Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma

BACKGROUND: Based on a 2-year survival of 43%, the Gastrointestinal Tumor Study Group (GITSG) recommended adjuvant 5-FU-based chemoradiation for resected patients with adenocarcinoma of the pancreatic head. Here we report improved survival over the GITSG protocol with a novel adjuvant chemoradiotherapy based on interferon-alpha (IFNalpha). METHODS: From July 1993 to September 1998, 33 patients with adenocarcinoma of the pancreatic head underwent pancreaticoduodenectomy (PD) and subsequently went on to adjuvant therapy (GITSG-type, n = 16) or IFNalpha-based (n = 17) typically given between 6 and 8 weeks after surgery. The latter protocol consisted of external-beam irradiation at a dose of 4,500 to 5,400 cGy (25 fractions per 5 weeks) and simultaneous three-drug chemotherapy consisting of (1) continuous infusion 5-FU (200 mg/m2 per day); (2) weekly intravenous bolus cisplatin (30 mg/m2 per day); and (3) IFNalpha (3 million units subcutaneously every other day) during the 5 weeks of radiation. This was then followed by two 6-week courses of continuous infusion 5-FU (200 mg/m2 per day, given weeks 9 to 14 and 17 to 22). Risk factors for recurrence and survival were compared for the two groups. RESULTS: A more advanced tumor stage was observed in the IFNalpha-treated patients (positive nodes and American Joint Committee on Cancer [AJCC] stage III = 76%) than the GITSG group (positive nodes and stage III = 44%, P = 0.052). The 2-year overall survival was superior in the IFNalpha cohort (84%) versus the GITSG group (54%). With a mean follow-up of 26 months in both cohorts, actuarial survival curves significantly favored the IFNalpha group (P = 0.04). CONCLUSIONS: With a limited number of patients, this phase II type trial suggests better survival in the interferon group as compared with the GITSG group even though the interferon group was associated with a more extensive tumor stage. The 2-year survival rate in the interferon group is the best published to date for resected pancreatic cancer. The interferon/cisplatin/5-FU-based adjuvant chemoradiation protocol appears to be a promising treatment for patients who have undergone PD for adenocarcinoma of the pancreatic head.     

A reappraisal of preoperative chemoradiation for localized pancreatic head ductal adenocarcinoma in a 5-year single-institution experience

Resection of localized pancreatic head ductal adenocarcinoma (LPHDA) has a limited impact on survival. Mechanisms of improvement provided by preoperative chemoradiation therapy (CRT) remain under debate. This study analyzes the outcome of patients treated for LPHDA to delineate the benefits of CRT. Among 87 patients with LPHDA, 17 had a pancreaticoduodenectomy alone (group I). Thirtynine with initially resectable cancers received CRT with 5-fluorouracil-based chemotherapy (group II). Thirty-one with initially unresectable cancers were similarly treated by CRT (group III). Patients in groups II and III were restaged after completion of CRT. In patients with resectable disease, resection was planned. Patients in groups I and II were statistically comparable in terms of age, sex, and pretherapeutic stage. Median survival and 2-year overall survival in group I were 13.7 months and 31%, respectively. In group II, 23 patients (59%) had a pancreaticoduodenectomy (group IIa) and 16 patients (41%) did not have resection (group IIb). Median survival and 2-year overall survival were as follows: group IIa, 26.6 months and 51%; and group IIb, 6.1 months and 0%, respectively. In group IIa, pathologic examination revealed eight major responses (35%) including two sterilized specimens, and none of the patients had locoregional recurrence. In group III, none of the patients had resection, and median survival was 8 months with one 2-year survivor. Patient selection appears to play a major role with regard to results achieved with preoperative CRT followed by pancreaticoduodenectomy. However, a high histologic response rate and excellent local control can also be achieved.     

Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma

BACKGROUND: Patients with cancer who undergo pancreaticoduodenectomy (PD) followed by radiation and 5-fluorouracil (5-FU) therapy have experienced median overall survival from 18 to 24 months and an actuarial 2-year overall survival from 34% to 48%. We previously reported an 84% 2-year survival using a novel adjuvant chemoradiation protocol that included alpha interferon. This report describes the continued observations regarding this methodology with longer follow-up and more than twice the number of patients as the original report. METHODS: From July 1995 to May 2002, 43 patients with adenocarcinomas in the pancreatic head underwent PD at our institution. The mean age was 62 years (range 29 to 77) and 60% were men. Final pathologic findings were stage I (2%), II (12%), III (72%), and IVa (14%) while 84% had positive lymph nodes (average number of nodes positive was 3.2 nodes, (range 0 to 13). Tumor extended through the capsule of the surgical specimen in 70%. These patients then received our investigational protocol consisting of external-beam irradiation at a dose of 4,500 to 5,400 cGy (25 fractions over 5 weeks) and three-drug chemotherapy: continuous infusion 5-FU (200 mg/m(2) daily, days 1 to 35), weekly intravenous bolus cisplatin (30 mg/m(2) daily, days 1,8,15,22,29), and subcutaneous alpha, interferon (3 x 10(6) units, days 1 to 35). This chemoradiation was followed by continuous infusion 5-FU (200 mg/m(2) daily, weeks 9 to 14 and 17 to 22). Chemoradiation was generally initiated between 6 and 8 weeks after surgery. RESULTS: All patients completed radiation therapy. There were no deaths due to chemoradiation but 42% were hospitalized during chemoradiation, virtually all due to gastrointestinal toxicity. With a mean follow-up time of 31.9 months, 67% of the patients are alive. Therefore, the median survivorship has not been reached. Actuarial overall survival for the 1-, 2-, and 5-year periods was 95% (confidence interval [CI] = 91% to 98%), 64% (CI = 56% to 72%), and 55% (CI = 46% to 65%), respectively. CONCLUSIONS: This follow-up report further suggests overall survival may be improved for patients with adenocarcinoma in the pancreatic head using an adjuvant interferon-based chemoradiation protocol. These results are obtained despite a high incidence of node involvement and advanced tumor stage. From this limited patient series, the actuarial 2-year and 5-year overall survival rates suggest a potential for improved long-term survival. Further study of this regimen in a multiinstitutional setting is needed.     

1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience

Pancreaticoduodenectomy (PD) with the possible addition of neoadjuvant or adjuvant therapy is the standard of care in the United States for adenocarcinoma originating in the pancreatic head, neck, and uncinate process. We reviewed 1423 patients who underwent a PD for a malignancy originating in the pancreas at our institution between 1970 and 2006. We examined 1175 PDs for ductal adenocarcinomas in greater detail. Eighteen different histological types of pancreatic cancer were identified; the most common diagnoses included ductal adenocarcinoma, neuroendocrine carcinoma, and IPMN with invasive cancer. Patients with ductal adenocarcinoma were analyzed in detail. The median age was 66 years, with patients in the present decade significantly older (68 years), on average, than patients in the three prior decades (e.g., 60 years in 1970, P=0.02). The median tumor diameter was 3 cm; 42% of the resections had positive margins and 78% had positive lymph nodes. The perioperative morbidity was 38%. The median postoperative stay declined over time, from 16 days in the 1980s to 8 days in the 2000s (P<0.001). The perioperative mortality declined from 30% in the 1970s to 1% in the 2000s (P<0.001). The median survival for all patients with ductal adenocarcinoma was 18 months (1-year survival =65 %, 2-year survival =37%, 5-year survival =18%). In a Cox proportional hazards model, pathological factors having a significant impact on survival included tumor diameter, resection margin status, lymph node status, and histologic grade. This is the largest single-institution experience with PD for pancreatic cancer. Patients who have cancers with favorable pathological features have a statistically significant improved long-term survival. Presented at the Forty-Seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, May 20–24, 2006, Los Angeles, California.     

Pancreaticoduodenectomy for pancreatic cancer: The Verona experience

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related mortality in the Western world. The current treatment is multimodal, and in resectable patients radical surgery represents the key-step toward long-term survival. Pancreaticoduodenectomy (PD) is the most widely performed operation, because the majority of ductal carcinomas arise in the head of the pancreas. Once considered extremely hazardous, PD has evolved into a safe procedure, with mortality below 5% and morbidity rates in the range from 20% to 60% at high-volume centers. Verona is regarded as one of the most prominent institutions for pancreatic surgery in Europe. More than 5500 patients with pancreatic diseases have been managed, and the surgical case load has increased substantially, with more than 1350 PDs performed. This review discusses this center’s experience in surgical treatment of pancreatic head cancer. Furthermore, the preliminary results of radiofrequency thermal ablation of locally advanced ductal cancer are presented.     

A single-institution experience with fistulojejunostomy for external pancreatic fistulas

External pancreatic fistulas resistant to medical treatment are an indication for surgery. Over the period from May 1986 to March 1999, we operated on 17 patients suffering from a stabilized external pancreatic fistula as a result of surgical treatment for severe acute pancreatitis in 12 cases, chronic pancreatitis in 3, duodenopancreatectomy in 1, and islet cell tumor enucleation in 1. The surgical repair consisted of precise identification of the fistula tract around the drainage tube and its anastomosis with a Roux-en-Y jejunal loop (fistulojejunostomy). The surgical mortality was nil, and the postoperative outcome was uneventful in 12 patients. Four patients experienced surgical complications, all of which were treated conservatively. After a median follow-up of 93 months, 14 patients are still alive and healthy, 1 had died of neoplastic cachexia, and 2 were lost to follow-up. In our experience, fistulojejunostomy appears to be safe, easy to perform, and curative.     

A single-institution experience with 491 cases of small bowel adenocarcinoma

Background

The optimal treatment of small bowel adenocarcinoma is unknown.

Methods

The records of 491 patients with small bowel adenocarcinoma diagnosis between 1970 and 2005 were reviewed for patient and tumor characteristics, treatment effects, and survival.

Results

The median age at diagnosis was 62 years. The most common tumor locations were the duodenum (57%), jejunum (29%), and ileum (10%). The median overall survival was 20.1 months, with a 5-year overall survival of 26%. Greater age, male sex, higher stage and grade, residual disease after resection, and a lymph node ratio of 50% or greater predicted decreased overall survival in univariate analysis. Age and stage were predictive of survival in multivariate analysis. The overall survival with metastatic disease was poor. Adjuvant therapy was not associated with longer overall survival (P = .44).

Conclusions

The prognosis of patients with small bowel adenocarcinoma is poor. Complete resection provides the only means of cure, and the role for adjuvant therapy remains uncertain.     

Laparoscopic pancreatic resection: single-institution experience of 19 patients

BACKGROUND: The number of laparoscopic pancreatic resections reported in the surgical literature has been remarkably low. Few substantive data are available concerning current indications and outcomes after laparoscopic pancreatectomy. The purpose of this article is to review the recent indications, complications, and outcomes after laparoscopic pancreatic resection. STUDY DESIGN: A retrospective analysis of the Mount Sinai hospital records was performed for all patients who underwent laparoscopic distal pancreatectomy or enucleation between the time of the first resection in November 1993 until the time of this study in March 2000. RESULTS: In the 19 patients (6 men) the mean age was 53 years (range 22 to 83 years). In 16 patients (84%) the entire procedure was done by laparoscopy; one operation was converted to a hand-assisted technique; and two cases were converted to open. Median operating time was 4.4 hours (range 1.6 to 6.6 hours), and median intraoperative blood loss was 200 mL. Postoperative complications included three pancreatic leaks (16%), one case of superficial phlebitis, and one prolonged ileus for 7 days (total morbidity of 26%). There were no deaths. The median length of postoperative hospital stay was 6 days (range 1 to 26 days). CONCLUSIONS: This represents the largest single-institution experience with laparoscopic pancreatic resection. The considerable morbidity rate is comparable to recently published open series, and is likely inherent in pancreatic surgery, rather than the technical approach. Laparoscopic pancreatic surgery resulted in shorter hospital stays and appears to be safe for benign diseases.     

Role of octreotide in the treatment of external pancreatic pure fistulas: a single-institution prospective experience

Introduction: Octreotide was studied in the treatment of pure external pancreatic fistulas. Methods: Eighteen cases (12 males, 6 females) were prospectively observed. Six patients (four after radical surgery for periampullary cancer, one endocrine tumor enucleation and one pancreojejunostomy in chronic pancreatitis) were treated as outpatients with octreotide alone because of low basal fistula output (mean±SD: 96.6±27.4 cc/24 h). Twelve (five radical surgery for cancer, five surgery for severe pancreatitis, one enucleation and one pancreojejunostomy) were treated as inpatients with octreotide plus total parenteral nutrition because of the high output (mean±SD: 448.4±248.2 cc/24 h). Results: Ten of the 12 high-output fistulas healed in 27.8±27.7 days, whereas all low-output fistulas healed in 12.1±6.6 days. Conclusion: Octreotide appears useful in the treatment of external pancreatic fistulas. For optimal results to be achieved, there must be no local infection and no mechanical or anatomical obstacles to the free flow of juice. Received: 4 May 1999; in revised form: 31 August 1999 Accepted: 7 September 1999     

Pancreaticoduodenectomy for pancreatic trauma. A case report

Pancreatic trauma is uncommon and severe, combined pancreaticoduodenal injuries are rare. Different surgical techniques for the management of these injuries have been used. In this article a case of severe pancreaticoduodenal injury which required pancreaticoduodenectomy is reported. This case is unusual because there was no history of trauma, the serum amylase level and abdominal radiograph were normal and the abdominal findings on admission to hospital were minimal. A system of grading pancreatic trauma in terms of severity is advocated and the management of pancreaticoduodenal injuries is discussed.     

Audit of postoperative chemoradiotherapy as adjuvant therapy for resected gastroesophageal adenocarcinoma: an Australian multicentre experience

BACKGROUND: Improved disease free and overall survivals were seen in curatively resected patients with gastric and gastroesophageal adenocarcinoma treated with the Intergroup 0116 (INT 0116) protocol of postoperative adjuvant chemoradiotherapy compared to surgery alone. This protocol has not been widely adopted in Australian centres because of perceived risks of toxicity. METHODS: We reviewed the case records from 45 consecutive patients treated between May 1998 and August 2003 with the INT 0116 protocol and variations at five Australian institutions. The median age was 61.5 years (range 38-79). Twenty-nine patients had gastric and 12 had gastroesophageal junction primaries. All patients had attempted curative resection, however, seven had involved microscopic margins (R1 resection). Thirty-five had regional node involvement and none had evidence of distant metastasis. RESULTS: The overall National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0 grade 3 and grade 4 toxicity rates for all patients were 37.8% and 4.4%, respectively. There were no treatment related deaths. Gastrointestinal grade 3 toxicity was observed in 20% of patients, while haematologic grade 3 and 4 toxicity was observed in 17.8%. Toxicities experienced led to chemotherapy dose reductions in 22 patients and dose delay in 11 patients. Seven patients had a delay in radiotherapy and two did not proceed with radiotherapy. At a median follow up of 16 months (range 5-35) from surgery, 28 patients have relapsed (six with local recurrence alone) with 22 deaths occurring, all but one caused by cancer. CONCLUSION: The INT 0116 protocol is a safe and feasible schedule in a multicentre setting with an acceptable rate of toxicity and is an appropriate adjuvant treatment option for high-risk resected gastroesophageal adenocarcinoma.     

EGF receptor antagonism improves survival in a murine model of pancreatic adenocarcinoma

INTRODUCTION: The purpose of this study was to determine whether inhibition of the epidermal growth factor receptor (EGFR) is a plausible therapeutic strategy in pancreatic cancer. METHODS: A human pancreatic cancer cell line (HPAC) was evaluated for the presence of EGFR with rtPCR and immunohistochemistry. Cells were grown in the presence of either 50 or 100 microM of erlotinib (EGFRI) for 72 hours and evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Eighty-six athymic nude/nude mice underwent orthotopic implantation of 10(7) HPAC cells and were blindly randomized into four groups: (1) Control; (2) Batimastat, a matrix metalloproteinase inhibitor (MMPI) at 400 ng/ml qod; (3) EGFRI at 100 mg/kg qd; and (4) MMPI and EGRRI (both). In vitro and in vivo effects of EGFRI with and without MMPI were compared. RESULTS: HPAC demonstrated high levels of expression of both the EGFR gene and the gene product. In vitro, both doses of EGFRI significantly reduced proliferation of HPAC at 48 (50 microM: 1.15 + 0.05 [st dev] versus 0.63 + 0.09 abs, P < 0.001) and 72 h (50 microM: 1.48 +/- 0.09 versus 0.73 +/- 0.05 abs, P < 0.001, paired Student's t-test). In vivo, each treatment group demonstrated a significant survival advantage (P = 0.0002 group 2, P = 0.0001 group 3, P = 0.012 group 4, log rank test) over controls. Mice treated with EGFRI showed reduced tumor implantation, size, weight, metastatic potential, and jaundice as compared to controls and MMPI-treated mice (all P < 0.05, Fisher's exact test). CONCLUSION: EGF receptor antagonism is not only a plausible therapy for treatment of ductal adenocarcinoma of the pancreas, but is also superior to matrix metalloproteinase inhibition alone or in combination.     

Pancreaticoduodenectomy. A 40-year experience.

One hundred six pancreaticoduodenectomies, including 10 cases done for benign disease were reviewed, retrospectively, and 51 factors analyzed. There is a significant difference in survival based upon final pathologic diagnosis. Five-year survivals were 0% for adenocarcinoma of the pancreas, 38% for duodenal carcinoma, 24% for CBD caracinoma, 30% for ampullary carcinoma, 24% for other cancers not considered part of the ampullary carcinoma, 24% for other cancers not considered part of the ampullary region, and 100% for those with benign disease (chi 2 = 24.66, df = 5, p = 0.0002). Four statistically significant poor prognostic factors were identified, including age greater than 51 years, serum bilirubin level greater than 6 mg/dl, SGOT greater than 100, and a previous drainage procedure. Results of this study seem to indicate that the pancreaticoduodenectomy has limited indications in adenocarcinoma of the pancreas, but remains the procedure of choice for all other periampullary lesions including suspicious lesions with a negative biopsy at the time of surgery.     

Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience

OBJECTIVE: To evaluate surgical strategies for neuroendocrine pancreatic tumors (NEPT) in the light of the new WHO classification from 2004 and to draw conclusions for future surgical concepts. BACKGROUND:: The extent of surgical resection in primary and recurrent NEPT is unclear. METHODS: Between 1987 and 2004, 62 patients with sporadic NEPT were treated at our institution and sections from biopsy and resection specimen were histopathologically reclassified. Clinical presentation, surgery, metastases, and pattern of recurrence were related to survival. RESULTS: Fifteen well-differentiated tumors (WDT, 24%), 39 low-grade carcinomas (LGC, 63%), and 8 high-grade carcinomas (HGC, 13%) were identified. Median observation time was 30.5 months; 48 of 62 patients (78%) were surgically resected, and in 45 patients R0/R1 status was achieved. Overall 2- and 5-year survival in the latter group was 80% and 64%, respectively. Retrospective WHO classification revealed that organ-preserving segmental resections had been performed in 10 LGC and 1 HGC. These patients showed equal outcome as radically resected counterparts (n = 19). Liver and other organ metastases were present in 19 of 62 patients (31%), and resection was accomplished in 7 of 19 patients, which conferred better overall survival (P = 0.026, log-rank test); 21 of 45 R0/R1-resected patients (47%) suffered from recurrence, and reoperation was accomplished in 9 patients, which resulted in better overall survival (P = 0.066). CONCLUSION: Organ-preserving resections offer sufficient local control in LGC; therefore, radical resections do not seem to be justified. On the other hand, radical resection is indicated even in metastasized patients or in case of loco-regional recurrence. The silent and slow course of the disease facilitates long-term surgical control.     

A novel scoring system predicts postsurgical survival and adjuvant chemotherapeutic benefits in patients with pancreatic adenocarcinoma: Implications for AJCC-TNM staging

Background

We evaluated the application of the latest 8^th American Joint Committee on Cancer (AJCC) staging system in Chinese patients and determined whether the addition of biologic markers could improve the prediction of postsurgical survival in pancreatic adenocarcinoma (PC).

A prospective randomized trial for postoperative vs. preoperative adjuvant radiotherapy for muscle-invasive bladder cancer

PurposeAlthough radical cystectomy is considered to be the primary treatment for muscle-invasive bladder cancer, it is associated with unfavorable outcome. Local recurrence is still a major problem. Survival rates as well as quality of live are far from being satisfactory. Postoperative radiotherapy is considered the standard adjuvant treatment in the NCI-Egypt. This is a prospective randomized study conducted to compare preoperative with postoperative radiotherapy as regard the survival and complication rates.Patients and methodsIn the period from May, 2004 to June 2007, 100 eligible patients were included into the study, 50 patients in each treatment arm. Pelvic irradiation was identical in both groups aiming at 50 Gy/25 Fs/5 wk. Radical cystectomy was the standard surgery. Locoregional control, survival rates, and complications rates were compared in both arms.ResultsPatients had a median follow-up period of 32 months (range 0–69 months). Patients had an average age of 54.8 ± 9.5 years with a male/female ratio 3:1. In the present study, transitional cell carcinoma constitutes (51%), while squamous cell carcinoma was reported in 46% of cases. Grades II and III pathology were 81% and 17%, respectively. Pathological stage P_2b was encountered in 39.5% of the patients followed by P₃b (33.3%) and P₃a (14.6%). For the preoperative group, the 3-year overall survival, disease-free survival, locoregional control, and metastases-free survival rates were 53.4%, 47.4%, 89.3%, and 61.5%, respectively. The corresponding figures for the postoperative group were 51.8%, 34.1%, 80.6%, and 55.7% for the postoperative group. None of the patients had serious radiation reactions.ConclusionIn our study, preoperative radiotherapy was almost equivalent to postoperative radiation therapy as regard OS, DFS, as well as complication rates. Given the recent physical developments in radiation therapy techniques and the biological rationale for treating the pelvis after cystectomy, adjuvant radiotherapy should be re-evaluated world wide. Preoperative radiotherapy may re-emerge as a useful tool for adjuvant treatment.