Summary Background In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET (18 FFDG-PET) during ...neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. Methods Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. Findings 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39–59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2·3 years (IQR 1·7–3·0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25·8 months (19·4–32·2) in non-responders (HR 2·13 1·14–3·99, p=0·015). Median event-free survival was 29·7 months (95% CI 23·6–35·7) in metabolic responders and 14·1 months (7·5–20·6) in non-responders (hazard ratio HR 2·18 1·32–3·62, p=0·002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% 95% CI 48–67), but no histological response was noted in metabolic non-responders. Interpretation This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The determination of prognosis in patients with esophageal squamous cell carcinoma (ESCC) is primarily based on staging according to the TNM-classification, whereas conventional grading is of minor ...clinical importance because of its deficiencies in prognostic patient stratification. Recently, a novel, highly prognostic grading scheme based on budding activity and cell nest size has been proposed for squamous cell carcinoma (SCC) of both pulmonary as well as oral origin. In order to investigate the utility and transferability of this approach to ESCC, we evaluated budding activity and cell nest size, as well as other histomorphologic characteristics, in a cohort of 135 primarily resected tumors and correlated the results with clinicopathologic and outcome parameters. High budding activity and small cell nest size showed a strong association with reduced overall, disease-specific, and disease-free survival (P<0.001, respectively) in ESCC. The combination of both markers in a 3-step grading system showed excellent prognostic separation of well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) carcinomas (P<0.001). The hazard ratio for disease-free survival in multivariate analysis under inclusion of stage was 2.97 for G2 and 5.42 for G3 ESCC (P<0.001). World Health Organization–based grading had no prognostic impact. Taken together, our data prove the value of tumor budding and cell nest size as excellent outcome predictors in ESCC and validate the utility of a previously established grading scheme proposed for oral and pulmonary SCC in this tumor entity. Ultimately, these combined efforts may result in a universal grading system for SCC regardless of the site of origin.
Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of ...purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines.
Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required.
This trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466).
This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).
Background
The optimal surgical approach for adenocarcinoma directly at the esophagogastric junction (AEG II) is still under debate. This study aims to evaluate the differences between right ...thoracoabdominal esophagectomy (TAE) (Ivor–Lewis operation) and transhiatal extended gastrectomy (THG) for AEG II.
Methods
From a prospective database, 242 patients with AEG II (TAE,
n
= 56; THG,
n
= 186) were included and analyzed according to characteristics and perioperative morbidity and mortality and overall survival (chi-square, Mann–Whitney
U
, log-rank, Cox regression).
Results
Groups were comparable at baseline with exception of age. Patients older than 70 years were more frequently resected by THG (
p
= 0.003). No differences in perioperative morbidity (
p
= 0.197) and mortality (
p
= 0.711) were observed, including anastomotic leakages (
p
= 0.625) and pulmonary complications (
p
= 0.494). There was no significant difference in R0 resection (
p
= 0.719) and number of resected lymph nodes (
p
= 0.202). Overall median survival was 38.4 months. Survival after TAE was significantly longer than after THG (median OS not reached versus 33.6 months,
p
= 0.02). Multivariate analysis revealed pN-category (
p
< 0.001) and type of surgery (
p
= 0.017) as independent prognostic factors. The type of surgery was confirmed as prognostic factor in locally advanced AEG II (cT 3/4 or cN1), but not in cT1/2 and cN0 patients.
Conclusions
Our single-center experience suggests that patients with (locally advanced) AEG II tumors may benefit from TAE compared to THG. For further evaluation, a randomized trial would be necessary.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In esophageal cancer, functional imaging using PET can provide important additional information beyond standard staging techniques that may eventually lead to therapeutic consequences. The most ...commonly used tracer is fluorodeoxyglucose (FDG), which has high avidity for both squamous cell cancer and adenocarcinoma of the esophagus. The value of FDG-PET is limited in early esophageal cancer, whereas additional information is provided in 15% to 20% of locally advanced tumors. Neoadjuvant treatment is currently the standard of care in locally advanced esophageal cancer in most countries because randomized studies have shown a significant survival benefit. Because responders and nonresponders have a significantly different prognosis, functional imaging to tailor preoperative treatment would be of interest. Metabolic imaging using FDG-PET is an established method of response evaluation in clinical trials. The value of metabolic response evaluation is known to depend on the histologic subtype and the type of preoperative treatment delivered. An association of FDG-PET-based metabolic response with clinical response and prognosis was shown for absolute standardized uptake value (SUV) or a decrease of SUV levels before, during, and after therapy. However, contradictory findings exist in the literature and prospective validation is missing. Additionally, no consensus exists on time points or cutoff levels for metabolic response evaluation. Furthermore, correct prediction of a posttherapeutic pathologic complete remission is currently not possible using FDG-PET. Of high interest is early response monitoring during preoperative chemotherapy, with potential subsequent therapy modification. This tailored approach still needs validation in prospective multicenter trials.
Background
To date there is no evidence that more intensive follow-up after surgery for esophagogastric adenocarcinoma translates into improved survival. This study aimed to evaluate the impact of ...standardized surveillance by a specialized center after resection on survival.
Methods
Data of 587 patients were analyzed who underwent curative surgery for esophagogastric adenocarcinoma in our institution. Based on their postoperative surveillance, patients were assigned to either standardized follow-up (SFU) by the National Center for Tumor Diseases (SFU group) or individual follow-up by other physicians (non-SFU group). Propensity score matching (PSM) was performed to compensate for heterogeneity between groups. Groups were compared regarding clinicopathological findings, recurrence, and impact on survival before and after PSM.
Results
Of 587 patients, 32.7% were in the SFU and 67.3% in the non-SFU group. Recurrence occurred in 39.4% of patients and 92.6% within the first 3 years; 73.6% were treated, and of those 17.1% underwent resection. In recurrent patients overall and post-recurrence survival (OS/PRS) was influenced by diagnostic tools (
p
< 0.05), treatment (
p
≤ 0.001), and resection of recurrence (
p
≤ 0.001). Standardized follow-up significantly improved OS (84.9 vs. 38.4 months,
p
= 0.040) in matched analysis and was an independent positive predictor of OS before and after PSM (
p
= 0.034/0.013, respectively).
Conclusion
After PSM, standardized follow-up by a specialized center significantly improved OS. Cross-sectional imaging and treatment of recurrence were associated with better outcome. Regular follow-up by cross-sectional imaging especially during the first 3 years should be recommended by national guidelines, since early detection might help select patients for treatment of recurrence and even resection in few designated cases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Recent data suggest primary resection as the preferable approach in patients with signet ring cell gastric cancer (SRC). The aim of our retrospective exploratory study was to evaluate the ...influence of SRC on prognosis and response in esophagogastric adenocarcinoma treated with neoadjuvant chemotherapy.
Methods
A total of 723 locally advanced esophagogastric adenocarcinomas (cT3/4 N any) documented in a prospective database from two academic centers were classified according to the WHO definition for SRC (more than 50 % SRC) and analyzed for their association with response and prognosis after neoadjuvant treatment.
Results
A total of 235 tumors (32.5 %) contained SRC. Median survival of SRC was 26.3 compared with 46.6 months (
p
< 0.001) for non-SRC. SRC were significantly associated with female gender, gastric localization, advanced ypT and R1/2 categories, and lower risk of surgical complications and anastomotic leakage (each
p
< 0.001). Clinical (21.1 vs. 33.7 %,
p
= 0.001) and histopathological response (less than 10 % residual tumor: 16.3 vs. 28.9 %,
p
< 0.001) were significantly less frequent in SRC. Clinical response (
p
= 0.003) and complete histopathological response (pCR) (3.4 %) (
p
= 0.003) were associated with improved prognosis in SRC. Clinical response, surgical complications, ypTN categories, but not SRC were independent prognostic factors in forward Cox regression analysis in R0 resected patients. Risk of peritoneal carcinomatosis was increased (
p
< 0.001), while local (
p
= 0.015) and distant metastases (
p
= 0.02) were less frequent than in non-SRC.
Conclusions
Prognosis of SRC is unfavorable. Although response to neoadjuvant chemotherapy is rare in SRC, it is associated with improved outcome. Thus, chemotherapy might not generally be abandoned in SRC. A stratification based on SRC should be included in clinical trials.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog 18Ffluorodeoxyglucose (FDG) allows to ...select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response.
Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET.
Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopathologic response rate of 5% (P = .001) and a 3-year survival rate of 35% (P = .01). A multivariate analysis (covariates: ypT-, ypN-category, histopathologic response) demonstrated that metabolic response was the only factor predicting recurrence (P = .018) in the subgroup of completely resected (R0) patients.
This study prospectively demonstrates that changes in tumor metabolic activity during chemotherapy predict response, prognosis, and recurrence. These data provide the basis for clinical trials in which preoperative treatment is changed for patients without a metabolic response early in the course of therapy. PET-guided induction therapy may even be applicable to earlier tumor stages because surgery is only minimally delayed in nonresponding patients.
Esophageal cancer can be divided in squamous-cell cancer (SCC) and adenocarcinoma (Barrett cancer: AEG I) by histopathology. However, most studies do not differentiate between these two tumor ...entities. SCC is associated with a lower socioeconomic level with nicotine and alcohol abuse resulting in comorbidities like liver cirrhosis and reduced pulmonary function; in contrast, AEG I is associated with a high socioeconomic level and cardiovascular risk factors. The median age of patients with SCC is 10 years younger than with AEG I. The localization of AEG I is in 94% below the tracheal bifurcation, whereas SCC has contact to the tracheal bronchial tree in 75%. Furthermore, SCC shows an earlier lymphatic spread and a worse prognosis compared to AEG I. The different localization and different comorbidities require different therapeutic strategies. The preoperative induction therapy consists of combined chemoradiotherapy for locally advanced SCC and of chemotherapy for AEG I in our department. Due to the favorable position of AEG I a classic Ivor-Lewis procedure ending with an intrathoracic anastomosis is possible, in contrast, SCC frequently requires a subtotal esophagectomy with cervical anastomosis (in a two step strategy). Therefore, at the moment there is no doubt that SCC and AEG I are two different diseases with different pathogenesis, epidemiology, tumor biology and prognosis requiring different therapeutic strategies. We suggest that the two different tumor entities should be analyzed and reported separately to provide comparable results in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
Response to neoadjuvant chemotherapy is an independent prognostic factor in locally advanced gastric cancer. However, no prospectively tested pretherapeutic parameters predicting response ...and/or survival in gastric cancer are available in clinical routine.
Methods
We evaluated the prognostic significance of various clinical pathologic parameters in 410 patients who were treated with neoadjuvant chemotherapy followed by gastrectomy. Clinical and histopathologic response evaluation was performed by using standardized criteria. A prognostic score was created on the basis of the variables identified in the multivariate analysis.
Results
Three pretherapeutic parameters were identified as positive predictive factors for response and prognosis: tumor localization in the middle third of the stomach (
P
= 0.001), well-differentiated tumors (
P
= 0.001), and intestinal tumor type according to Laurén classification (
P
= 0.03). A prognostic index was constructed, dividing the patients into three risk groups: low (
n
= 73), intermediate (
n
= 274), and high (
n
= 63). The three groups had significantly different clinical (
P
= 0.007) and histopathologic response rates (
P
= 0.001) and survival times, with a median survival time that was not reached in the low-risk group, 39.2 months in the intermediate-risk group, and 20.5 months in the high-risk group. The corresponding 5-year survival rates were 65.3, 41.2, and 21.2% (
P
< 0.001), respectively.
Conclusions
A simple scoring system based on three clinicopathologic parameters accurately predicts response and prognosis in neoadjuvant treated gastric cancer. This system provides additional useful information that could be applied to select gastric cancer patients pretherapeutically for different treatment approaches. Prospective testing of the score in an independent patient cohort is warranted.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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