Susanne Blank

Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas

Background:Recently, histopathological tumour regression, prevalence of signet ring cells, and localisation were reported as prognostic factors in neoadjuvantly treated oesophagogastric (junctional and gastric) cancer. This exploratory retrospective study analyses independent prognostic factors within a large patient cohort after preoperative chemotherapy including clinical and histopathological factors.Methods:In all, 850 patients presenting with oesophagogastric cancer staged cT3/4 Nany cM0/x were treated with neoadjuvant chemotherapy followed by resection in two academic centres. Patient data were documented in a prospective database and retrospectively analysed.Results:Of all factors prognostic on univariate analysis, only clinical response, complications, ypTNM stage, and R category were independently prognostic (P<0.01) on multivariate analysis. Tumour localisation and signet ring cells were independently prognostic only when investigator-dependent clinical response evaluation was excluded from the multivariate model. Histopathological tumour regression correlates with tumour grading, Laurén classification, clinical response, ypT, ypN, and R categories but was not identified as an independent prognostic factor. Within R0-resected patients only surgical complications and ypTNM stage were independent prognostic factors.Conclusions:Only established prognostic factors like ypTNM stage, R category, and complications were identified as independent prognostic factors in resected patients after neoadjuvant chemotherapy. In contrast, histopathological tumour regression was not found as an independent prognostic marker.

Prognostic impact of lymph node involvement and the extent of lymphadenectomy (LAD) in adenocarcinoma of the esophagogastric junction (AEG)

BackgroundThe prognostic importance of lymph node (LN) involvement for patients with adenocarcinoma of the esophagogastric junction (AEG) is well-known. In the latest edition of the UICC staging system, the number of metastatic LNs was taken into account, while the extent of lymphadenectomy (LAD) remains unaddressed. Removal of at least six LNs is recommended, but there is no defined minimum number as to classify as (y)pN0. We examined the prognostic value of the number of positive LNs, number of LNs removed, and LN ratio (LNR) in order to determine the influence of an adequate LAD on overall survival (OS).MethodsWe analyzed data of 316 patients with AEG treated in our institution (2001–2011) regarding clinicopathological data, treatment, morbidity, mortality, and long-term prognosis. Univariate and multivariate analysis was performed using Cox regression to evaluate the prognostic impact of(y)pN category, number of LNs removed and LNR.ResultsOS decreased with higher count of positive LNs (p < 0.001) and higher LNR (p < 0.001). Whether >6, >15, or >30 LNs were removed did not influence OS, neither in the entire study population nor within individual (y)pT or (y)pN categories. Multivariate analysis revealed LNR (p < 0.001) besides M category (p = 0.015) and tracheotomy during the postoperative course (p = 0.005) as independent predictors of OS.ConclusionThe classification according to the number of involved LNs in the latest edition of the UICC staging system improves prognostication in patients with AEG. The importance of an adequate LAD is shown by the high prognostic relevance of the LNR rather than the absolute number of LNs removed.

Impact of pretherapeutic routine clinical staging for the individualization of treatment in gastric cancer patients.

PurposeThe usefulness and prognostic impact of a pretherapeutic clinical staging is still a matter of discussion. However, a pretherapeutic estimation of the prognosis would be essential to adjust the patients therapy. Our aim was to compare clinical and histopathological staging and to analyze the predictive value of routine clinical staging and its significance for the individualization of treatment.Patients and methodsWe analyzed the data of 368 patients treated with gastric cancer in the University of Heidelberg, Department of Surgery, from January 2001 to June 2009. Pretherapeutic parameters including sex, age, cTNM, grading, Laurén classification, tumor localization, as well as posttherapeutic parameters were analyzed, and their impact for survival was evaluated. Follow-up data was obtained for all patients (2.17% lost to follow-up).ResultsThe overall accuracy was 64.1% for pT category, 54.5% for pN category, and 80.3% for M category for the primary resected patients. For the patients treated neoadjuvantly, the overall accuracy was 21.8% for the pT category, 58.0% for the pN category, and 80.0% for the M category. The prognosis was associated to the age (p = 0.017), tumor localization (p < 0.001), grading (p = 0.041), cT category (p < 0.001), cN category (p < 0.001), and cM category (p = 0.001). The multivariate analysis, including pre- and postoperative factors, revealed tumor localization (p = 0.002), cN category (p = 0.019), and metastatic lymph node rate (p < 0.001) as independent prognostic factors.ConclusionThe accordance between clinical and histopathological staging is limited, but nevertheless pretherapeutic parameters have a high prognostic impact and could be used for individualized therapy planning. The relevant pretherapeutic prognostic factors can all be determined by routine clinical staging including CT and endoscopy. Consequently pretherapeutic prognostic evaluation and therapy planning seem to be feasible with routine staging methods.

Surgery of gastric cancer and esophageal cancer: Does age matter?

In the past, elderly patients with upper GI cancers were excluded from surgery or multimodal treatment only due to their advanced age. In an aging society this way of patient selection seems to be questionable. The aim of this retrospective exploratory study was to investigate how patients with upper GI cancer over the age of 70 years differ from younger patients in the postoperative course and which parameters influence overall survival in older patient populations.

Surgery in oesophago-gastric cancer with metastatic disease: Treatment, prognosis and preoperative patient selection

BACKGROUND The role of surgical resection in metastatic oesophago-gastric adenocarcinomas (EGA) is not defined and regularly discussed in interdisciplinary tumour boards. Primary objective of this retrospective study was the outcome of patients after surgery. We additionally evaluated our preoperative prognostic score (PPS) based on tumour grading, clinical response to chemotherapy and presumed R-status. METHODS 123 of 811 EGA patients were evaluated as cM1, either confirmed intraoperatively or by imaging. Response evaluation after chemotherapy was performed by endoscopy, CT-scan and histopathologically. The prospectively documented patient and outcome data were analysed retrospectively. RESULTS 70 patients with adenocarcinoma of the oesophago-gastric junction and 53 patients with gastric cancer were included. The majority had one M1 site (n = 102). 72 received preoperative chemotherapy (CTx) and 51 underwent primary resection. 11 were explored without resection. 49/112 (40%) had multivisceral resections and 63/112 (56%) were completely resected (R0). 26/72 (36%) were clinical responders and 30 patients had a favourable PPS. Median survival was 20.0 months. Survival was significantly prolonged by resection, especially complete resection, and by preoperative CTx (all p = 0.001). Multivisceral resection, type or number of metastases, or primary tumour localization had no impact on survival. In patients undergoing preoperative CTx, clinical response and the PPS influenced survival significantly. In R0 resected patients, preoperative CTx, clinical response and the PPS remained prognostic. CONCLUSION Primary resection without preoperative CTx is not appropriate for metastatic EGA. Subgroups of patients with a favourable PPS with response to CTx may be good candidates for surgical resection in metastatic oesophago-gastric cancer.

A retrospective comparative exploratory study on two Methylentetrahydrofolate Reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients

BackgroundMethylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas.Methods569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression).ResultsOnly the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact.ConclusionsThe MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

Inflammatory cytokines are associated with response and prognosis in patients with esophageal cancer

Background Esophageal cancer is often marked by aggressive tumor growth and poor prognosis. Patient groups who benefit from perioperative therapy are not yet defined. The tumor microenvironment and circulating factors as possible predictors of response and prognosis gain interest. This study aimed to investigate cytokines in patients’ serum and tumor tissue with regard to response and prognosis. Results Median survival between SCC and AC was not different (published previously). Lower levels of CCL11 (Eotaxin-1) and CXCL10 (IP-10) in the tumor tissue were associated with a better prognosis (p = 0.022; p = 0.002). In the AC subgroup higher concentrations of TGF-β3 in serum and corresponding tumor tissue were associated with adverse prognosis (p = 0.035; p = 0.006). An association with histopathological response was found for IL-12(p70) and CXCL10 in patients’ sera (p = 0.041; p = 0.032). The tissue levels of TGF-β1 and TGF-β2 were significantly lower in histopathological responders than in nonresponders (p = 0.033; p = 0.007). A similar trend was seen for TGF-β3, without statistical significance (p = 0.097). Materials and Methods Preoperative serum samples and corresponding tumor tissue (n = 54), only serum (n = 20) or only tissue (n = 4) were collected from patients undergoing surgery for cT3/4 esophageal squamous cell cancer (SCC) (n = 34) and adenocarcinoma (AC) (n = 44). All samples were taken after neoadjuvant treatment. All patients received perioperative chemo(radio)therapy. Cytokine levels of 17 different cytokines were measured by multiplex immunoassay and correlated with clinicopathological factors. Conclusions Two chemokines (CCL11 and CXCL10) in posttherapeutic tumor tissue were associated with prognosis in patients with esophageal cancer, lower levels indicating a better prognosis. Lower levels of TGF-β were associated with better response and prognosis in patients with AC.

Minimalinvasive Chirurgie bei Malignomen des Gastrointestinaltrakts: Magen - Kontra-Position

Hintergrund: Bedingt durch Änderungen im Lebensstil gewinnen laparoskopische Verfahren zunehmend an Bedeutung. Zur laparoskopischen Magenchirugie existieren vor allem Studien aus Asien, wo die Inzidenz des Magenkarzinoms und besonders des Frühkarzinoms hoch ist und wo Tumoren häufig im unteren Magendrittel lokalisiert sind. Konträr verhält es sich in Deutschland mit einer rückläufigen Inzidenz des Magenkarzinoms und mit meist lokal fortgeschrittenen Tumoren proximaler Lokalisation. Methode und Ergebnisse: Die Metaanalysen enthalten überwiegend Daten zur laparoskopisch assistierten distalen Gastrektomie mit einer Inzision von 5-6 cm zum Bergen bzw. für schwierige Operationsschritte wie Schließen der Anastomose bzw. Komplettierung der Lymphadenektomie. Für das laparoskopische Vorgehen sprechen übereinstimmend der geringere intraoperative Blutverlust, die kürzere Hospitalisierungsdauer, der geringere postoperative Schmerzmittelverbrauch und das frühere Einsetzen der Darmtätigkeit - allesamt Parameter, die theoretisch auch durch den Einsatz von entsprechendem Instrumentarium und die Etablierung von standardisierten «FastTrack»-Abläufen in der offenen Chirurgie erreicht werden könnten. Bezüglich der Kosten sowie der Morbidität sind die Studien nicht eindeutig. Mit etwa 300 min bleibt die Operationsdauer signifikant länger, auch nach abgeschlossener Lernkurve von etwa 20-60 laparoskopischen Operationen pro Operateur. Dies sind Operationszahlen, die im Westen nur an wenigen Zentren realistisch erreicht werden können. Schlussfolgerungen: Onkologische Gleichwertigkeit konnte bisher nur durch eine ähnliche Anzahl entfernter Lymphknoten, nicht durch ein Langzeit-Follow-up gezeigt werden. Somit ist die laparoskopische Magenchirurgie derzeit in Deutschland kein Standard.

Clinically Staged cT2 Adenocarcinomas of the Gastroesophageal Junction: Accuracy of Staging and Therapeutic Consequences

Background: Multimodality treatment options in locally advanced adenocarcinomas of the esophagogastric junction (AEGs) have been established in the last years. However, the therapeutic approach in patients with clinically staged cT2 tumors remains controversial. The most important determinant is the accuracy of clinical staging. We aimed to evaluate the association of clinical and histopathological staging in patients with cT2 tumors in respect of possible therapeutic consequences. Patients and Methods: Between 2001 and 2011, 71 patients with AEG tumors were clinically staged as cT2 (cN0 = 48 (68%); cN+ = 23 (32%)) and underwent surgical resection. Results: A primary tumor resection was performed in 59 (83%) patients while 12 (17%) patients received neoadjuvant therapy. Primarily resected patients showed the following pT/pN categories: pT1: 13 (22%), pT2: 35 (59%), pT3: 11 (19%), pN0: 23 (39%), whereas the clinical/histopathological pN category included 55% of the patients. Neoadjuvantly treated patients showed the following pT/pN categories: ypT0: 3 (25%), ypT1: 3 (25%), ypT2: 6 (50%), ypN0: 6 (50%). The overall survival of primarily resected patients compared with patients undergoing neoadjuvant therapy was not significantly different. Conclusions: The accuracy of clinical staging in patients with cT2 tumors of the gastroesophageal junction is poor. As in primarily resected patients, over- and understaging balance each other; correct pretherapeutic staging occurs in just about 60% of the patients. Moreover, our study suggests that a radical surgical resection with adequate lymphadenectomy seems to be appropriate for cT2N0 and even in cT2N+ tumors, since down-categorizing and prognosis are not improved for neoadjuvantly treated patients. However, the data have to be interpreted with caution because of the small patient numbers.

A novel pretherapeutic gene expression based risk score for treatment guidance in gastric cancer.

Background Perioperative chemotherapy is an established treatment of advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients. Patients and methods We analyzed 626 carcinomas of the stomach and of the gastro-esophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of 11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analyzing 50 tumor areas from 10 patients. Results A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathologic type suggested two groups with a significant difference in OS [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.17-0.52]. The risk score was successfully validated in an independent cohort (HR 0.32; 95% CI 0.21-0.51; P < 0.001) as well as in subgroups of primarily resected (HR 0.30; 95% CI 0.17-0.54; P < 0.001) and pre-/perioperatively treated patients (HR 0.37; 95% CI 0.17-0.81; P = 0.009). A significant difference in OS of high- and low-risk patients was also found in primarily resected patients with intestinal (HR 0.45; 95% CI 0.23-0.90; P = 0.020) and nonintestinal-type carcinomas (HR 0.1; 95% CI 0.02-0.42; P < 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies. Conclusion The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.