Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.

BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Endoscopic ultrasound for structured surveillance after curative treatment of esophageal cancer.

BACKGROUND: Structured surveillance after treatment of esophageal cancer is not established. Due to a paucity of data, no agreement exists on how surveillance should be performed. The main argument against intensive follow-up in esophageal cancer is that it may not lead to true survival advantage. METHODS: Structured surveillance was performed in 42 patients after multimodal therapy with peri-operative chemotherapy (29) or definitive chemoradiotherapy (13) of esophageal cancer. The surveillance protocol included gastroscopy, endoscopic ultrasound, chest X-ray, abdominal ultrasound, and CEA measurement at regular intervals of up to five years. We analyzed relapse rate, time to relapse, localization of recurrence, diagnosis within or without structured surveillance, diagnostic method providing the first evidence of a relapse, treatment of recurrence, and outcome. RESULTS: Median follow-up was 48 months; 18/42 patients suffered from tumor relapse, with 16 asymptomatic patients diagnosed within structured surveillance. Median time to recurrence was 9 months. Isolated local or locoregional recurrence occurred in 6, and isolated distant relapse in 9 patients. All patients with isolated locoregional recurrence were exclusively diagnosed with endoscopic ultrasound. Six patients received curatively intended therapy with surgery or chemoradiation, leading to long-lasting survival. CONCLUSION: Structured surveillance offers the chance to identify limited and asymptomatic tumor relapse. Especially in cases of locoregional recurrence, long-lasting survival or even a cure can be achieved. Endoscopic ultrasound is the best method for the detection of locoregional tumor recurrence and should be an integral part of structured surveillance after curative treatment of esophageal cancer.

Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma - A Prospective Multicenter DEGUM Study.

BACKGROUND: This prospective multicenter study funded by the DEGUM assesses the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. METHODS: Patients at high risk for HCC with a histologically proven focal liver lesion on B-mode ultrasound were recruited prospectively in a multicenter approach. Clinical and imaging data were entered via online entry forms. The diagnostic accuracies for the noninvasive diagnosis of HCC were compared for the conventional interpretation of standardized CEUS at the time of the examination (= CEUS on-site) and the two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). RESULTS: 321 patients were recruited in 43 centers; 299 (93.1 %) had liver cirrhosis. The diagnosis according to histology was HCC in 256 cases, and intrahepatic cholangiocarcinoma (iCCA) in 23 cases. In the subgroup of cirrhotic patients (n = 299), the highest sensitivity for the diagnosis of HCC was achieved with the CEUS algorithm ESCULAP (94.2 %) and CEUS on-site (90.9 %). The lowest sensitivity was reached with the CEUS LI-RADS algorithm (64 %; p < 0.001). However, the specificity of CEUS LI-RADS (78.9 %) was superior to that of ESCULAP (50.9 %) and CEUS on-site (64.9 %; p < 0.001). At the same time, the negative predictive value (NPV) of CEUS LI-RADS was significantly inferior to that of ESCULAP (34.1 % vs. 67.4 %; p < 0.001) and CEUS on-site (62.7 %; p < 0.001). The positive predictive values of all modalities were high (around 90 %), with the best results seen for CEUS LI-RADS and CEUS on-site. CONCLUSION: This is the first multicenter, prospective comparison of standardized CEUS and the recently developed CEUS-based algorithms in histologically proven liver lesions in cirrhotic patients. Our results reaffirm the excellent diagnostic accuracy of CEUS for the noninvasive diagnosis of HCC in high-risk patients. However, on-site diagnosis by an experienced examiner achieves an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms.

Efficacy of palliative chemotherapy in elderly patients with colorectal cancer.

BACKGROUND: The number of old patients suffering from colorectal cancer rises. In clinical trials, old patients are underrepresented, and chemotherapy is significantly less often performed in elderly patients. We analyzed the impact of elder age for palliative chemotherapy in patients suffering from metastatic colorectal cancer, according to therapeutic drugs used, intensity of treatment performed, and therapeutic results. MATERIALS AND METHODS: We analyzed consecutive patients with metastatic colorectal cancer treated in palliative intention in our department. Assessed data included age ( 75 years), sex, comorbidity, site of primary tumor, k-ras-status, site and amount of metastasis, number and kind of chemotherapeutic agents used, number of consecutive therapy lines performed, dose intensity, toxicity, time between start and end of palliative chemotherapy, and overall survival. Prognostic variables were tested in uni- and multivariate analysis. RESULTS: Ninety-seven patients (69 < 75, 18 > 75 years) were included. Age groups were well balanced according to site of primary tumor, k-ras-mutational status, localization, and number of metastatic sites. Cardial and renal comorbidity was more frequent in elderly patients. The median number of chemotherapeutic drugs used and lines of therapy performed did not differ between age groups, except of oxaliplatin, which was significantly less often used in old patients. Median survival did not differ between age groups (23.4 vs. 23.5 months). In multivariate analysis, only left-sided primary tumor and more than 3 lines of therapy performed were prognostic positive variables. CONCLUSION: Old patients can profit from palliative chemotherapy to the same extent as younger ones.

Sequential endoscopic ultrasound identifies predictive variables for relapse-free follow-up after neoadjuvant chemotherapy in gastric cancer.

BACKGROUND: The accuracy of endosonographic tumor staging after neoadjuvant therapy is less reliable than in primary staging. Therefore, the value of sequential endosonographic examinations after neaodjuvant chemotherapy in gastro-esophageal cancer is discussed controversially. Previous data suggest, that endoscopic ultrasound (EUS) after neoadjuvant treatment using other variables than classic uTN-criteria may identify patients with a better prognosis. METHODS: In 67 patients with locally advanced gastric cancer treated in curative intent, we performed EUS before and after neoadjuvant chemotherapy. Endosonographic yTN-stage was compared to pathohistological yTN-stage after curative resection. The uTN-stage, yuTN-stage, maximal tumor thickness and maximal lymph node diameter as well as the shift of these variables after neoadjuvant therapy were analyzed for their usefulness to predict recurrence-free follow-up. RESULTS: Accuracy of EUS for yTN-staging after neoadjuvant therapy was poor, especially in lower tumor stages. However, three heavily correlated variables analyzed by sequential EUS could be used for the prediction of prognosis: low endosonographic tumor stage (yuT0-2) after neoadjuvant chemotherapy, a decrease of two or more steps in uT-stage and a maximal tumor thickness of <15 mm after chemotherapy were significantly associated with recurrence-free follow-up. Endosonographic T-stage before neoadjuvant therapy, as well as lymph node variables before or after chemotherapy, were of no predictive value. CONCLUSION: In spite of poor concordance between endosonographic and pathohistological TN-stage after neoadjuvant treatment, sequential EUS, performed before and after neoadjuvant therapy, possibly identify patients at risk for tumor relapse after multimodal treatment in gastric cancer. This finding should be validated in a larger patient cohort.

Different accuracy of endosonographic tumor staging after neoadjuvant chemotherapy and chemoradiotherapy in esophageal cancer.

BACKGROUND: Treatment response to neoadjuvant therapy is histologically associated with more or less intensive inflammation and fibrosis. In consequence, accuracy of endosonographic TN-tumor staging after neoadjuvant treatment is hampered. We analyzed whether the kind of treatment chosen [chemoradiotherapy (CRT) or chemotherapy (CT)] differently influences the accuracy of endoscopic ultrasound after neoadjuvant therapy in esophageal cancer. METHODS: We performed serial endoscopic ultrasound examinations in 18 patients after neoadjuvant CRT and 30 patients after neoadjuvant CT. TN-stage was classified according to the standard parameter. Histological examination of the surgical resection specimen served as gold standard. RESULTS: The most frequent error was overstaging, especially in patients with complete tumor response or minimal residual disease. Accuracy of T-staging was significantly worse after CRT (0.16) than after CT (0.43), obviously due to difficulty in distinguishing residual tumor from treatment-associated fibrosis and inflammation. Accuracy of N-staging was also hampered, but to a less extent (sensitivity/specificity 0.85/0.36 after CRT, and 0.5/0.42 after CT). CONCLUSIONS: Accuracy of endosonographic TN-tumor staging is significantly more hampered by neoadjuvant CRT than after CT. However, endoscopic ultrasound is insufficient for TN-staging irrespective of the kind of neoadjuvant therapy performed.

Treatment Intensity, not Age, Affects Survival Time of Patients with Advanced Pancreatic Cancer.

BACKGROUND AND AIMS: Despite older-aged individuals accounting for most patients with pancreatic cancer, elderly patients are still underrepresented in the clinical trials. Our study aims to identify treatment differences as well as to analyze survival times in the younger and older patient group. METHODS: We evaluated the data of 97 pancreatic cancer patients (72 <75 years; 25 ≥75 years) receiving palliative chemotherapy. Age, comorbidity, body mass index (BMI), tumor localization, metastases, carbohydrate-antigen 19-9 (CA19-9) value, number and type of chemotherapeutic agents and treatment regimens used, treatment lines, toxicity and survival time were assessed. RESULTS: The age groups did not differ in their initial conditions (comorbidity, BMI, tumor characteristics). However, treatment intensity of patients ≥ 75 years was lower. Elderly patients received significantly fewer different chemotherapeutic agents and therapeutic regimens, therapy lines and fewer combination chemotherapies. Moreover, elderly patients survived significantly shorter (7.6 vs. 12.7 months, p=0.001). In multivariance analysis, a significant negative influence on survival time was revealed for low therapy intensity (≤2 chemotherapeutics, ≤2 therapy lines), but not for age. In addition, therapy discontinuation and underweight were significantly associated with survival time. CONCLUSION: Not age per se but lower therapy intensity leads to a shorter overall survival in the elderly patient group.

Vocal Fold Paralysis is a Common Complication in Esophageal Cancer Patients with Esophagorespiratory Fistula.

BACKGROUND AND AIMS: The development of an esophagorespiratory fistula (ERF) in patients with esophageal cancer (EC) is associated with poor prognosis. We observed a high rate of vocal fold paralysis (VFP) in patients with ERF. Data on prevalence and complications of VFP in ERF are lacking. The present study investigated the incidence of VFP in patients with malignant ERF and examined possible risk factors and the impact on survival. METHODS: We performed a retrospective case-control study of 46 institutional cases of EC patients with ERF in a time period of eleven years. Patients were matched to 92 randomly selected controls (EC patients without ERF) in a 1:2 fashion for tumor localization and histology. Demographics, clinical characteristics, recurrence, treatment modalities as well as survival were analyzed. RESULTS: Esophageal cancer patients with ERF developed more often VFP than EC patients without ERF (59% vs. 21%; p=0.02; odds ratio (OR) 4.9). Esophageal cancer patients with ERF had a more pronounced weight loss (7.1 vs. 11.5 kg; P = 0.008), as well as higher rates of esophageal (p=<0.001; OR 22.9) and tracheal stenting (p=<0.001; OR 76.8). Proximal tumor growth (p=0.004; OR 7.9), fistula formation to the trachea (p=<0.001; OR 17.2) and recurrent disease (p=0.04, OR 4.7) was associated with VFP development in EC patients with ERF. Vocal fold paralysis in ERF did not adversely affect five-year survival. CONCLUSIONS: Vocal fold paralysis is a common complication in more than half of the patients with ERF in EC. It is associated with proximal tumor growth, fistula formation to the trachea and disease recurrence, but does not influence survival.

Predictors for Treatment Failure of Self-Expandable Metal Stents for Anastomotic Leak after Gastro-Esophageal Resection.

BACKGROUND AND AIMS: Self-expandable metal stents are used for the treatment of anastomotic leaks after gastro- esophageal surgery. Predictors for treatment failure and complications are unknown. In this observational retrospective study, we summarize our experience with self-expandable metal stents for the treatment of anastomotic leaks, in order to determine the predictors of treatment failure. METHODS: Between 2009 and 2015, 34 patients with anastomotic leak after curative resection of gastro- esophageal cancer were treated with self-expandable metal stents. Gender, histology, comorbidity, body mass index, neoadjuvant therapy, previous surgery, leak size, and stent diameter were analyzed for their predictive value according to treatment success and complication rate. RESULTS: Leak closure rate was 76%. Risk factors for treatment failure were neoadjuvant chemo-radiotherapy, squamous cell histology, and esophageal tumor location. Gender, comorbidity, body mass index, neoadjuvant chemotherapy, and previous surgery were not correlated with outcome. Mortality rate was 20%, most often due to uncontrolled leak. Severe stent-related complications occurred in 15% of patients, most of them following insertion of a large-sized stent. CONCLUSION: Squamous cell histology, neoadjuvant chemo-radiotherapy, and esophageal tumor location are predictors for treatment failure. Severe stent-related complications seem to be preferentially associated with the use of large-sized stents.

Multicenter, randomized comparison of the diagnostic accuracy of 19-gauge stainless steel and nitinol-based needles for endoscopic ultrasound-guided fine-needle biopsy of solid pancreatic masses.

BACKGROUND: The use of 19-gauge (G) stainless steel needles for endoscopic ultrasound-guided fine-needle biopsy of a pancreatic mass often results in technical difficulties due to an inability to advance the relatively rigid needle out of the endoscope. More flexible nitinol-based needles might decrease such technical difficulties and thus increase diagnostic accuracy. OBJECTIVE: In this prospective multicenter randomized single-blinded study we compared the diagnostic value of those two needle types in patients with a solid pancreatic lesion. METHODS: Patients with a solid pancreatic mass were diagnosed with endoscopic ultrasound-guided fine-needle biopsy using one puncture with each needle in a randomized fashion. The primary endpoint was the diagnostic accuracy of each needle. Secondary endpoints included time for puncture, amount of tumour tissue obtained, and technical failure. Histological specimens were centrally reviewed by a pathologist blinded to the final needle type and final diagnosis (ClinicalTrials.gov Identifier: NCT02909530). RESULTS: Out of 46 prospectively recruited patients, central pathological examination was available for 41. Diagnostic accuracy for the two needles combined was 87.8%. Diagnostic accuracy was 66% and 68% using the stainless steel- and nitinol-based needle respectively. Time spent for puncturing was 137 ± 61 s (mean ± standard deviation) for the stainless steel and 111 ± 53 s for the nitinol-based needle (p = 0.037). Technical failure occurred in three (6.5%) cases using the stainless steel- and in none using the nitinol-based needle. CONCLUSIONS: Usage of a nitinol-based 19-G needle failed to present a significant superior accuracy compared with a stainless steel needle in endoscopic ultrasound-guided fine-needle biopsy of solid pancreatic lesions.

Risk Factors for the Development of Esophagorespiratory Fistula in Esophageal Cancer.

BACKGROUND AND AIMS: The development of esophagorespiratory fistula (ERF) in esophageal cancer (EC) is a devastating complication, leading to poor survival rates and low quality of life. Goal of this study was to identify risk factors leading to fistula formation in esophageal cancer. METHODS: We identified 47 patients with malignant ERF formation in EC in a period of 10 years. Clinical characteristics were compared by univariable analysis to 47 randomly selected patients with EC, but without ERF. A case-control study was conducted for patients with squamous cell carcinoma (SCC) and ERF matching in a 1:2 fashion for primary tumor localization. RESULTS: Identifiable risk factors in EC patients were histology of SCC (P-value < 0.001), former or current smoking status (P = 0.002) and primary tumor localization in the proximal esophagus (P < 0.001). The "hot spot" for ERF formation was tumor growth 20-25cm distal to dental arch. An additional risk factor in SCC patients was age. Patients with ERF formation in SCC were younger than patients without ERF (median 63 vs. 67 years, P = 0.02). No difference in the rate of fistula formation was seen between esophagectomy and definitive chemoradiation, but the latter developed ERF earlier in the course of the disease (237 vs. 596.5 days, P = 0.01). CONCLUSION: Patients with proximal SCC of the esophagus and a smoking history, as well as young patients with SCC should be closely monitored for ERF formation.

Feasibility of alternating induction and maintenance chemotherapy in pancreatic cancer.

Chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC) have changed since the introduction of FOLFIRINOX. Due to toxicity, dosage and number of applied cycles are limited. In analogy to chemotherapy strategies in colon cancer we used a scheme of induction, maintenance and re-induction therapy in PDAC to alleviate such toxicities and increase the number of applied cycles. Here we report first experiences with this approach. Data of all patients who received FOLFIRINOX for metastatic or locally advanced PDAC in our center using induction chemotherapy followed by maintenance therapy from 2011 until November 2016 was collected and analyzed retrospectively. Progression free survival was assessed starting induction therapy until progressive disease (PD) during maintenance or treatment pause (PFS1) and until progression during re-induction therapy (PFS2). 13 patients received induction therapy which was followed by maintenance therapy. Re-induction due to PD during therapy was applied in 11 patients. The median PFS1 was 10.6 months (95% CI; 6.7-14.4), PFS2 was 14.1 months (95% CI; 8.2-19.9) and overall survival was 18.3 months (95% CI; 14.8-21.8). The use of FOLFIRINOX as induction, followed by maintenance and re-induction therapy in case of PD is feasible in the treatment of PDAC and might lead to a prolonged PFS with less toxicity.

Endosonographic tumor staging for treatment decision in resectable gastric cancer.

BACKGROUND AND AIMS: Neoadjuvant preoperative chemotherapy is the standard of care in locally advanced resectable gastric cancer. Therefore, accurate locoregional staging is essential for treatment decision. EUS is believed to be the most performant diagnostic method for locoregional staging. However, it is questionable, if results from centers of excellence can be maintained in clinical routine. METHODS: We retrospectively analyzed the data of 62 resectable gastric cancers staged by EUS during routine clinical work-up. Preoperative variables (tumor size and site, histological differentiation) were compared with the postoperative pathology. RESULTS: 19 locally limited (T1-2, N0), and 43 locally advanced (T3-4, or N+ irrespective of T stage) were analyzed. The sensitivity of EUS for the detection of locally advanced disease was 93%, with a specificity of 78%. CONCLUSIONS: Even in daily routine practice, differentiation of locally limited and advanced disease with EUS can be performed with high sensitivity and good specificity. Therefore, EUS is an essential part of the diagnostic procedure in patients with gastric cancer.

An unusual cause of dysphagia: esophageal tuberculosis.

A 25-year old Indian exchange-student presented to our department with a three week history of dysphagia. Diagnostic evaluation by upper gastrointestinal endoscopy, endosonography and chest-CT revealed a tumor-suspect ulcerative lesion at the middle esophagus, and a mediastinal lymph node enlargement. Initial histopathological evaluation of multiple esophageal tissue biopsies showed an unspecific esophagitis without signs for malignancy. A positive T-spot (R) TB assay result, together with the bronchoscopic detection of a small exophytic lesion at the right main bronchus depicting caseating epitheloid cell granulomas, provided evidence for a tuberculous etiology of the esophageal tumor. Multiple further deep submucosal biopsies were needed to finally detect epitheloid cell granulomas in the esophageal lesion. Microbacteriological or molecular tests were negative for M. tuberculosis. Tuberculostatic treatment resulted in a good response with complete remission of the esophageal lesion and the mediastinal lymph node enlargement. Esophageal tuberculosis is rare in developed countries, and its possible presence deserves consideration particularly in patients at risk.