Sergio Pedrazzoli

Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial

ObjectiveTo assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. Summary Background DataPancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. MethodsESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. ResultsOf 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. ConclusionsResection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas a multicenter, prospective, randomized study. Discussion

OBJECTIVE The study was conducted to determine whether the performance of an extended lymphadenectomy and retroperitoneal soft-tissue clearance in association with a pancreatoduodenal resection improves the long-term survival of patients with a potentially curable adenocarcinoma of the head of the pancreas. SUMMARY BACKGROUND DATA The usefulness of performing an extended lymphadenectomy and retroperitoneal soft-tissue clearance in conjunction with a pancreatoduodenal resection in the treatment of ductal adenocarcinoma of the head of the pancreas is still unknown. Published studies suggest a benefit for the procedure in terms of better long-term survival rates; however, these studies were retrospective or did not prospectively evaluate large series of patients. MATERIALS AND METHODS Eighty-one patients undergoing a pancreatoduodenal resection for a potentially curable ductal adenocarcinoma of the head of the pancreas were randomized to a standard (n = 40) or extended (n = 41) lymphadenectomy and retroperitoneal soft-tissue clearance in a prospective, multicentric study. The standard lymphadenectomy included removal of the anterior and posterior pancreatoduodenal, pyloric, and biliary duct, superior and inferior pancreatic head, and body lymph node stations. In addition to the above, the extended lymphadenectomy included removal of lymph nodes from the hepatic hilum and along the aorta from the diaphragmatic hiatus to the inferior mesenteric artery and laterally to both renal hila, with circumferential clearance of the origin of the celiac trunk and superior mesenteric artery. Patients did not receive any postoperative adjuvant therapy. RESULTS Demographic (age, gender) and histopathologic (tumor size, stage, differentiation, oncologic clearance) characteristics were similar in the two patient groups. Performance of the extended lymphadenectomy added time to the procedure, although the difference did not reach statistical significance (397 +/- 50 minutes vs. 372 +/- 50 minutes, p > 0.05). Transfusion requirements, postoperative morbidity and mortality rates, and overall survival did not differ between the two groups. When subgroups of patients were analyzed, using an a posteriori analysis that was not planned at the time of study design, there was a significantly (p < 0.05) longer survival rate in node positive patients after an extended rather than a standard lymphadenectomy. The survival curve of node positive patients after an extended lymphadenectomy could be superimposed onto the curves of node negative patients. Survival curves in node negative patients did not differ according to the magnitude of the lymphadenectomy. Multivariate analysis of all patients showed that long-term survival was affected by tumor differentiation (well vs. moderately vs. poorly differentiated, p > 0.001), diameter (< or = 2.0 cm. vs. > 2.0 cm., p < 0.01), lymph node metastasis (absent vs. present, p < 0.01) and need for 4 or more units of transfused blood (< 4 vs. > or = 4, p <0.01). CONCLUSIONS The addition of an extended lymphadenectomy and retroperitoneal soft-tissue clearance to a pancreatoduodenal resection does not significantly increase morbidity and mortality rates. Although the overall survival rate does not differ in the two groups, there appears to be a trend toward longer survival in node positive patients treated with an extended rather than a standard lymphadenectomy.

Recurrence after resection for ductal adenocarcinoma of the pancreas

We analyzed the pattern of failure and clinicopathologic factors influencing the disease-free survival of 78 patients who died after macroscopic curative resection for pancreatic cancer. Local recurrence was a component of failure in 56 patients (71.8%) and hepatic recurrence in 48 (61.5%), both accounting for 97% of the total recurrence rate. About 95% of recurrences occurred by 24 months after operation. Median disease-free survival time was 8 months, and cumulative 1-, 3-, and 5-year actuarial disease-free survival rates were 66%, 7%, and 3%, respectively. Multivariate analysis showed that tumor grade (p = 0.04), microscopic radicality of resection (p = 0.04), lymph node status (p = 0.01), and size of the tumor (p = 0.005) were independent predictors of disease-free survival. Patterns of failure and disease-free survival were not statistically influenced by the type of surgical procedure performed. Median survival time from the detection of recurrence until death was 7 months for local recurrence versus 3 months for hepatic or local plus hepatic recurrence (p < 0.05). From our experience and the data collected from the literature, it appears that surgery alone is an inadequate treatment for cure in patients with pancreatic carcinoma. Effective adjuvant therapies are needed to improve locoregional control of pancreatic cancer after surgical resection.RésuméLes échecs thérapeutiques et les facteurs clinico-pathologiques jouant un rôle sur la survie sans maladic ont étéanalysés chez 78 patients décédés après une résection pancréatique à visée macroscopiquement curatrice. La récidive locale a été constatée chez 56 patients (71.8%), la récidive sous forme de localisation hépatique chez 48 (61.5%), l’ensemble des deux représentant 97% des récidives globales. Quatre-vingt quinze pour-cent des récidives se sont produites moins de 24 mois après l’intervention. La durée médiane de survie sans maladie a été de 8 mois et les survies cumulatives actuarielles à 1, 3 et à 5 ans ont été respectivement de 66%, 7% et 3%. L’analyse multifactorielle a montré que le stade tumoral (p = 0.04), la radicalité de la résection (p = 0.04), l’état ganglionnaire (p = 0.01) et la taille de la tumeur (p = 0.005) étaient des facteurs indépendants de prédiction de survie sans maladie. Ni les échecs ni la survie n’ont été statistiquement influencés par le type de chirurgie effectuée. La durée médiane entre la détection de la récidive et le décès a été de 7 mois pour la récidive locale contre trois mois pour la récidive hépatique ou combinée, hépatique et locale (p < 0.05). A partir de notre expérience et l’information recucillie dans la littérature, il apparaît que la chirurgie scule ne suffit pas pour traiter le cancer pancréatique. On a besoin de thérapeutiques adjuvantes pour améliorer le contrôle locorégional du cancer du pancréas après résection.ResumenAnalizamos el patrón de falla y los factores clínico-patológicos que tienen influencia sobre la sobrevida libre de enfermedad de 78 pacientes que murieron luego de resectión macroscópicamente curativa de cáncer pancreático. La recurrencia local fue el componente de falla en 56 pacientes (71.8%), la recurrencia hepática en 48 (61.5%), con ambos factores representando el 97% de la tasa total de recurrencia. Noventa y cinco porciento de las recurrencias ocurrieron en los primeros 24 meses luego de la operación. El intervalo libre de enfermedad promedio fue de 8 meses y las tasas actuariales de sobrevida libre de enfermedad acumulativas a 1, 3 y 5 años fueron 66%, 7% y 3% respectivamente. El análisis multivariado demostró que el grado tumoral (P = 0.04), el estado de los ganglios linfáticos (P = 0.01) y el tamaño del tumor (P = 0.005) son predictores independientes de la sobrevida libre de enfermedad. Los patrones de falla y de sobrevida libre de enfermedad no aparecieron estadísticamente afectados por el tipo de cirugía realizada. El tiempo medio de sobrevida a partir de la detección de la recurrencia hasta la muerte fue de 7 meses para la recurrencia local versus 3 meses para la recurrencia hepática o la recurrencia local más hepática (P < 0.05). Según nuestra experiencia y los datos recolectados de la literatura, parece que la cirugía sola es un tratamiento inadecuado para la curación de pacientes con carcinoma pancreático. Se requieren terapias coadyuvantes eficaces para mejorar el control local-regional del cáncer pancreático luego de la resección quirúrgica.

Neuroendocrine tumor imaging: can 18F-fluorodeoxyglucose positron emission tomography detect tumors with poor prognosis and aggressive behavior?

Abstract. We evaluated the clinical value of positron emission tomography (PET) using 18 F-fluorodeoxyglucose (FDG) for neuroendocrine tumor (NET) detection. Sixteen patients with cytologically or histologically proved NETs were investigated. Patients were divided in two groups of eight patients each according to the clinicopathologic features related to prognosis: slow-growing NETs and aggressive NETs. Results of FDG tumor uptake as detected by PET were compared with computed tomography (CT) scans and with scans obtained with 111 In-octreotide scintigraphy (n= 13). Tumor FDG uptake was increased in the primary lesion of all eight aggressive NETs; the tracer was shown also in lymph nodes, liver metastases, or both in five of six of them (83%). In four cases, additional unknown tumor sites undetected by CT scan were identified. A slight positivity was found in only one of eight cases with a slow-growing NET. The overall octreotide scintiscan sensitivity was 85%, but in the aggressive NETs it failed to detect the primary lesion in two of seven cases. Uptake of the tracer in some but not all tumor lesions in the same patient was seen by both FDG-PET and octreotide scintiscans. From our limited experience 18F-FDG PET seems to be useful for identifying NETs characterized by rapid growth or aggressive behavior. Uptake of the FDG tracer by the tumor may be related to a worse prognosis. Despite the heterogeneity of tracer uptake in the various lesions of NETs with multiple tumor sites, FDG-PET was able to detect unsuspected distant metastases, contributing to better staging of advanced disease.

Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome.

Objectives: An impaired host immunity might concur in determining the dismal prognosis of patients with pancreatic cancer (PC). Our aim was to ascertain whether the immunophenotype pattern of blood lymphocytes in PC correlates with tumor stage, grade, or survival. Methods: We studied 115 patients with PC, 44 with chronic pancreatitis (CP), 23 with tumors of the pancreatico-biliary tract, and 34 healthy controls (CS). Survival data were available for 77 patients with PC. Lymphocyte subsets were determined by fluorescent activated cell sorter (FACS) analysis. Results: In patients with PC, total lymphocyte counts were lower than in CP or CS, and CD8+ lymphocyte subset levels were higher with respect to CS. Lower circulating lymphocytes were found in advanced PC stages (IIB-IV; χ2 = 11.55, P < 0.05) compared with stages 0 to IIA. Cox regression analysis, made considering total lymphocyte counts and tumor stage as covariates, was found to be significant for both tumor stage (P < 0.001) and total lymphocyte counts (P < 0.05). Conclusions: The reduction of total lymphocytes in blood is the main immunologic change in advanced PC. The survival of these patients depends mainly on tumor stage, but it is also affected by the number of circulating lymphocytes, suggesting that the immune system plays an important role in pancreatic adenocarcinoma immunosurveillance and immunoediting.

F-18-fluorodeoxyglucose positron emission tomography in differentiating malignant from benign pancreatic cysts: a prospective study

The differential diagnosis between benign and malignant pancreatic cystic lesions may be very difficult. We recently found that F-18-.uorodeoxyglucose positron emission tomography (18-FDG PET) was useful for the preoperative work-up of pancreatic cystic lesions. This study was undertaken to confirm these results. From February 2000 to July 2003, 50 patients with a pancreatic cystic lesion were prospectively investigated with 18-FDG PET in addition to helical computed tomography (CT) and, in some instances, magnetic resonance imaging (MRI). The validation of diagnosis was based on pathologic findings after surgery (n = 31), percutaneous biopsy (n = 4), and according to follow-up in 15 patients. The 18-FDG PET was analyzed visually and semiquantitatively using the standard uptake value (SUV). The accuracy of FDG PET and CT was determined for preoperative diagnosis of malignant cystic lesions. Seventeen patients had malignant cystic lesions. Sixteen (94%) showed increased 18-FDG uptake (SUV >2.5), including two patients with carcinoma in situ. Eleven patients (65%) were correctly identified as having malignancy by CT. Thirty-three patients had benign tumors: two patients showed increased 18-FDG uptake, and four patients showed CT findings of malignancy. Sensitivity, specificity, positive and negative predictive value, and accuracy of 18-FDG PET and CT in detecting malignant tumors were 94%, 94%, 89%, 97%, and 94% and 65%, 88%, 73%, 83%, and 80%, respectively. 18-FDG PET is accurate in identifying malignant pancreatic cystic lesions and should be used in combination with CT in the preoperative evaluation of patients with pancreatic cystic lesions. A negative result with 18-FDG PET may avoid unnecessary operation in asymptomatic or high-risk patients.

Serum tumor markers and cyst fluid analysis are useful for the diagnosis of pancreatic cystic tumors

This study was performed to evaluate the utility of serum and cyst fluid analysis for enzymes (amylase and lipase) and tumor markers (carcinoembryonic antigen, CA 19‐9, CA 125, and CA 72‐4) in the differential diagnosis of cystic pancreatic lesions.

Value of 18-Fluorodeoxyglucose Positron Emission Tomography in the Management of Patients With Cystic Tumors of the Pancreas

ObjectiveTo assess the reliability of 18-fluorodeoxyglucose positron emission tomography (18-FDG PET) in distinguishing benign from malignant cystic lesions of the pancreas. Summary Background DataThe preoperative differential diagnosis of cystic lesions of the pancreas remains difficult: the most important point is to identify malignant or premalignant cysts that require resection. 18-FDG PET is a new imaging procedure based on the increased glucose metabolism by tumor cells and has been proposed for the diagnosis and staging of pancreatic cancer. MethodsDuring a 4-year period, 56 patients with a suspected cystic tumor of the pancreas underwent 18-FDG PET in addition to computed tomography scanning, serum CA 19-9 assay, and in some instances magnetic resonance imaging or endoscopic retrograde cholangiopancreatography. The 18-FDG PET was analyzed visually and semiquantitatively using the standard uptake value. The accuracy of 18-FDG PET and computed tomography was determined for preoperative diagnosis of a malignant cyst. ResultsSeventeen patients had malignant tumors. Sixteen patients (94%) showed 18-FDG uptake with a standard uptake value of 2.6 to 12.0. Twelve patients (70%) were correctly identified as having malignancy by computed tomography, CA 19-9 assay, or both. Thirty-nine patients had benign tumors: only one mucinous cystadenoma showed increased 18-FDG uptake (standard uptake value 2.6). Five patients with benign cysts showed computed tomography findings of malignancy. Sensitivity, specificity, and positive and negative predictive values for 18-FDG PET and computed tomography scanning in detecting malignant tumors were 94%, 97%, 94%, and 97% and 65%, 87%, 69%, and 85%, respectively. Conclusions18-FDG PET is more accurate than computed tomography in identifying malignant pancreatic cystic lesions and should be used, in combination with computed tomography and tumor markers assay, in the preoperative evaluation of patients with pancreatic cystic lesions. A positive result on 18-FDG PET strongly suggests malignancy and, therefore, a need for resection; a negative result shows a benign tumor that may be treated with limited resection or, in selected high-risk patients, with biopsy, follow-up, or both.

18-fluorodeoxyglucose positron emission tomography enhances computed tomography diagnosis of malignant intraductal papillary mucinous neoplasms of the pancreas.

Objective:To assess the reliability of 18-fluorodeoxyglucose positron emission tomography (18-FDG PET) in distinguishing benign from malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and its contribution to surgical decision making. Summary Background Data:Pancreatic IPMNs are increasingly recognized, often as incidental findings, especially in people over age 70 and 80. Computed tomography (CT) and magnetic resonance (MR) are unreliable in discriminating a benign from a malignant neoplasm. 18-FDG PET as imaging procedure based on the increased glucose uptake by tumor cells has been suggested for diagnosis and staging of pancreatic cancer. Methods:From January 1998 to December 2005, 64 patients with suspected IPMNs were prospectively investigated with 18-FDG PET in addition to conventional imaging techniques [helical-CT in all and MR and magnetic resonance cholangiopancreatography (MRCP) in 60]. 18-FDG PET was analyzed visually and semiquantitatively using the standard uptake value (SUV). The validation of the diagnosis was made by a surgical procedure (n = 44), a percutaneous biopsy (n = 2), main duct cytology (n = 1), or follow-up (n = 17). Mean and median follow-up times were 25 and 27.5 months, respectively (range, 12–90 months). Results:Twenty-seven patients (42%) were asymptomatic. Forty-two patients underwent pancreatic resection, 2 palliative surgery, and 20 did not undergo surgery. An adenoma was diagnosed in 13 patients, a borderline tumor in 8, a carcinoma in situ in 5, and an invasive cancer in 21; in 17 patients a tumor sampling was not performed and therefore the histology remained undetermined. Positive criteria of increased uptake on 18-FDG PET was absent in 13 of 13 adenomas and 7 of 8 borderline IPMNs, but was present in 4 of 5 carcinoma in situ (80%) and in 20 of 21 invasive cancers (95%). Conventional imaging technique was strongly suggestive of malignancy in 2 of 5 carcinomas in situ and in 13 of 21 invasive carcinomas (62%). Furthermore, conventional imaging had findings that would be considered falsely positive in 1 of 13 adenomas (8%) and in 3 of 8 borderline neoplasms (37.5%). Therefore, positive 18-FDG PET influenced surgical decision making in 10 patients with malignant IPMN. Furthermore, negative findings on 18-FDG PET prompted us to use a more limited resection in 15 patients, and offered a follow-up strategy in 18 patients (3 positive at CT scan) for the future development of a malignancy. Conclusions:18-FDG PET is more accurate than conventional imaging techniques (CT and MR) in distinguishing benign from malignant (invasive and noninvasive) IPMNs. 18-FDG PET seems to be much better than conventional imaging techniques in selecting IPMNs patients, especially when old and asymptomatic, for surgical treatment or follow-up.

Median pancreatectomy for tumors of the neck and body of the pancreas1

BACKGROUND When enucleation is too risky because of possible damage of the main pancreatic duct, benign tumors located in the neck or body of the pancreas are usually removed by a left (spleno)-pancreatectomy or by a pancreatoduodenectomy. But standard pancreatic resection results in an important loss of normal pancreatic parenchyma and may cause impairment of exocrine and endocrine function. The aim of this study was to evaluate early and longterm results of median pancreatectomy, a limited resection of the midportion of the pancreas, in selected patients with benign or borderline tumors of the pancreas. STUDY DESIGN Records of patients at Ospedale Busonera between November 1985 and September 1998 were reviewed. Ten patients with tumors of the neck or body of the pancreas underwent median pancreatectomy; the cephalic stump was sutured and the distal stump was anastomosed with a Roux-en-Y jejunal loop. Followup included clinical evaluation and routine laboratory tests: abdominal ultrasonography, exocrine and endocrine pancreatic function with fecal chymotrypsin, and an oral glucose tolerance test. RESULTS Pathologic examination showed: insulinoma (n = 3), mucinous cystadenoma (n = 3), nonfunctioning endocrine tumor (n = 1), papillary-cystic neoplasm (n= 1), serous cystadenoma (n = 1), and intraductal mucinous tumor (n = 1). Operative mortality and morbidity were 0% and 40%, respectively; pancreatic fistula occurred in three patients. At mean followup of 62.7 months, no recurrence was found and no patient had exocrine insufficiency or glucose metabolism impairment. CONCLUSIONS Median pancreatectomy is a safe and effective alternative to major pancreatic resection in selected patients with benign or low-malignant lesions of the pancreas. This procedure carries a surgical risk similar to that of the standard operation, but avoids extensive pancreatic resection and pancreatic function impairment.