Johnny Moons

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.

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.

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.

Minimally invasive oesophagectomy: a valuable alternative to open oesophagectomy for the treatment of early oesophageal and gastro-oesophageal junction carcinoma

OBJECTIVE The aim was to conduct a comparative analysis of outcome after minimally invasive oesophagectomy (MIO) versus open oesophagectomy (OO) for early oesophageal and gastro-oesophageal junction (GOJ) carcinoma. METHODS Inclusion criteria for MIO and a matched group of OO were pT<2 and N0. Surgical outcome, complications, survival and health-related quality of life (HRQL) were assessed. RESULTS Between January 2005 and January 2010, 175 patients (101 OOs, 65 MIOs and nine MIOs converted to OO) fulfilled the abovementioned criteria. Histology was predominantly adenocarcinoma (75%), equally distributed between both groups as were preoperative co-morbidities (p = 0.43), pathologic staging (pT: p = 0.56) and mean number of resected lymph nodes in pTIS/1a (p = 0.23) and pT1b (p = 0.13). Blood loss was less (p = 0.01) and duration of operation longer (p = 0.001) in MIO. Hospital mortality (p = 0.66) and postoperative complications (p = 0.34) were comparable. However, respiratory complications (p = 0.008) and intensive care unit (ICU) admission (p = 0.02) were higher in OO. Gastrointestinal complications (p = 0.005), that is, gastroparesis (p = 0.004) were more frequent in MIO. At 3 months, postoperative fatigue, pain (general) and gastrointestinal pain were less in MIO (p = 0.09, 0.05 and 0.01, respectively). Five-year cancer-specific and recurrence-free survival stratified to the pathologic T-stage were not statistically different between MIO and OO. CONCLUSION MIO is a valuable alternative to OO for the treatment of early oesophageal and GOJ carcinoma. This study underscores the need for large-scale, preferably multicentric studies to assess the real value of MIO versus OO.

Recurrence pattern in patients with a pathologically complete response after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer

Little is known about recurrence patterns in patients with a pathologically complete response (pCR) or an incomplete response after neoadjuvant chemoradiotherapy (CRT) followed by resection for oesophageal cancer. This study was performed to determine the pattern of recurrence in patients with a pCR after neoadjuvant CRT followed by surgery.

Surgical management of submucosal esophageal cancer: extended or regional lymphadenectomy?

Introduction:Radical esophagectomy is considered the standard therapy for tumors that infiltrate the submucosa of the esophagus (T1b), as the prevalence of lymph node metastases has been reported in up to 40% of these patients. It remains unclear whether radical esophagectomy with extended lymphadenectomy is needed or whether a surgical procedure with only regional lymphadenectomy suffices. The aim of this study was to compare outcomes of patients who underwent esophagectomy for T1b cancer through a transthoracic approach with extended lymphadenectomy (TTE) with those of patients in whom transhiatal esophagectomy (THE) was performed with a regional lymph node dissection. Methods:Patients who underwent esophagectomy for T1b cancer between 1990 and 2004 and who did not receive (neo)adjuvant therapy were included. Data were collected from prospective databases of 4 centers. In Leuven, Belgium (n = 101), and Los Angeles, CA (n = 31), patients with T1b tumors had been operated on via TTE with extended lymphadenectomy, whereas in Amsterdam (n = 43) and Rotterdam (n = 47), the Netherlands, THE with regional lymphadenectomy had been performed. Results:The 2 patient groups (TTE, n = 132; THE, n = 90) were comparable with regard to age, body mass index, and ASA classification. Operative time was longer in patients who underwent TTE (390 minutes) versus THE (250 minutes) (P < 0.001). The yield of lymph nodes resected was higher in the TTE group (median: 32) versus THE (median: 10) (P < 0.001). Overall morbidity, in-hospital mortality, and length of hospital stay were comparable between both the groups. In the TTE group, 27.3% of complications were classified as major versus 14.4% in the THE group (P < 0.001); however, the reoperation rate was higher after THE (12.2%) versus TTE (3.8%) (P = 0.01). There was no difference in pathological outcomes (infiltration depth, pN stage, pM stage, positive lymph node ratio) between both groups. Overall, 5-year survival (63.4% TTE vs 69.4% THE; P = 0.55) and disease-free 5-year survival (76.9% TTE vs 78.3% THE; P = 0.65) were comparable between both the groups. In patients with N1 disease, disease-free 5-year survival was 49.8% in the TTE group versus 40.0% in the THE group (P = 0.57). Conclusions:In patients with submucosal esophageal cancer (T1b), TTE with extended lymphadenectomy and THE with regional lymphadenectomy had similar short-term outcome and long-term survival. In the selected group of T1bN1 patients, TTE may be the preferred operative technique because of a potential disease-free survival benefit; in patients with T1bN0 disease, THE with en bloc dissection of the esophagus and regional lymph nodes offers an oncologically safe and less invasive treatment.

Predicting individual survival after potentially curative esophagectomy for adenocarcinoma of the esophagus or gastroesophageal junction.

Introduction:Even after potentially curative esophagectomy, the majority of patients with adenocarcinoma of the esophagus or gastroesophageal junction die due to cancer recurrence. To predict individual disease-specific survival, a nomogram has been developed in a high-volume center in the Netherlands. The validity of this nomogram was externally tested in patients treated in another country at a different high-volume institution. Methods:Clinicopathological data from patients who underwent a macroscopically radical resection in a high-volume center in Leuven, Belgium, were used to validate the original nomogram based on a Cox regression model. Moreover, it was examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the nomogram in the validation cohort. Calibration was evaluated by comparing the observed survival with the expected survival as predicted by the original nomogram across patients with different risk profiles. The discriminatory ability of the nomogram was determined in the validation cohort, using the concordance index and compared with the original estimate. Results:A total of 382 patients were used in the validation study. The median esophageal cancer-specific survival was 38 months. None of the coefficients re-estimated in the validation cohort differed significantly from the values of the original nomogram. Observed and expected survival curves showed good calibration. Discrimination of the original nomogram was preserved in the validation cohort: the concordance index hardly decreased from 0.77 in the original cohort to 0.76 in the validation cohort. Conclusions:The nomogram model that was originally developed in a Dutch institute had good individual discriminatory properties and good overall calibration when applied to an independent series of patients. The nomogram was updated using the data from both cohorts to provide even more robust estimates of survival for individual patients. This tool is clinically helpful to supply more reliable prognostic information, to offer tailored follow-up schedules and/or novel therapeutic strategies in subgroups of patients with higher risk of recurrence.

Signet Ring Cells in Esophageal and Gastroesophageal Junction Carcinomas Have a More Aggressive Biological Behavior

Objective:To clarify the biologic behavior of esophageal signet ring cell (SRC) carcinomas of the esophagus and gastroesophageal junction (GEJ). To evaluate the accuracy of pretreatment biopsies in diagnosing true SRC carcinoma. Background:In contrast with gastric cancer, little is known about the biologic behavior and prognosis of SRC. Methods:All adenocarcinomas (ADC) of the esophagus and GEJ-patients undergoing primary resection between 1990 and 2009 were included (n = 920). Specimens containing SRCs (n = 114) were classified according to World Health Organization criteria (>50% SRC or <50% SRC). Results:Thirty-two patients showed more than 50% SRC and 71 patients showed less than 50% SRC. Overall cancer-specific 5-year survival was worse for SRC (22.4%, P < 0.0001) and for SRC > 50% (13.6%, P = 0.0001) compared with ADC. Complete resection was achieved in 86.5% of patients (n = 697) in ADC, 69.5% (n = 57) in SRC < 50%, and 78.1% (n = 25) in SRC > 50% (vs ADC, respectively, P < 0.0001 and P = 0.1801). In 379 pN + R0 patients, the median number of positive lymph nodes was comparable between ADC and SRC < 50% (4 vs 5, P = 0.207) or SRC > 50% (4 vs 8, P = 0.077). Compared with ADC, SRC > 50% showed more pN3s (30% vs 61%, P = 0.006), higher recurrence (56% vs 42% for ADC, P = 0.003), and local-regional recurrences (29% vs 16%, P = 0.002). Pretreatment biopsies were unreliable to define the presence of SRC > 50% (sensitivity = 56.3%, positive predictive value = 43.9%). Conclusions:SRCs are aggressive neoplasms associated with poorer prognosis than other ADCs after primary esophagectomy. Because our data suggest that pretreatment biopsies failed to reliably define presence of SRC > 50%, presence of SRCs in pretreatment biopsies seems to be of no use to define treatment strategy or prognosis.

Assessing the relationships between health-related quality of life and postoperative length of hospital stay after oesophagectomy for cancer of the oesophagus and the gastro-oesophageal junction

OBJECTIVES To evaluate baseline health-related quality of life (HRQL) factors that influence short-term outcome after oesophagectomy for cancer of the oesophagus and gastro-oesophageal junction and the effects of postoperative length of hospital stay on postoperative HRQL, as perceived by the patients themselves. METHODS Four hundred and fifty-five patients operated on with curative intent between January 2005 and December 2009 were analysed. HRQL scores were obtained by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30 and oesophageal-specific symptoms (OES-18) questionnaires at baseline (=day before surgery) and 3-monthly post-surgery for the first year. RESULTS There were 372 males and 83 females, with a mean age of 63.1 years. Hospital mortality was 3.7% (17 patients). When analysing postoperative length of stay (LOS), a median of 10 days was found. In a multivariable analysis, using a binary logistic regression model, independent prognosticators for a longer LOS (>10 days) were: medical [hazard ratio, HR, 6.2 (3.62-10.56); P < 0.0001] and surgical [HR 2.79 (1.70-4.59); P < 0.0001] morbidity, readmittance to intensive care unit [HR 33.82 (4.55-251.21); P = 0.001] and poor physical functioning [HR 1.89 (1.14-3.14); P = 0.014]. Postoperatively, patients with early discharge (LOS <10 days) indicated, at 3 and 12 months postoperatively, significant better HRQL scores in the functional scales (physical, emotional, social and role functioning) and in symptoms scales (fatigue, nausea, dyspnoea appetite loss and dry mouth) when compared with LOS >10 days. Return to the level of the reference population scores was achieved at 1 year in the LOS ≤10 days for almost all the scales, but not in the LOS >10 days group. CONCLUSIONS A better perception of preoperative physical functioning might have a beneficial effect on LOS. Our data, furthermore, suggest that early discharge correlates with improved postoperative HRQL outcomes. A clear decrease of the HRQL is seen at 3 months after the surgery, particularly in the LOS >10 days group. Generally, return to the level of the reference population scores is achieved at 1 year in the LOS ≤10 days, but not in the LOS >10 days group.