17.6% GEJ) and 25% of the patients with squamous cell carcinoma (26.2% middle third) had positive cervical nodes resulting in a change of pTNM staging specifically related to the unforeseen cervical lymph node involvement in 12%. Cervical lymph node involvement was unforeseen in 75.6% of patients with cervical nodes at pathologic examinations. Five-year survival for patients with positive cervical nodes was 27.7% for middle third squamous cell carcinoma. For distal third adenocarcinomas, 4-year survival was 35.7% and 5-year survival 11.9%. No GEJ adenocarcinoma with positive cervical nodes survived for 5 years. Conclusions:Esophagectomy with 3-field lymph node dissection can be performed with low mortality and acceptable morbidity. The prevalence of involved cervical nodes is high, regardless of the type and location of tumor resulting in a change of final staging specifically related to the cervical field in 12% of this series. Overall 5-year and disease-free survival after R0 resection of 41.9% and 46.3%, respectively, may indicate a real survival benefit. A 5-year survival of 27.2% in patients with positive cervical nodes in middle third carcinomas indicates that these nodes should be considered as regional (N1) rather than distant metastasis (M1b) in middle third carcinomas. These patients seem to benefit from a 3-field lymphadenectomy. The role of 3-field lymphadenectomy in distal third adenocarcinoma remains investigational.

Prospective Comparative Study of Integrated Positron Emission Tomography-Computed Tomography Scan Compared With Remediastinoscopy in the Assessment of Residual Mediastinal Lymph Node Disease After Induction Chemotherapy for Mediastinoscopy-Proven Stage IIIA-N2 Non–Small-Cell Lung Cancer: A Leuven Lung Cancer Group Study

PURPOSE Mediastinal restaging after induction therapy for non-small-cell lung cancer remains a difficult and controversial issue. The goal of this prospective study was to compare the performance of integrated positron emission tomography (PET)--computed tomography (CT) and remediastinoscopy in the evaluation of mediastinal lymph node metastasis after induction chemotherapy. PATIENTS AND METHODS Thirty consecutive stage IIIA-N2 non-small-cell lung cancer patients surgically treated at our institution were entered onto this prospective study. N2 disease was proven by cervical mediastinoscopy, at which a mean number of 3.8 lymph node levels were biopsied. After completion of induction chemotherapy, the mediastinum was reassessed by integrated PET-CT and remediastinoscopy. All patients underwent thoracotomy with attempted complete resection and systematic nodal dissection. RESULTS PET-CT showed no evidence of nodal disease (N0) in 13 patients, Hilar nodal disease (N1) disease in three patients, and residual mediastinal disease (N2) in 14 patients. Remediastinoscopy was positive in only five patients. The preinduction involved lymph node level could be accurately re-evaluated in 18 patients. This was not the case in the other 12 because of extensive fibrosis and adhesions. In 17 patients, persistent N2 disease was found at thoracotomy. The sensitivity, specificity, and accuracy of PET-CT were 77%, 92%, and 83%, respectively. These parameters for remediastinoscopy were 29%, 100%, and 60%, respectively. Sensitivity (P < .0001) and accuracy (P = .012) were significantly better for PET-CT. CONCLUSION After a thorough staging mediastinoscopy, postinduction remediastinoscopy had a disappointing sensitivity because of adhesions and fibrosis. Integrated PET-CT yielded a better result than that obtained in previous studies with side-by-side PET and CT images.

Postoperative complications after transthoracic esophagectomy for cancer of the esophagus and gastroesophageal junction are correlated with early cancer recurrence: role of systematic grading of complications using the modified Clavien classification.

Objectives:To assess the impact of postoperative complications after transthoracic esophagectomy, using the modified Clavien classification, on recurrence and on its timing in patients with cancer of the esophagus or gastroesophageal junction. Background Data:It is hypothesized that complications after esophagectomy for cancer may have a negative effect on recurrence and its timing because of negative interference with the immune system. Methods:Out of 150 consecutive patients operated with curative intent between January 2005 and May 2006, the data of 138 patients with macroscopically complete resection and no synchronous other malignancy were graded according to the modified Clavien classification. Uni- and multivariable analyses were performed to study the impact of postoperative complications on tumor recurrence and its timing. Results:Mean age was 63.1 years, male-female ratio was 4:1; 76.1% of the patients underwent primary surgery, 23.9% received induction therapy, R0-resection rate was 92.8%. Adenocarcinoma was found in 75%. Complication rates according to the modified Clavien classification were grade 0: 29.7%, grade 2: 35.5%, grade 3: 17.4%, grade 4: 15.9%, and grade 5 (postoperative mortality): 1.4%. Ten patients developed recurrence within 6 months, 29 within 12 months, 39 within 18 months, 42 within 24 months, totaling up to 47 at 3 years. Univariable analysis retained complications, LN-status, number of positive nodes, extracapsular lymph node involvement (EC LNI), pStage, pT, and R1-status as factors significantly influencing occurrence of recurrence. In the multivariable model, presence of complications, EC LNI, and R1-status were independent negative factors. Cox-regression analysis also identified these same 3 factors as significant determinators for the timing of recurrence. Conclusions:This study indicates a correlation between complications and early recurrence and its timing. Modified Clavien classification, beside R1-status and EC LNI, appears to be a useful prognostic indicator of early recurrence and its timing. Achieving esophagectomy without postoperative complications is of utmost importance also for oncologic reasons given its negative potential on early oncologic outcome.

Anastomotic complications after esophagectomy.

Anastomotic complications after esophagectomy continue to be a burden jeopardizing the quality of life and of swallowing. However, incidence, mortality and morbidity of anastomotic complications have substantially decreased in recent years. It seems that this is not so much related to the use of a particular conduit, approach or route for reconstruction, but rather related to refinement in anastomotic techniques and perhaps even more to progress in modern perioperative management. Knowledge of surgical anatomy and meticulous technique are of paramount importance and obviously related to individual expertise. As to the management, most leaks can be treated by conservative measures and reintervention surgery today is rather exceptional. Early endoscopy and dilatation seem to decrease the incidence and severity of anastomotic stenosis.

Expression of Carbonic Anhydrase IX (CA IX), a Hypoxia- Related Protein, Rather Than Vascular-Endothelial Growth Factor (VEGF), a Pro-Angiogenic Factor, Correlates With an Extremely Poor Prognosis in Esophageal and Gastric Adenocarcinomas

Objective:To evaluate the expression of carbonic anhydrase IX (CA IX) and vascular-endothelial growth factor (VEGF) in esophageal and gastric adenocarcinomas and in turn with the histologic subtype. Summary Background Data:Tumor hypoxia is an important factor in therapy resistance. A low oxygen concentration in tumors stimulates a.o. the expression of CA IX, a marker of hypoxia, and VEGF, a pro-angiogenic factor. Methods:We evaluated the immunohistochemical expression of CA IX and VEGF on paraffin-embedded material of 154 resection specimens: 39 esophageal, 73 cardiac, and 42 distal gastric adenocarcinomas (UICC classification). The adenocarcinomas were subtyped according to the Lauren classification (intestinal- and diffuse-type). Statistical Analysis:&khgr;2 test, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards model. Results:CA IX and VEGF expression were independent of the localization of the tumor. However, intestinal-type adenocarcinomas showed a significantly higher expression of CA IX as well as VEGF than diffuse-type tumors. VEGF expression was associated with a high microvessel density. Although survival analysis showed that CA IX expression (P = 0.008) as well as the coexpression of CA IX and VEGF (P = 0.008) correlate with a poor outcome, only CA IX expression is an independent prognostic factor for overall survival and metastasis-free survival. Conclusion:The difference in expression of CA IX and VEGF between intestinal- and diffuse-type adenocarcinomas may possibly explain the different clinical behavior of these tumors. CA IX expression, rather than VEGF positivity in tumors, enables the identification of a subpopulation, characterized by a more aggressive behavior and a poorer prognosis.

Early Outcome After Lung Transplantation From Non–Heart-Beating Donors is Comparable to Heart-Beating Donors

BACKGROUND The use of non-heart-beating donors (NHBD) to overcome organ shortage is moving into the clinic. In 2007, 5 of 51 lung transplantations (LTx) in our center were performed with lungs from controlled NHBD. METHODS Our aim was to describe these 5 NHBD LTx recipients and compare early outcome (<or= 6 months) with a cohort of 10 heart-beating donor (HBD) LTx recipients matched for age, gender, underlying disease, and time of surgery. Clinical outcomes were assessed, including ischemic times, gas exchange, primary graft dysfunction, time to extubation, time of discharge from intensive care unit/hospital, and pulmonary function. Airway and systematic inflammation were evaluated by bronchoalveolar lavage, total and differential cell counts, and plasma C-reactive protein levels, respectively. RESULTS Early outcome in the NHBD group was comparable to the HBD group at the clinical and inflammatory level. The NHBD group showed a trend for earlier extubation (p = 0.054), greater increase in forced expiratory volume in 1 second (p = 0.054), and a significantly lower number of infections (p = 0.01). The NHBD group also had lower numbers of total cells (p = 0.04) and macrophages (p = 0.03) in bronchoalveolar lavage on day 21. CONCLUSIONS Outcome after LTx in NHBD recipients is not inferior to HBD recipients during the first 6 months. Late results and effect on chronic rejection should be further awaited. Controlled NHBD may offer a valid source of lungs to overcome organ shortage in LTx.

Extracapsular lymph node involvement is a negative prognostic factor in T3 adenocarcinoma of the distal esophagus and gastroesophageal junction.

OBJECTIVE To assess prognosis according to whether lymph node involvement is intracapsular or with extracapsular breakthrough in adenocarcinoma of the distal esophagus and gastroesophageal junction. Materials and methods One hundred ninety-five consecutive patients with T3 adenocarcinoma of the distal esophagus and gastroesophageal junction between 1990 and 1999 were studied. All patients underwent primary R0 esophagectomy. The mean number of resected nodes per patient was 36.9. Survival was analyzed according to intracapsular and extracapsular involvement. RESULTS In N0 patients 5-year survival was 57% and 9-year survival was 38.7%. In patients with positive nodes these figures were 26.2% and 18.1%, respectively (P =.0069). Intracapsular and extracapsular node involvement showed 5- and 10-year survival of 40.9% and 21.7% versus 18% and 15.7%, respectively. There was no significant difference in 5- and 10-year survival between N0 and intracapsular node involvement (P =.43). However, there was a significant difference in survival between N0 and extracapsular node involvement (P =.002) and between intracapsular and extracapsular node involvement (P =.0001). CONCLUSIONS This study shows a significant difference in survival according to whether lymph node involvement was intracapsular or extracapsular. Patients with intracapsular lymph node involvement have similar survival rates as N0 patients. Extracapsular lymph node involvement is a bad prognostic factor, independent of the number of involved lymph nodes. The number of involved lymph nodes has an additive negative effect. These data may have an impact on treatment strategies.

Survival after resection of synchronous bilateral lung cancer

OBJECTIVE Due to recent advances in imaging, the incidence of patients presenting with bilateral lung lesions is increasing. A single contralateral lung lesion can be an isolated metastasis or a synchronous second primary lung cancer. For the revision of the TNM in 2009, the International Association for the Study of Lung Cancer Staging Committee proposes that patients with contralateral lung nodules remain classified as M1 disease. In this retrospective study, the survival after resection of synchronous bilateral lung cancer is evaluated. METHODS From our database of bronchial carcinoma, all patients with bilateral synchronous lung lesions between 1990 and 2007 were retrieved. We analysed 57 patients in which, after functional assessment and thorough staging, the decision was taken to treat the disease with bilateral resection. All these files were retrospectively reviewed. Twenty-one patients were excluded from this analysis because only one side was resected (n=15) or one of the lesions was non-neoplastic on final pathology (n=6). RESULTS Thirty-six patients underwent bilateral resection for synchronous multiple primary lung cancer. All resections were performed as sequential procedures. In 23 patients, one side was anatomically resected (2 pneumonectomies) and the contralateral side was resected by limited resection. In 10 patients a bilateral lobectomy was performed, and 3 patients had bilateral limited resections. Postoperative mortality was 2.8%. Eighteen patients had a tumour with a different histological pattern, confirmed by comparing both specimens by an experienced senior pathologist. The median survival after resection of synchronous bilateral lung cancer in our series was 25.4 months with a 5-year survival rate of 38%. There was no significant difference in survival between patients with different versus same histology. This survival is much higher compared to the survival of assumed stage IV disease. CONCLUSIONS Our study shows that selected patients with bilateral lung cancer may benefit from an aggressive approach, with acceptable morbidity and mortality, and rewarding long-term survival. Patients with a single contralateral lung lesion should not be treated as disseminated disease (stage IV). After extensive searching for metastatic spread, bilateral surgical resection should be considered in fit patients.

Outcome after esophagectomy for cancer of the esophagus and GEJ in patients aged over 75 years

OBJECTIVE Though the surgical treatment of esophageal cancer is increasingly accepted for elderly people defined as aged over 70 years, less is reported about the results in patients over 75. This study is a single institution retrospective analysis of outcome after esophagectomy for cancer of the esophagus and GEJ in patients aged over 75 years. METHODS All consecutive patients 76 years old and over undergoing curative esophagectomy for cancer in the period 1991-2006 were analyzed as to comorbidities, outcome and long-term survival. All the data had been prospectively collected in a database. Postoperative mortality risk was assessed by P-POSSUM and O-POSSUM score for in-hospital mortality and by the recently published Steyerbergs score system [Steyerberg EW, Neville BA, Koppert LB, Lemmens VEPP, Tilanus HW, Coebergh JWW, Weeks JC, Earle CC. Surgical mortality in patients with esophageal cancer: development and validation of a simple risk score. J Clin Oncol 2006;24:4277-84.] for 30-day mortality. Five-year survival was compared to the standardized survival in the general population. RESULTS One hundred and eight patients fulfilling the abovementioned criteria were found (76 males and 32 females, mean age 79.5 years, mean standardized life-expectancy: 7.36 years). Among them, 69% had esophageal tumors and 31% GEJ tumors. The predominant histology was adenocarcinoma (74%). Eighty-six (79.6%) presented with one or more major comorbidities or a history of previous major upper-GI surgery, potentially affecting the surgical outcome. All underwent resection with curative intent (R(0) 83.3%, R(1) 12%, R(2) 4.6%). The overall postoperative morbidity rate was 51.9%, pulmonary complications (37%) being the most frequent. Postoperative mortality, mainly due to cardiopulmonary complications, was 7.4%, which was consistent with that predicted by P-POSSUM score (7.2%) and lower than that predicted by O-POSSUM score (15.1%). Thirty-day mortality was 5.5%, being consistent with that predicted by the Steyerbergs score (6.8%). Overall 5-year survival was 35.7%, while R(0) overall survival 42% and cancer specific R(0) survival 51.7%. CONCLUSIONS Patients 76 years old and over with esophageal or GEJ cancer should not be denied surgery solely on the basis of age. Outcome and long-term results in the selected elderly are not differing from those reported for younger patients. However, despite thorough preoperative assessment being applied in the selection of the candidates for surgery, a practical and reliable individual risk-analysis stratification is still lacking.

Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival

OBJECTIVE Analysis of single centre results and identification of prognostic factors of surgical combined modality treatment in pathological proven stage IIIA-N2 non-small cell lung cancer (NSCLC). METHODS Out of a total of 996 resections for NSCLC between 2000 and 2006, 92 patients with radiological response or stable disease after induction chemotherapy for pathologically proven ipsilateral positive lymph nodes (N2-disease) underwent surgical exploration with the aim of complete resection. Adenocarcinoma and squamous cell carcinomas were equally present (48% vs 43%). Median follow-up of surviving patients (n=36) was 51 (10-94) months. RESULTS Complete resection (i.e., tumour with free margins and negative highest mediastinal lymph nodes, R0) was achieved in 68% (n=63), resection was uncertain or incomplete in 24% (n=22), while surgery was explorative in 8% (n=7). Pneumonectomy was performed in 24%, (bi)lobectomy in 62%, and sleeve lobectomy in 13% of patients. In-hospital mortality was 2.3%. Overall need for ICU stay was 18% (30% after pneumonectomy). Median hospital stay was 10 days (6-157). Downstaging of mediastinal lymph nodes (ypN0-1) was found in 43% (n=40). Overall survival at 5 years (5YS) was 33% (n=92), and after complete resection 43% (n=63). Detection of multilevel compared to single level positive nodes at initial mediastinoscopy was related to lower 5YS (17% vs 39%; p<0.005), and this was identified as an independent prognostic factor in a multivariate analysis of the examined presurgical variables. We found a trend for a better 5YS in patients with mediastinal nodal downstaging compared to patients with persistent N2 disease (49% vs 27%; p=0.095). In the subgroup with persistent N2 disease, single level disease has a significantly better survival (37% vs 7% 5YS, p<0.005). Multivariate survival analysis of the examined surgical variables identified completeness of resection and classification of ypN category (ypN0-1 and ypN2-single level vs multilevel-ypN2 and ypN3) as independent prognostic factors. CONCLUSIONS Surgery after induction chemotherapy for stage IIIA-N2 NSCLC can be performed with an acceptable mortality and morbidity. Baseline single level N2 disease is an independent prognostic factor for long-term survival. Patients with mediastinal downstaging, but also a subgroup of patients with single level persistent N2 disease, after induction therapy have a rewarding survival.