Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum

HYPOTHESIS: Adjuvant chemoradiation improves local control and survival in patients with node-positive duodenal adenocarcinoma treated with pancreaticoduodenectomy. DESIGN: A retrospective review of outcomes, with a planned comparison with historical controls. SETTING: A single, high-volume academic referral center. PATIENTS: All patients with periampullary carcinoma treated with pancreaticoduodenectomy and adjuvant chemoradiotherapy at The Johns Hopkins Hospital between 1994 and 2003. Fourteen cases of node-positive duodenal adenocarcinoma were identified. Median radiation dose was 5000 cGy (range, 4000-5760 cGy). Concurrent fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. RESULTS: The median follow-up was 12 months for patients who died and 42 months for those who lived. Death occurred in 7 of 14 patients (50%) during the follow-up period. Median survival for all patients was 41 months, and the 5-year survival rate was 44%. Of the 7 patients who experienced disease recurrence, 6 experienced distant metastasis as first recurrence. One of these 7 patients experienced both local recurrence and distant metastasis. Local control for all patients in the study was 93%, which compares favorably with local control reported in a series of patients treated with surgery alone (67%). Compared with historical controls treated with surgery alone, patients who received adjuvant chemoradiation therapy had an improved median survival (21 months vs 41 months, respectively). Overall 5-year survival, however, was not improved (44% vs 43%, respectively). CONCLUSION: Adjuvant chemoradiation therapy after pancreaticoduodenectomy for node-positive duodenal adenocarcinoma may improve local control and median survival but does not impact 5-year overall survival.     

Adenocarcinoma of the head of the pancreas: effects of surgical and nonsurgical therapy on survival--a ten-year experience

A retrospective analysis of all patients treated for adenocarcinoma of the head of the pancreas from 1989 to 1998 was performed. Excluded were cancers in the body and tail, cystic neoplasms, ampullary tumors, and cancers of the duodenum and bile ducts. One hundred forty-five patients were reviewed, and 43 patients underwent pancreaticoduodenectomy. Data collected included the stage, lymph node status, surgical margins, adjuvant therapies, and survival. Statistical analysis was performed with Cox's Proportional Hazards Analysis and Log-Rank Life Table Analysis. The surgical population had a 21 per cent 3-year survival rate and a 7 per cent operative mortality rate. Median survival was: 1) the resection group versus no resection was 13.5 versus 3.1 months; 2) adjuvant therapy versus no therapy after resection was 16.1 versus 5.1 months; and 3) chemoradiation therapy versus no therapy for unresectable disease was 5.3 versus 1.8 months. The presence of positive surgical margins was found in 33 per cent of the surgical specimens and carried an increased mortality hazard ratio of 3.1. Patients with negative lymph nodes had a 15 per cent 5-year survival, versus 0 per cent with positive nodes. Seventy-three per cent of those resected had a T2 lesion, and 46 per cent of patients presented with metastatic disease. Surgical resection and adjuvant therapy significantly improves survival in patients with adenocarcinoma of the head of the pancreas. All patients who underwent resection as part of their therapy showed extended survival compared with chemoradiation therapy alone. Adjuvant chemoradiation improved survival when compared with surgery alone. Multimodality treatment in carcinoma of the head of the pancreas provides the best treatment option. However, better adjuvant therapies are needed.     

Preoperative chemoradiation in resectable pancreatic cancer

Despite advancements in the field of surgical oncology, the diagnosis of pancreatic cancer still carries a grave and dismal prognosis. Surgery alone for adenocarcinoma of the pancreatic head or uncinate process has a median survival time of 12 months. These grim statistics have led many to study the effects of combined multimodality therapy in the fight against pancreatic cancer. The long recovery time associated with pancreaticoduodenectomy has resulted in as many as 25% of patients unable to proceed with planned adjuvant therapy. For these reasons preoperative or neoadjuvant chemoradiation therapy (CRT) has been evaluated. Preoperative CRT ensures that all eligible patients receive the benefits of multimodality therapy, and patients who manifest metastatic disease on restaging evaluations are spared the morbidity of an unnecessary laparotomy. Multimodality therapy appears to lengthen the survival duration in patients with pancreatic cancer. It also affords a selection advantage, in that patients with aggressive disease biology with advanced metastatic disease following CRT are spared the morbidity of surgery. Conversely, a limited subset of patients may even be downstaged, allowing for a potentially curative resection. In this article we review the current status of neoadjuvant chemoradiation in adenocarcinoma of the pancreas. We discuss its rationale in light of the reported strengths and weaknesses of postoperative adjuvant CRT. Received: March 20, 2002 / Accepted: April 15, 2002 RID="*" ID="*" Offprint requests to: M.P. Callery     

The feasibility of dose escalation using concurrent radiation and 5-fluorouracil therapy following pancreaticoduodenectomy for pancreatic carcinoma

We evaluated the feasibility of dose escalation using external beam radiation therapy (RT) and 5-fluorouracil (5-FU) following pancreaticoduodenectomy for pancreatic carcinoma. Fourteen patients who underwent pancreaticoduodenectomy for stage I–III adenocarcinoma of the pancreas received postoperative high-dose chemoradiation. RT was given at 1.8-Gy daily fractions to total doses of 54 Gy for patients with negative surgical margins (n = 12), and 64.8 Gy for those with gross residual disease (n = 2). Concurrent 5-FU was given as a continuous infusion (CI) at 225 mg/m² per day (n = 9) beginning or day 1 and continuing until the completion of RT, or by bolus injection at 500 mg/m² per day (n = 5) during weeks 1 and 4 of RT. Follow-up ranged from 32 to 36 months (median, 35 months). All patients were able to complete the planned high-dose postoperative chemoradiation and none required a treatment break. No grade 4 acute toxicity was observed. Grade 3 acute toxicity was limited to 2 patients. Two patients developed grade 3 (n = 1) or 4 (n = 1) subacute toxicity, all gastrointestinal-related. There have been no fatal toxicities and no grade 3 or 4 late toxicity has been observed. The 3-year survival is 21%. Dose escalation of postoperative 5-FU chemoradiation following pancreaticoduodenectomy for pancreatic carcinoma is well tolerated. Further dose-intensification of postoperative adjuvant therapy in these patients appears feasible and is being evaluated in a recently activated national trial. Received for publication on Feb. 16, 1999; accepted on June 10, 1999     

Preoperative chemoradiation strategies for localized adenocarcinoma of the pancreas

Patients who undergo pancreaticoduodenectomy alone for adenocarcinoma of the pancreatic head or uncinate process have a median survival of 12 months, and a high incidence of local tumor recurrence (50%–80%) due to the common finding of positive margins following pathologic evaluation of pancreaticoduodenectomy specimens. The available prospective and retrospective data suggest improved survival duration and local-regional tumor control when pancreaticoduodenectomy is combined with 5-FU–based chemoradiation. However, the morbidity and prolonged recovery associated with pancreaticoduodenectomy frequently prevent the timely delivery of postoperative chemoradiation. In contrast, chemoradiation delivered prior to pancreaticoduodenectomy is not associated with toxic effects which delay surgery and has not been shown to increase surgical morbidity or mortality. In fact, recent data suggest that pancreaticojejunal anastomotic leaks, the most common major complication following pancreaticoduodenectomy, are decreased in patients who receive preoperative radiation therapy. Current and future multimodality treatment strategies will capitalize on our expanding understanding of tumor growth and metastasis, allowing more effective radiation sensitizing agents to be combined with external-beam irradiation and surgery, followed by the systemic or regional delivery of novel agents that inhibit essential steps in tumor cell growth. Received for publication on July 17, 1998; accepted on July 27, 1998     

Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.

OBJECTIVE: This single-institution study examined the outcome after pancreaticoduodenectomy in patients with adenocarcinoma of the head of the pancreas. SUMMARY OF BACKGROUND DATA: In recent years, pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas has been associated with decreased morbidity and mortality and, in some centers, 5-year survival rates in excess of 20%. METHODS: Two hundred one patients with pathologically verified adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy at The Johns Hopkins Hospital between 1970 and 1994 were analyzed (the last 100 resections were performed between March 1991 and April 1994). This is the largest single-institution experience reported to date. RESULTS: The overall postoperative in-hospital mortality rate was 5%, but has been 0.7% for the last 149 patients. The actuarial 5-year survival for all 201 patients was 21%, with a median survival of 15.5 months. There were 11 5-year survivors. Patients resected with negative margins (curative resections: n = 143) had an actuarial 5-year survival rate of 26%, with a median survival of 18 months, whereas those with positive margins (palliative resections; n = 58) fared significantly worse, with an actuarial 5-year survival rate of 8% and a median survival of 10 months (p < 0.0001). Survival has improved significantly from decade to decade (p < 0.002), with the 3-year actuarial survival of 14% in the 1970s, 21% in the 1980s, and 36% in the 1990s. Factors significantly favoring long-term survival by univariate analyses included tumor diameter < 3 cm, negative nodal status, diploid tumor DNA content, tumor S phase fraction < 18%, pylorus-preserving resection, < 800 mL intraoperative blood loss, < 2 units of blood transfused, negative resection margins, and use of postoperative adjuvant chemotherapy and radiation therapy. Multivariate analyses indicated the strongest predictors of long-term survival were diploid tumor DNA content, tumor diameter < 3 cm, negative nodal status, negative resection margins, and decade of resection. CONCLUSIONS: The survival of patients with pancreatic adenocarcinoma treated by pancreaticoduodenectomy is improving. Aspects of tumor biology, such as DNA content, tumor diameter, nodal status and margin status, are the strongest predictors of outcome.     

Resected adenocarcinoma of the pancreas— 616 patients: Results, outcomes, and prognostic indicators

This large-volume, single-institution review examines factors influencing long-term survival after resection in patients with adenocarcinoma of the head, neck, uncinate process, body, or tail of the pancreas. Between January 1984 and July 1999 inclusive, 616 patients with adenocarcinoma of the pancreas underwent surgical resection. A retrospective analysis of a prospectively collected database was performed. Both univariate and multivariate models were used to determine the factors influencing survival. Of the 616 patients, 526 (85%) underwent pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas, 52 (9%) underwent distal pancreatectomy for adenocarcinoma of the body or tail, and 38 (6%) underwent total pancreatectomy for adenocarcinoma extensively involving the gland. The mean age of the patients was 64.3 years, with 54% being male and 91% being white. The overall perioperative mortality rate was 2.3%, whereas the incidence of postoperative complications was 30%. The median postoperative length of stay was 11 days. The mean tumor diameter was 3.2 cm, with 72 % of patients having positive lymph nodes, 30% having positive resection margins, and 36% having poorly differentiated tumors. Patients undergoing distal pancreatectomy for left-sided lesions had larger tumors (4.7 vs. 3.1 cm, P <0.0001), but fewer node-positive resections (59% vs. 73%, P = 0.03) and fewer poorly differentiated tumors (29% vs. 36%, P<0.001), as compared to those undergoing pancreaticoduodenectomy for right-sided lesions. The overall survival of the entire cohort was 63% at 1 year and 17% at 5 years, with a median survival of 17 months. For right-sided lesions the 1- and 5-year survival rates were 64% and 17%, respectively, compared to 50% and 15% for left-sided lesions. Factors shown to have favorable independent prognostic significance by multivariate analysis were negative resection margins (hazard ratio [HR] = 0.64, confidence interval [CI] = 0.50 to 0.82, P = 0.0004), tumor diameter less than 3 cm (HR = 0.72, CI = 0.57 to 0.90, P = 0.004), estimated blood loss less than 750 ml (HR = 0.75, CI = 0.58 to 0.96, P = 0.02), well/moderate tumor differentiation (HR = 0.71, CI = 0.56 to 0.90, P = 0.005), and postoperative chemoradiation (HR = 0.50, CI = 0.39 to 0.64, P } < 0.0001). Tumor location in head, neck, or uncinate process approached significance in the final multivariate model (HR = 0.60, CI = 0.35 to 1.0, P = 0.06). Pancreatic resection remains the only hope for long-term survival in patients with adenocarcinoma of the pancreas. Completeness of resection and tumor characteristics including tumor size and degree of differentiation are important independent prognostic indicators. Adjuvant chemoradiation is a strong predictor of outcome and likely decreases the independent significance of tumor location and nodal status. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

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.     

Neoadjuvant Chemoradiotherapy for Adenocarcinoma of the Pancreas: Treatment Variables and Survival Duration

Background:For patients with potentially resectable pancreatic cancer, the poor outcome associated with resection alone and the survival advantage demonstrated for combined-modality therapy have stimulated interest in preoperative chemoradiotherapy. The goal of this study was to analyze the effects of different preoperative chemoradiotherapy schedules, intraoperative radiation therapy, patient factors, and histopathologic variables on survival duration and patterns of treatment failure in patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head.Methods:Data on 132 consecutive patients who received preoperative chemoradiation followed by pancreaticoduodenectomy for adenocarcinoma of the pancreatic head between June 1990 and June 1999 were retrieved from a prospective pancreatic tumor database. Patients received either 45.0 or 50.4 Gy radiation at 1.8 Gy per fraction in 28 fractions or 30.0 Gy at 3.0 Gy per fraction in 10 fractions with concomitant infusional chemotherapy (5-fluorouracil, paclitaxel, or gemcitabine). If restaging studies demonstrated no evidence of disease progression, patients underwent pancreaticoduodenectomy. All patients were evaluated with serial postoperative computed tomography scans to document first sites of tumor recurrence.Results:The overall median survival from the time of tissue diagnosis was 21 months (range 19–26, 95%CI). At last follow-up, 41 patients (31%) were alive with no clinical or radiographic evidence of disease. The survival duration was superior for women (P = .04) and for patients with no evidence of lymph node metastasis (P = .03). There was no difference in survival duration associated with patient age, dose of preoperative radiation therapy, the delivery of intraoperative radiotherapy, tumor grade, tumor size, retroperitoneal margin status, or the histologic grade of chemoradiation treatment effect.Conclusion:This analysis supports prior studies which suggest that the survival duration of patients with potentially resectable pancreatic cancer is maximized by the combination of chemoradiation and pancreaticoduodenectomy. Furthermore, there was no difference in survival duration between patients who received the less toxic rapid-fractionation chemoradiotherapy schedule (30 Gy, 2 weeks) and those who received standard-fractionation chemoradiotherapy (50.4 Gy, 5.5 weeks). Short-course rapid-fractionation preoperative chemoradiotherapy combined with pancreaticoduodenectomy, when performed on accurately staged patients, maximizes survival duration and is associated with a low incidence of local tumor recurrence.Presented at the 53rd Annual Cancer Symposium of the Society of Surgical Oncology, New Orleans, Louisiana, March 18, 2000     

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.     

Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.

A retrospective review of the pathology and clinical course of 72 patients undergoing resection of carcinoma of the head of the pancreas was undertaken to identify the frequency of tumor involvement at standard surgical transection margins (stomach, duodenum, pancreas, and bile duct) as well as the peripancreatic soft tissue margin and the potential clinical significance of these findings. Of 72 patients undergoing resection, 37 patients (51%) were found to have tumor extension to the surgical margins. The most commonly involved margin was peripancreatic soft tissue (27 patients) followed by pancreatic transection line (14 patients) and bile duct transection line (4 patients). For 37 patients with tumor present at a resection margin, there were no survivors beyond 41 months. No difference in survival or local control was seen between 14 patients receiving postoperative radiation therapy and 5-fluorouracil (5-FU) compared with 23 patients not receiving additional treatment. In contrast, the 5-year actuarial survival and local control of 35 patients undergoing resection without tumor invasion to a resection margin was 22% and 43%, respectively. The 5-year survival and local control of 16 patients receiving adjuvant radiation therapy and 5-FU was 29% and 42%, respectively, whereas these figures were 18% and 31% for 19 patients not receiving adjuvant therapy (p > 0.10). Because residual local tumor after resection is common, preoperative radiation therapy may be beneficial in this disease. It should minimize the risk of dissemination during operative manipulation and facilitate a curative resection by promoting tumor regression. Because local failure rates approach 60% after resection and adjuvant therapy even in cases having clear resection margins, intraoperative radiation therapy to the tumor bed at the time of resection also might be considered. Protocols evaluating the feasibility and efficacy of preoperative radiation therapy and resection with intraoperative radiation therapy for patients with pancreatic cancer are underway.     

Insulin-like growth factor I receptor antagonism augments response to chemoradiation therapy in colon cancer cells

BACKGROUND: Colorectal cancer remains one of the most prevalent malignancies in the United States. Improvement in local disease control is seen when 5-fluorouracil (5-FU) is used in combination with pelvic irradiation for rectal adenocarcinoma. The frequent overexpression of insulin-like growth factor I receptor (IGF-I-R) in rectal adenocarcinoma suggests that inhibition of the signal transduction pathway may be a novel approach to enhance tumor response. This investigation seeks to define the role of IGF-I-R antagonism, using monoclonal antibody alpha-IR3, in augmenting cytotoxicity to adjuvant chemoradiation therapy for adenocarcinoma of the rectum. MATERIALS AND METHODS: SW 480 colon cancer cells were cultured to semiconfluent conditions with dose titrations performed for 5-FU to determine that the IC(50) (inhibitory concentration of 50% of the cells) was 0.5 microg/ml. The IC(50) for 5-FU was reassessed in the presence of IGF-I. Experimental groups included colon cancer cells combined with 5-FU; 6-MeV external beam radiation (100-500 cGy); and alpha-IR-3. RESULTS: The addition of 100 ng/ml IGF-I 1 h prior to 5-FU or radiation significantly blunted the expected cytotoxicity, resulting in a 10-fold increase in the IC(50) (from 0.5 to 5 microg/ml). Receptor antagonism using the monoclonal antibody alpha-IR-3 (100-400 ng/ml) produced a dose-dependent increase in cytotoxicity compared with 5-FU alone. The addition of radiation produced synergistic amplification of this response. CONCLUSIONS: IGF-I-R activation blocks the expected cytotoxic effects of 5-FU and external beam radiation. Receptor antagonism increased the cytotoxic response of chemoradiation therapy. These data suggest the utility of inhibiting IGF-I-R signal transduction in the treatment of rectal adenocarcinoma.     

An evidence-based approach to the surgical management of resectable pancreatic adenocarcinoma

BACKGROUND: Randomized prospective trials have addressed various treatment approaches to pancreatic adenocarcinoma in order to improve on the dismal prognosis associated with this disease. We conducted a comprehensive review of prospective randomized clinical trials and summarized the contemporary treatment of resectable pancreatic carcinoma. STUDY DESIGN: A literature search strategy identified prospective randomized clinical trials for pancreatic carcinoma using standard medical subject heading terms. The articles were critically reviewed and ranked according to a standardized three-tiered system (Ia, Ib, Ic) by a panel of experts. RESULTS: Surgical studies have demonstrated that morbidity and mortality are similar for pylorus-preserving and classic pancreaticoduodenectomy. Extended retroperitoneal lymphadenectomy can be performed with similar mortality but increased morbidity compared with standard pancreaticoduodenectomy but does not prolong survival. Pancreaticogastrostomy and pancreaticojejunostomy appear to be comparable techniques for pancreatic duct reconstruction. Pancreatic-enteric anastomosis is associated with lower rates of pancreatic fistula and endocrine insufficiency than duct occlusion without anastomosis. Intraperitoneal drainage after pancreatic resection is unwarranted and may contribute to intraabdominal complications. Routine use of prophylactic octreotide does not lower the rate of pancreatic fistula; it should be considered for reoperative pancreatic resection or for a soft gland. Early trials found that adjuvant chemoradiation therapy prolongs survival. But in more recent studies chemoradiation after resection has failed to show a survival advantage over surgery alone. CONCLUSIONS: Surgical resection remains the only potentially curative therapy for adenocarcinoma of the pancreas. There is no clear indication as to a single preferable resection approach.     

Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas.

Chemoradiation prior to pancreaticoduodenectomy ensures that all patients who undergo resection complete multimodality therapy, avoids resection in patients with rapidly progressive disease, and allows radiation therapy to be delivered to well-oxygenated cells before surgical devascularization. Twenty-eight patients with cytologic or histologic proof of localized adenocarcinoma of the pancreatic head received preoperative chemoradiation (fluorouracil, 300 mg/m2 per day, and 50.4 Gy) with the intent of proceeding to resection; all 28 completed this preoperative therapy. Hospital admission because of gastrointestinal toxic effects was required in nine patients, yet no patient experienced a delay in operation. Restaging was performed 4 to 5 weeks after completion of chemoradiation, and five patients were found to have metastatic disease; the 23 patients without evidence of progressive disease underwent laparotomy. At laparotomy, three patients were found to have unsuspected metastatic disease, three patients had unresectable locally advanced disease, and 17 patients were able to undergo pancreaticoduodenectomy. One perioperative death resulted from myocardial infarction, and perioperative complications occurred in three patients. Histologic evidence of tumor cell injury was present in all resected specimens. Our results suggest that pancreaticoduodenectomy can be performed with a low incidence of complications after chemoradiation for localized adenocarcinoma of the pancreas.     

Downstaging of esophageal cancer after preoperative radiation and chemotherapy.

OBJECTIVE: This retrospective, nonrandomized review evaluates 125 patients with esophageal carcinoma (adenocarcinoma and squamous cell) who underwent either surgery only or preoperative chemotherapy and/or radiation therapy followed by surgery. Major end points were survival and postchemoradiation downstaging. METHODS: Forty-four patients underwent radiation therapy of 4500 cGy over 5 weeks. Fluorouracil and cisplatin were administered on the first and fifth week of radiotherapy. Ninety-eight patients underwent "potentially curative" resections-transhiatal esophagectomy (70), Lewis esophagogastrectomy (25), and left esophagogastrectomy (3). All patients with preoperative adjuvant therapy underwent endoscopy and biopsy before surgery. RESULTS: There were no differences in overall mortality (5%) or surgical complications in either group. Fourteen of 44 patients (32%) downstaged to complete pathologic response, with 5-year survival of 57%. Fifteen of 44 patients (34%) downstaged to microscopic residual tumor, with 1- and 3-year survival of 77% and 31%, respectively. Twenty-eight of 29 patients in the two downstaged groups were lymph node negative. Overall, 5-year survival in the adjuvant therapy plus surgery group versus surgery only was 36% and 11% (p = 0.04). Five-year survival in lymph node-negative adjuvant therapy and surgery patients was 49% (p = 0.005). Positive nodes in the surgery only group was 48% versus 23% in the adjuvant therapy and surgery group (p = 0.02). CONCLUSION: Although retrospective and nonrandomized, these results suggest that preoperative chemoradiation results in significant clinical and pathologic downstaging, increases survival, and may sterilize local and regional lymph nodes, accounting for both downstaging and survival statistics.     

Feasibility and Efficacy of Combination Therapy With Preoperative and Postoperative Chemoradiation, Extended Pancreatectomy, and Postoperative Liver Perfusion Chemotherapy for Locally Advanced Cancers of the Pancreatic Head

Background The outcome after resection of advanced pancreatic cancers is extremely poor because of the high incidence of the postoperative development of liver metastasis and local recurrence. We performed a combination of chemoradiation and liver perfusion chemotherapy and extended pancreatectomy.Methods Nineteen patients with T3 pancreatic head cancers were enrolled. A total of 24 Gy in 12 fractions of 10-MV x-rays with a concurrent intravenous infusion of 5-fluorouracil (5-FU; 3 g/12 days) was administered to the pancreatic head area. An extended pancreaticoduodenectomy was performed, and catheters were placed into the gastroduodenal artery and the superior mesenteric vein. During the first 28 postoperative days, 5-FU was continuously infused via the hepatic artery and portal vein (3.5 g/28 days × 2). Finally, 36 Gy in 18 fractions with 5-FU (3 g/6 days) was applied to the pancreatic bed.Results After preoperative chemoradiation, four patients did not undergo surgical resection because of distant metastases. Fifteen patients underwent pancreaticoduodenectomy, liver perfusion chemotherapy, and postoperative chemoradiation. No patient developed grade 3 toxicity as a result of preoperative chemoradiation, but one patient (7%) developed grade 3 leukopenia during the postoperative treatments. The morbidity rate was 20% (3 of 15 patients), and the mortality rate was 0%. The overall 3-year survival rate was 53%. The 3-year disease-free survival rate was 66% in patients who pathologically responded well (>50%), versus 0% in patients with poor responses (P = .04).Conclusions A combination of preoperative and postoperative chemoradiation plus postoperative liver perfusion chemotherapy with an extended pancreatectomy is feasible, and the long-term outcomes are also promising.     

Impact of Lymph Node Involvement on Long-term Survival after R0 Pancreaticoduodenectomy for Ductal Adenocarcinoma of the Pancreas

Pancreaticoduodenectomy remains the only potentially curative treatment for adenocarcinoma of the pancreas. The aim of this study was to analyze prognostic factors impacting survival after R0 pancreaticoduodenectomy for adenocarcinoma in the head of the pancreas. Between 1995 and 2002, a potentially curative (R0) pancreaticoduodenectomy with pancreatogastrostomy for ductal adenocarcinoma in the head of the pancreas was performed in 81 patients (42 women and 39 men) with a mean age of 64 years (range 35–84). Patients were identified from a prospective database and records were reviewed retrospectively. Postoperative mortality was 1%, and 40% of patients had complications. Median survival was 18 months, and the 5-year survival was 24%. Fifteen patients were alive at 5 years. Factors associated with poor survival in multivariate analysis were (1) two or more positive lymph nodes, (2) tumor diameter greater than 30 mm, and (3) age greater than 70 years. In patients with no or with one positive lymph node, the 5-year survival was 44%. On the other hand, in patients with two or more positive lymph nodes, both the 3- and 5-year survival was 5%. The main risk factor associated with poor survival after an R0 pancreaticoduodenectomy for adenocarcinoma in the head of pancreas was lymph node status: The presence of two or more positive lymph nodes was associated with decreased survival.     

化疗和放疗对可切除性胃癌的临床治疗研究进展

基于各项Ⅲ期临床研究,近年来,术后化放疗、围手术期ECF方案（表柔比星、顺铂和氟尿嘧啶）化疗以及术后口服S-1辅助化疗分别成为了美国、欧洲和日本治疗可切除性胃癌的标准辅助治疗方式.2001年,美国西南肿瘤组（SWOG）报道的大型Ⅲ期随机临床试验（INT0116）结果,使得术后化放疗在美国成为可切除性胃癌的标准治疗方式.随着化放疗技术的快速发展,术前化放疗、术后化放疗、化放疗联合术中放疗等各种化放疗方案不断地被业内学者所报道.本综述总结近年来报道的关于胃癌患者手术前后的辅助性化放疗方案及其临床试验结果,并综合评价化放疗在可切除性胃癌中的治疗价值及意义.     

Margin Positive Pancreaticoduodenectomy Is Superior to Palliative Bypass in Locally Advanced Pancreatic Ductal Adenocarcinoma

Background

Pancreatic ductal adenocarcinoma is an aggressive disease. Surgical resection with negative margins (R0) offers the only opportunity for cure. Patients who have advanced disease that limits the chance for R0 surgical resection may undergo margin positive (MP) pancreaticoduodenectomy (PD), palliative surgical bypass (PB), celiac plexus neurolysis alone (PX), or neoadjuvant chemoradiation therapy in anticipation of future resection.

Objective

The aim of this study was to determine if there is a difference in the perioperative outcomes and survival patterns between patients who undergo MP PD and those who undergo PB for locally advanced disease in the treatment of pancreatic ductal adenocarcinoma.

Methods

We reviewed our pancreatic surgery database (January 2005–December 2007) to identify all patients who underwent exploration with curative intent of pancreatic ductal adenocarcinoma of the head/neck/uncinate process of the pancreas. Four groups of patients were identified, R0 PD, MP PD, PB, and PX.

Results

We identified 126 patients who underwent PD, PB, or PX. Fifty-six patients underwent R0 PD, 37 patients underwent MP PD, 24 patients underwent a PB procedure, and nine patients underwent PX. In the PB group, 58% underwent gastrojejunostomy (GJ) plus hepaticojejunostomy (HJ), 38% underwent GJ alone, and 4% underwent HJ alone. Of these PB patients, 25% had locally advanced disease and 75% had metastatic disease. All nine patients in the PX group had metastatic disease. The mean age, gender distribution, and preoperative comorbidities were similar between the groups. For the MP PD group, the distribution of positive margins on permanent section was 57% retroperitoneal soft tissue, 19% with more than one positive margin, 11% pancreatic neck, and 8% bile duct. The perioperative complication rates for the respective groups were R0 36%, MP 49%, PB 33%, and PX 22%. The 30-day perioperative mortality rate for the entire cohort was 2%, with all three of these deaths being in the R0 group. The median follow-up for the entire cohort was 14.4 months. Median survival for the respective groups was R0 27.2 months, MP 15.6 months, PB 6.5 months, and PX 5.4 months.

Conclusions

Margin positive pancreaticoduodenectomy in highly selected patients can be performed safely, with low perioperative morbidity and mortality. Further investigation to determine the role of adjuvant treatment and longer-term follow-up are required to assess the durability of survival outcomes for patients undergoing MP PD resection.     

胰腺钩突部根治性完整切除的新方法(附306例报告)

目的 探讨壶腹部周围恶性肿瘤患者胰腺钩突部根治性完整切除的技巧和方法.方法 2005年3月至2010年3月共连续完成了306例壶腹部周围恶性肿瘤的根治性胰十二指肠切除(RPD),男性169例,女性137例;发病年龄37～79岁,平均58岁.其中胰头颈部肿瘤151例,胆总管下端肿瘤48例,壶腹部肿瘤55例,十二指肠乳头部肿瘤52例.采用肠系膜上血管交换和胰腺钩突部血流控制法顺利完成所有患者的钩突部根治性完整切除;消化道重建均采用Child法;胰肠吻合均采用简化的捆绑式胰肠吻合术.结果 306例接受RPD的患者中,手术时间4～6 h,出血量200～600 ml,无术中及术后胰腺钩突部位的出血.术后患者出血发生率和病死率分别为3.3%和0.9%;术后胰瘘和胆瘘发生率分别为1.6%和0.6%,胆瘘、胰瘘患者均在B超引导下经穿刺引流等保守治疗后痊愈.随访至2010年3月,未见因肠系膜上血管周围肿瘤复发死亡患者.结论 采用肠系膜上血管交换和胰腺钩突部血流控制法可顺利完成壶腹部周围恶性肿瘤患者胰腺钩突部的根治性完整切除;并可减少术中出血量,缩短手术时间,减少肠系膜上静脉和(或)肠系膜上动脉的误切,可避免因胰腺钩突部残留引起的术后胰腺组织坏死脱落、感染和出血;还可从理论上减少肿瘤细胞播散的机会.