Improving the Quality of Care for Cancer Patients through Oncological Second Opinions in a Comprehensive Cancer Center: Feasibility of Patient-Initiated Second Opinions through a Health-Insurance Service Point.

BACKGROUND: To improve the quality and cost-effectiveness of care, cancer patients can obtain a second medical opinion on their treatment. Validation of the diagnostic procedure (e.g., imaging), diagnosis, and treatment recommendation allows oncological therapy to be applied in a more targeted way, optimizing interdisciplinary care. This study describes patients who received second opinions at the Comprehensive Cancer Center for Erlangen-Nuremberg metropolitan area in Germany over a 6-year period, as well as the amount of time spent on second-opinion counseling. METHODS: This prospective, descriptive, single-center observational study included 584 male and female cancer patients undergoing gynecological, urologic, or general surgery who sought a second medical opinion. The extent to which the first opinion complied with standard guidelines was assessed solely descriptively. RESULTS: The first opinion was in accordance with the guidelines and complete in 54.5% of the patients, and guideline compliant but incomplete in 13.2%. The median time taken to form a second opinion was 225 min, and the cancer information service was contacted by patients an average of eight times. CONCLUSIONS: The initial opinion was guideline compliant and complete in every second case. Without a second opinion, the remaining patients would have been denied a guideline-compliant treatment recommendation. Obtaining a second opinion gives patients an opportunity to receive a guideline-compliant treatment recommendation and enables them to benefit from newer, individualized therapeutic approaches in clinical trials. Establishing patient-initiated second opinions via central contact points appears to be a feasible option for improving guideline compliance.

The health-related quality of life of sarcoma patients treated with neoadjuvant versus adjuvant radiotherapy - Results of a multi-center observational study.

AIM: The sequence of radiotherapy and resection in patients with soft tissue sarcomas is usually discussed on an individual basis. Better understanding of potential differences of health-related quality of life (QoL) between patients undergoing adjuvant (ART) versus neoadjuvant radiotherapy (NART) is therefore helpful for clinical decision making. METHODS: Adult sarcoma patients from 39 hospitals completed the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). Differences in global QoL, physical functioning, role functioning, fatigue, pain, and insomnia between ART versus NART were investigated with multivariate regression, adjusting for age, gender, chemotherapy, grading, stage, tumor location, recurrence/distant metastasis, sarcoma type, time since last treatment, and treatment status using validated thresholds. RESULTS: A total of 1110 patients participated. Of them, 340 had received radiotherapy (NART: n = 95, 28%; ART: n = 245, 72%). Global QoL was 59.3 on average after NART and 60.5 after ART (Badj = 1.0, p = 0.74). Physical functioning was 65.9 compared to 70.5 (Badj = 4.2; p = 0.16), role function 48.8 vs. 56.7 (Badj = 7.0, p = 0.08), fatigue 47.5 vs. 45.4 (Badj = -1.2; p = 0.71), pain 40.2 vs. 34.1 (Badj = -6.8; p = 0.08), and insomnia 33.7 vs. 41.6 (Badj = 5.5, p = 0.16). Among patients with NART, clinically relevant QoL impairments were less frequent 2 years after treatment compared to < 2 years thereafter (n = 6 vs. n = 4 on average). CONCLUSION: There is little evidence for QoL differences in most domains and overall QoL between the two irradiation groups. However, patients after NART might experience worse role functioning and pain but fewer problems with insomnia compared to patients after ART.

Continuous or interrupted suture technique for hepaticojejunostomy during pancreatoduodenectomy (HEKTIK trial): study protocol of a randomized controlled multicenter trial.

BACKGROUND: Hepaticojejunostomy is commonly performed in hepato-bilio-pancreatic surgery, particularly during pancreaticoduodenectomy. The purpose of this study is to evaluate the safety and efficiency of two commonly applied suture techniques (the interrupted versus the continuous suture technique) in patients undergoing a hepaticojejunostomy during pancreatoduodenectomy. METHODS: The HEKTIK trial is a multicenter, randomized controlled, patient-blinded surgical explorative trial with two parallel study groups. An adaptive sample size design was chosen: First, 100 patients scheduled for surgery including a hepaticojejunostomy will be randomized 1:1 either to the interrupted suture technique or the continuous suture technique after informed consent. Based on this data, needed sample size will be adjusted. The primary endpoint will be the occurrence of anastomotic leakage of hepaticojejunostomy, defined as bilirubin concentration in the drain fluid at least 3 times the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis (according to the definition of ISGLS). Further perioperative parameters like other morbidities as well as duration and costs of the hepaticojejunostomy will be analyzed as secondary outcomes. DISCUSSION: Until now there are no randomized controlled comparative data of these two suture techniques for hepaticojejunostomy. The HEKTIK trial will investigate the yet unanswered question of whether the interrupted suture or the continuous suture technique has advantages performing a hepaticojejunostomy during pancreatoduodenectomy. TRIAL REGISTRATION: German Clinical Trials Register DRKS00024395 . Registered on 01 February 2021.

Consensus Statement on Mandatory Measurements for Pancreatic Cancer Trials for Patients With Resectable or Borderline Resectable Disease (COMM-PACT-RB): A Systematic Review and Delphi Consensus Statement.

Importance: Pancreatic cancer is the third most common cause of cancer death; however, randomized clinical trials (RCTs) of survival in patients with resectable pancreatic cancer lack mandatory measures for reporting baseline and prognostic factors, which hampers comparisons between outcome measures. Objective: To develop a consensus on baseline and prognostic factors to be used as mandatory measurements in RCTs of resectable and borderline resectable pancreatic cancer. Evidence Review: We performed a systematic literature search of the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Embase for RCTs on resectable and borderline resectable pancreatic cancer with overall survival as the primary outcome. We produced a systematic summary of all baseline and prognostic factors identified in the RCTs. A Delphi panel that included 13 experts was surveyed to reach a consensus on mandatory and recommended baseline and prognostic factors. Findings: The 42 RCTs that met inclusion criteria reported a total of 60 baseline and 19 prognostic factors. After 2 Delphi rounds, agreement was reached on 50 mandatory baseline and 20 mandatory prognostic factors for future RCTs, with a distinction between studies of neoadjuvant vs adjuvant treatment. Conclusion and Relevance: This findings of this systematic review and international expert consensus have produced this Consensus Statement on Mandatory Measurements in Pancreatic Cancer Trials for Resectable and Borderline Resectable Disease (COMM-PACT-RB). The baseline and prognostic factors comprising the mandatory measures will facilitate better comparison across RCTs and eventually will enable improved clinical practice among patients with resectable and borderline resectable pancreatic cancer.

Pancreatoduodenectomy with or without prophylactic falciform ligament wrap around the hepatic artery for prevention of postpancreatectomy haemorrhage: randomized clinical trial (PANDA trial).

BACKGROUND: Postpancreatectomy haemorrhage (PPH) is a rare but potentially fatal complication after pancreatoduodenectomy. Preventive strategies are lacking with scarce data for support. The aim of this study was to investigate whether a prophylactic falciform ligament wrap around the hepatic and gastroduodenal artery can prevent PPH from these vessels. METHODS: In a randomized, controlled, multicentre trial, patients who were scheduled for elective open partial pancreatoduodenectomy with pancreatojejunostomy between 5 November 2015 and 2 April 2020 were randomly allocated in a 1 : 1 ratio to undergo pancreatoduodenectomy with (intervention) or without (control) a falciform ligament wrap around the hepatic artery. The primary endpoint was the rate of clinically relevant PPH from the hepatic artery or gastroduodenal artery stump within 3 months after pancreatoduodenectomy. Secondary endpoints were the rates of associated postoperative complications, for example postoperative pancreatic fistula (POPF) and PPH. RESULTS: Altogether, 445 patients were randomized with 222 and 223 in each group. Among the patients included in modified intention-to-treat analysis (207 in the intervention group and 210 in the control group), the primary endpoint was observed in six of 207 in the intervention group compared with 15 of 210 in the control group (2.9 versus 7.1 per cent respectively; odds ratio 0.39 (95 per cent c.i. 0.15 to 1.02); P = 0.071). Per protocol analysis showed a significant reduction in the intervention group (odds ratio 0.26 (95 per cent c.i. 0.09 to 0.80); P = 0.017). A soft pancreas texture (43 per cent) and the rate of a clinically relevant POPF were evenly (20 per cent) distributed between the groups. The rate of any clinically relevant PPH including the primary endpoint and other bleeding sites was not significantly different between intervention and control groups (9.7 versus 14.8 per cent respectively). CONCLUSION: A falciform ligament wrap may reduce PPH from the hepatic artery or gastroduodenal artery stump and should be considered during pancreatoduodenectomy. REGISTRATION NUMBER: NCT02588066 (http://www.clinicaltrials.gov).

Neoadjuvant Therapy for Resectable Pancreatic Cancer: A New Standard of Care. Pooled Data From 3 Randomized Controlled Trials.

OBJECTIVE: The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome. SUMMARY BACKGROUND DATA: Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations. METHODS: Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards. RESULTS: A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI®) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters. CONCLUSION: Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.

Utilization of Interdisciplinary Tumor Boards for Sarcoma Care in Germany: Results from the PROSa Study.

BACKGROUND: Data on institutional structures of sarcoma care in Germany are scarce. The utilization of an interdisciplinary tumor board (IDTB) is an essential part of modern cancer care. We investigated to which extent and when IDTB are used in sarcoma care. We hypothesized that IDTB before treatment initiation were used more often at certified cancer centers and at high-volume centers and that IDTB utilization increased over time. METHODS: From 2017 to 2020 we conducted a prospective cohort study, undertaking major efforts to include the whole spectrum of sarcoma treatment facilities. To analyze potential predictors of IDTB utilization, we calculated multivariable logistic regressions. RESULTS: Patients and survivors (n = 1,309) from 39 study centers (22 tertiary referral hospitals, 9 other hospitals, and 8 office-based practices) participated; 88.3% of the patients were discussed at some stage of their disease in an IDTB (56.1% before treatment, 78% after therapy, and 85.9% in metastatic disease). Hypotheses were confirmed regarding the utilization of IDTB in certified cancer centers (vs. all others: OR = 5.39; 95% CI 3.28-8.85) and the time of diagnosis (2018/2019 vs. until 2013: OR = 4.95; 95% CI 2.67-9.21). CONCLUSION: Our study adds to the evidence regarding the institutional structures of sarcoma care in Germany. Utilization of a tumor board before therapy seems to be in an implementation process that is making progress but is far from complete. Certification is a possible tool to accelerate this development.

Reducing Patient Burden and Improving Data Quality With the New Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire.

BACKGROUND: The Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire was developed in response to the need for a new, fast, and comprehensive tool for evaluating quality of life in patients who have colorectal cancer. Available surveys such as the SF-12, SF-36, Functional Assessment of Cancer Therapy-Colorectal, and European Organization for Research and Treatment of Cancer are either too general to be informative or too lengthy to complete. OBJECTIVE: The aim was to validate the Cleveland Clinic Foundation Colorectal Quality of Life Questionnaire. DESIGN: Data were obtained as part of a prospective randomized controlled trial. SETTINGS: This was a worldwide multicenter study with 2 domestic and 5 international locations. PATIENTS: This study randomly assigned 190 patients between the ages of 18 and 80 undergoing surgery for low rectal cancer. Of those randomly assigned, 142 with partially complete surveys were analyzed for selection bias and acceptability, and 95 with complete surveys were analyzed for survey validity. INTERVENTIONS: Patients received either a J-pouch, side-to-end anastomosis, or straight anastomosis. MAIN OUTCOME MEASURE: The study evaluated survey validity measures such as standardized Cronbach α for internal consistency and Spearman correlation coefficients for construct validity, convergent validity, and responsiveness. Univariate analyses were used to assess discriminative validity. RESULTS: Sufficient acceptability, construct, and convergent validity and responsiveness were achieved. All scores showed great internal consistency (Cronbach α >0.8). Superior discriminative ability was demonstrated by significant differences (p < 0.05) in 2 of 7 scores between neoadjuvant treatment groups, and in 6 of 7 scores between complication groups, none of which were detected by the SF-12 or Functional Assessment of Cancer Therapy-Colorectal surveys. LIMITATIONS: Limitations included a small sample size, cultural differences, and failure to assess test-retest ability of the questionnaire. CONCLUSIONS: The Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire is an efficient and reliable quality-of-life measure that better incorporates factors specific to colorectal cancer surgery. See Video Abstract at http://links.lww.com/DCR/B155. REDUCIENDO LA CARGA AL PACIENTE Y MEJORANDO LA CALIDAD DE DATOS CON EL NUEVO CUESTIONARIO DE CALIDAD DE VIDA EN CÁNCER COLORRECTAL DE CLEVELAND CLINIC (CCF-CAQL): El cuestionario de calidad de vida en cáncer colorrectal de Cleveland Clinic se desarrolló en respuesta a la necesidad de una herramienta nueva, rápida e integral para evaluar la calidad de vida en pacientes con cáncer colorrectal. Los cuestionarios disponibles como SF-12, SF-36, FACT-C y EORTC son demasiado generales para ser informativas o demasiado largas para completar.El objetivo fue validar el cuestionario de calidad de vida colorrectal de la Cleveland Clinic Foundation.Los datos se obtuvieron como parte de un ensayo prospectivo aleatorizado y controlado.Este fue un estudio multicéntrico mundial con dos sedes nacionales y cinco internacionales.Este estudio aleatorizó a 190 pacientes entre las edades de 18 y 80 sometidos a cirugía por cáncer rectal bajo. De aquellos aleatorizados, 142 con encuestas parcialmente completas se analizaron para determinar el sesgo de selección y la aceptabilidad, y 95 con encuestas completas se analizaron para determinar la validez de la encuesta.Los pacientes recibieron un reservorio en J, anastomosis latero-terminal o anastomosis termino-terminal.El estudio evaluó medidas de validez de la encuesta, como el Alfa de Cronbach estandarizado para la consistencia interna y los coeficientes de correlación de Spearman para la validez de construcción, la validez de convergencia y la capacidad de respuesta. Se utilizaron análisis univariados para evaluar la validez discriminativa.Se obtuvo suficiente aceptabilidad, construcción, validez de convergencia, y capacidad de respuesta. Todos los puntajes mostraron una gran consistencia interna (alfa de Cronbach > 0.8). Una capacidad discriminativa superior fue demostrada por diferencias significativas (p < 0.05) en dos de siete puntajes entre grupos de tratamiento neoadyuvante, y en seis de siete puntajes entre grupos de complicaciones, ninguno de los cuales fue detectado por SF-12 o FACT-C.Las limitaciones incluyeron un tamaño de muestra pequeño, diferencias culturales y la falta de evaluación de la confiabilidad test-retest del cuestionario.El Cuestionario de Calidad de Vida en Cáncer Colorrectal de Cleveland Clinic es una medida de calidad de vida eficiente y confiable que incorpora mejor factores específicos asociados a la cirugía de cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B155.

HiatoGast 1: an exploring, semiblinded trial establishing a new endoscopical categorisation of axial hiatal hernias.

INTRODUCTION: Axial hiatal hernias are a common incidental finding in endoscopical examinations, but reflux symptoms do not necessarily correspond to the presence of hiatal hernias. Diagnosing a reflux disease is difficult due to a leak of existing distinct criteria, especially in order to evaluate a surgical indication. Also a preoperative measurement of the hernia is necessary to choose between surgical options. METHODS AND ANALYSIS: We planned a semiblinded trial including a questionnaire and an oesophagogastroduodenoscopy afterwards. While the endoscopy is done, the hiatus oesophagi should be measured in inversion technique under maximum insufflation including length, width and herniated volume. A sample of 210 participants until December 2020 is determined to evaluate the primary endpoint: we look forward to evaluate the anatomical parameters of reflux and non-reflux participants. ETHICS AND DISSEMINATION: The study has been approved by the local ethics committee on 12th February 2019, the data will bei published after closure of inclusion. TRIAL REGISTRATION NUMBER: German Clinical Trials Register (DRKS00016863).

Better Function With a Colonic J-Pouch or a Side-to-end Anastomosis?: A Randomized Controlled Trial to Compare the Complications, Functional Outcome, and Quality of Life in Patients With Low Rectal Cancer After a J-Pouch or a Side-to-end Anastomosis.

BACKGROUND INFORMATION: We aimed to compare prospectively the complications and functional outcome of patients undergoing a J-Pouch (JP) or a side-to-end anastomosis (SE) for treatment of low rectal cancer at a 2-year time point after resection for rectal cancer. METHODS: A multicenter study was conducted on patients with low rectal cancer who were randomized to receive either a JP or SE and were followed for 24 months utilizing SF-12 and FACT-C surveys to evaluate the quality of life (QOL). Fecal incontinence was evaluated using the Fecal Incontinence Severity Index (FISI). Bowel function, complications, and their treatments were recorded. RESULTS: Two hundred thirty-eight patients (165 males) were randomized with 167 final eligible patients, 80 in the JP group and 87 in the SE group for evaluation. The mean age at surgery was 61 (range 29 to 82) years. The overall mean recurrence rate was 12 of 238, 5% and similar in both groups. COMPLICATIONS: Overall, 37 of 190 (19%) patients reported complications, 14 of these were Clavien Dindo Grade 3b and 2 were 3a: leak 3 (2 JP,1 SE), fistula 4 (1 JP, 3 SE), small bowel obstruction 4 (3JP, 1 SE), stricture 4 (3 SE, 1 SA), pouch necrosis 2 (JP), and wound infection 5 (2 JP, 3 SE). QOL scores using either instrument between the 2 groups at 12 and 24 months were similar (P > 0.05). Bowel movements, clustering, and FISI scores were similar. CONCLUSION: At time points of 1 and 2 years after a JP or a SE for low rectal cancer, QOL, functional outcome, and complications are comparable between the groups. Although choosing a particular procedure may depend on surgeon/patient choice or anatomical considerations at the time of surgery, SE functions similar to JP and may be chosen due to the ease of construction.

Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial.

BACKGROUND: In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS). RESULTS: The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48% (A) and 52% (B, P = 0.81) and (y)pN0 was 30% (A) vs. 39% (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79). CONCLUSION: This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543.

Detection of methylated SEPT9 in plasma is a reliable screening method for both left- and right-sided colon cancers.

BACKGROUND: Methylated Septin 9 (SEPT9) is a sensitive biomarker for colorectal cancer (CRC) from peripheral blood. However, its relationship to cancer localization, guaiac-based fecal occult blood test (gFOBT) and carcinoembryonic antigen (CEA) have not been described. METHODOLOGY/PRINCIPAL FINDINGS: Plasma samples were collected for SEPT9 analysis from patients with no evidence of disease (NED) (n=92) before colonoscopy and CRC (n=92) before surgical treatment. DNA was isolated and bisulfite-converted using Epi proColon kit 2.0. Qualitative determination was performed using Epi proColon 2.0 RT-PCR assay. Samples for gFOBT and CEA analysis were collected from NED (n=17 and 27, respectively) and CRC (n=22 and 27, respectively). SEPT9 test was positive in 15.2% (14/92) of NED and 95.6% (88/92) of CRC, including 100% (67/67) from stage II to stage IV CRC and 84% (21/25) of stage I CRC when a sample was called positive if 1 out of 3 PCR replicates was positive. In a second analysis (2 out of 3 PCR replicates) specificity improved to 99% (91/92) of NEDs, at a sensitivity of 79.3% (73/92) of SEPT9 positives in CRC. gFOBT was positive in 29.4% (5/17) of NED and 68.2% (15/22) of CRC and elevated CEA levels were detected in 14.8% (4/27) of NED and 51.8% (14/27) of CRC. Both SEPT9 (84.8%) and CEA (85.2%) showed higher specificity than gFOBT (70.6%). SEPT9 was positive in 96.4% (54/56) of left-sided colon cancer (LSCC) cases and 94.4% (34/36) of right-sided colon cancer (RSCC) cases. gFOBT was positive in 83.3% (10/12) of cases with LSCC and 50% (5/10) of cases with RSCC, elevated CEA was detected 60% (9/15) of LSCC and 41.7% (5/12) of RSCC. CONCLUSIONS/SIGNIFICANCE: The high degree of sensitivity and specificity of SEPT9 in plasma makes it a better method to detect CRC than gFOBT and CEA, even for the more difficult to detect RSCC.

An EMR based cancer diary - utilisation and initial usability evaluation of a new cancer data visualization tool.

We present an EMR based approach to visualize all cancer relevant data in a so-called cancer diary at a single glance. System log and results of a user survey demonstrate increasing use and good usability of the cancer diary compared to traditional searches for relevant information in the entire patient EMR. We conclude that a cancer diary, aggregating data of diagnostic staging, tumor conference decisions and therapeutic actions may be a valuable EMR extension for hospitals focusing on cancer care e.g. within comprehensive cancer centers.

To whom do the results of the multicenter, randomized, controlled INSECT trial (ISRCTN 24023541) apply?--assessment of external validity.

UNLABELLED: A response to Seiler et al: Interrupted or continuous slowly absorbable sutures for closure of primary elective midline abdominal incisions: a multicenter randomized trial (INSECT: ISRCTN24023541). Ann Surg 2009, 249(4):576-582. BACKGROUND: Existing evidence suggests that the transfer of results of randomized controlled trials into clinical practice may be limited. Potential reasons can be attributed to aspects of external validity. The aim of this study is to investigate issues related to the external validity of the INSECT trial. METHODS: All participating surgical departments were categorized and the clinical and baseline characteristics of randomized patients were evaluated. In addition, demographic and clinical data of all screened and randomized patients at the Departments of Surgery in Heidelberg and Erlangen were analyzed. RESULTS: Twenty-five centers enrolled a total of 625 patients. These centers included eight primary, 11 secondary, and six tertiary care centers. The tertiary care centers enrolled the most patients (n = 237, 38%) followed by the primary care centers (n = 199, 32%) and the secondary care centers (n = 189 patients; 30%). The mean number and baseline data of randomized patients did not differ between the three types of care centers (p = 0.09). Overall, the treatment according to protocol was at least 92%. At the Department of Surgery, University of Heidelberg, 307 patients were screened and 60 out of 130 eligible patients were randomized. There were no differences in demographic and clinical baseline data between included and non-included patients. In Erlangen, 351 patients were screened and 57 out of 106 eligible patients randomized. CONCLUSIONS: Results of the INSECT trial are applicable to a broad spectrum of patients treated at different hospital levels.

Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing.

BACKGROUND: The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV). MATERIAL/METHODS: From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m²) as 1-h infusion followed by 5-FU (2000 mg/m²) combined with FA (500 mg/m²) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57). RESULTS: Median age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months. CONCLUSIONS: Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001).

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10.

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.

PURPOSE: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are approximately $3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. EXPERIMENTAL DESIGN: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. RESULTS: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. CONCLUSIONS: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations.

Downstaging of pancreatic carcinoma after neoadjuvant chemoradiation.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiation could improve survival in patients with pancreatic cancer because of a higher rate of R0 resections, lower rate of nodal metastasis (ypN) and of local recurrence. This approach was tested in a cohort to estimate its effect on survival. PATIENTS AND METHODS: Three-dimensional, conformal radiation to the primary tumor (55.8 Gy) and the lymphatics (50.4 Gy) was combined with chemotherapy. Resection was performed 6 weeks after completion of chemoradiation. RESULTS: 38 of 120 patients with locally advanced cancer underwent tumor resection thereafter. Three patients (8%) had pathologic complete response. Median tumor-specific survival was 29 months and overall survival 25 months. Patients with clear margins (35/38; 89%) had a 3-year disease-specific survival rate of 51% versus 0% with positive margins (p = 0.008). Nodal disease rate decreased from 50% at pretherapeutic imaging to 32% at resection. Patients with ypN0 status (n = 26/38) had a 3-year tumor-specific survival rate of 50% compared to 31% in patients with ypN1 status. At multivariate analysis, resection status and nodal spread significantly predicted tumor-specific survival. Chemoradiation was generally well tolerated. CONCLUSION: The current results support randomized testing of neoadjuvant chemoradiation to prove survival prolongation. Compared to the literature this approach seems to reduce the number of positive nodes.

Interrupted or continuous slowly absorbable sutures for closure of primary elective midline abdominal incisions: a multicenter randomized trial (INSECT: ISRCTN24023541).

OBJECTIVE: In patients undergoing midline incisions, the abdominal fascia can be closed with a continuous or interrupted suture using various materials. The aim of this study is to compare: (1) interrupted technique with rapidly absorbable sutures and (2) continuous techniques with different slowly absorbable sutures, focusing on the incidence of incisional hernias within 1 year. SUMMARY OF BACKGROUND DATA: A meta-analysis suggested that the incidence of incisional hernias can be more effectively reduced with slowly absorbable continuous sutures. METHODS: Multicenter randomized surgical trial with 3 parallel groups. Patients were scheduled for primary elective midline incisions. All surgeons were trained (4:1 suture wound length in continuous groups) and monitored. Primary end point, measured within 1 year after surgery, was the frequency of incisional hernias diagnosed by clinical examination and confirmed by ultrasound. Complications and safety were used as secondary end points. This study has been registered with the ISRCTN Register (INSECT: ISRCTN24023541). RESULTS: Conducted on 625 randomized patients (210 interrupted Vicryl, 205 continuous polydioxanone suture (PDS), 210 continuous Monoplus), the primary analysis showed an incidence of 28 incisional hernias (15.9%) versus 15 (8.4%) versus 22 (12.5%) for the 3 closure techniques, respectively (P = 0.09). No significant difference was observed between the 3 groups with regard to burst abdomen (4 [2.0%] vs. 6 [3.0%] vs. 8 [4.0%], P = 0.46), wound infection (26 [12.7%] vs. 39 [19.4%] vs. 33 [16.3%], P = 0.19), pulmonary infections (9 [4.4%] vs. 5 [2.5%] vs. 5 [2.5%], P = 0.46), serious adverse events (63 [30.0%] vs. 57 [27.8%] vs. 61 [29.1%], P = 0.89), and 1-year mortality (16 [7.9%] vs. 11 [5.5%] vs. 16 [7.9%], P = 0.54). CONCLUSIONS: The incidence of incisional hernias and the frequency of wound infection was higher than expected in all groups. New concepts need to be developed and studied to substantially reduce the frequency of incisional hernias.

Primary resection versus neoadjuvant chemoradiation followed by resection for locally resectable or potentially resectable pancreatic carcinoma without distant metastasis. A multi-centre prospectively randomised phase II-study of the Interdisciplinary Working Group Gastrointestinal Tumours (AIO, ARO, and CAO).

BACKGROUND: The disappointing results of surgical therapy alone of ductal pancreatic cancer can only be improved using multimodal approaches. In contrast to adjuvant therapy, neoadjuvant chemoradiation is able to facilitate resectability with free margins and to lower lymphatic spread. Another advantage is better tolerability which consecutively allows applying multimodal treatment in a higher number of patients. Furthermore, the synopsis of the overall survival results of neoadjuvant trials suggests a higher rate compared to adjuvant trials. METHODS/DESIGN: As there are no prospectively randomised studies for neoadjuvant therapy, the Interdisciplinary Study Group of Gastrointestinal Tumours of the German Cancer Aid has started such a trial. The study investigates the effect of neoadjuvant chemoradiation in locally resectable or probably resectable cancer of the pancreatic head without distant metastasis on median overall survival time compared to primary surgery. Adjuvant chemotherapy is integrated into both arms. DISCUSSION: The protocol of the study is presented in condensed form after an introducing survey on adjuvant and neoadjuvant therapy in pancreatic cancer.