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     

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperkoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected when-ever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P <0.001), and number of previous operations, which was greater in group II (P <0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher’s exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07). Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

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.     

Preoperative chemoradiation in patients with resectable rectal cancer: Results on tumor response

Background There is no consensus about the role of preoperative radiotherapy (RT) and chemotherapy (CT) in patients with resectable cancer of the distal rectum. This study analyzed the local clinical and pathologic response in patients receiving preoperative RT/CT for rectal cancer. Methods Thirty-two consecutive patients with a palpable adenocarcinoma of the rectum received preoperative RT (45 Gy in 25 fractions over 5 weeks), plus continuous chemotherapy with doxifluridine and leucovorin or 5-fluorouracil by continuous intravenous infusion during RT. Surgery was performed 8 weeks later. The Wilcoxon andχ ² tests were used for data analysis. Results Twelve patients had mild gastrointestinal toxicity, only one of whom required interruption of therapy. The tumor shrank to 57.8% of its original size, and at the echoendoscopy (u) there was a 58.7% decrease of the maximum diameter (P<.001). Downstaging from uT3 and uT2 to <uT3 and <uT2, respectively, occurred in 41.6% of patients (P=.0020). Total and major regression of the tumor at the histopathologic examination occurred in 12.5% and 50% of patients. Conclusions Local response to preoperative RT/CT was highly satisfactory and allowed conservative surgery in 81% of patients. Optimization of the combined therapy could achieve even better results.     

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     

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.     

Distal pancreatectomy for resectable adenocarcinoma of the body and tail of the pancreas

The study goal was to analyze outcome after distal pancreatectomy for three subtypes of adenocarcinoma to determine the role of en bloc resection in surgical management. A secondary aim was to identify those clinicopathologic factors correlating with survival in an analysis limited to ductal adenocarcinoma. Medical records of consecutive patients undergoing distal pancreatectomy for adenocarcinoma between 1987 and 2003 were reviewed. A comparative analysis was undertaken of the safety and outcome of patients undergoing standard and en bloc resections. Clinicopathologic factors for patients undergoing distal pancreatectomy for ductal adenocarcinoma were subjected to both univariate and multivariate survival analyses. Ninety-three patients underwent resection for ductal adenocarcinoma (66, 71%), mucinous cystadenocarcinoma (18, 19%), or adenocarcinoma associated with intraductal papillary mucinous neoplasm (IPMN) (9, 10%). En bloc resection was required in 33 (35%) patients. There was no operative mortality. Median survival was 15.5 months, 30.2 months, and 50.7 months for ductal adenocarcinoma, mucinous cystadenocarcinoma, and adenocarcinoma associated with IPMN, respectively. Patients undergoing en bloc resection had a higher overall complication rate, required more transfusions and more intensive care unit admissions, and had a higher rate of positive margins; however, there were no deaths. For ductal adenocarcinoma, tumor size greater than 3.5 cm, age greater than 60 years, and stage were factors that correlated with survival on a univariate analysis. None were significant on multivariate analysis. Four patients with ductal adenocarcinoma were actual 5-year survivors. While en bloc resections are associated with a higher rate of complications, the majority are self-limited and mortality is low. Resection, including adjacent organs, should be performed when appropriate. Long-term survival for patients with cystadenocarcinoma or IPMN-associated adenocarcinoma can be anticipated. While rare, long-term survival for patients with ductal adenocarcinoma after distal pancreatectomy can be achieved. Presented at the Thirty-Eighth Annual Meeting of the Pancreas Club, New Orleans, Louisiana, May 16, 2004.     

Preoperative chemotherapy of chemoradiotherapy for the treatment of adenocarcinoma of the pancreas and ampulla of Vater

Much has been written about preoperative strategies in the treatment of pancreatic adenocarcinoma, yet there has been very little comment concerning other periampullary malignancies. This review discusses current issues relevant to the further development of preoperative adjuvant treatment of pancreatic adenocarcinoma. A small series of patients with ampullary adenocarcinomas treated with preoperative adjuvant chemoradiotherapy is also described. Received for publication on June 17, 1998; accepted on July 30, 1998     

Diffuse pancreatic adenocarcinoma identified in an adult with annular pancreas

Annular pancreas is a congenital anomaly resulting from malrotation of the pancreatic ventral bud. Although annular pancreas in the adult is rare, it may be recognized with increased frequency as a result of more liberal use of pancreatic imaging studies in patients with chronic abdominal pain and suspected chronic pancreatitis. Malignancy in the setting of annular pancreas is an uncommon event that has been reported previously but has almost always been related to the annular (ventral) segment. We report an interesting case in which pancreatic adenocarcinoma diffusely involving the dorsal (nonannular) segment presented in a middle-aged female patient. This unusual presentation points out the importance of considering neoplasia as part of the differential diagnosis and the possibility of pancreatic pathology in the dorsal, nonannular segment when there is no obvious duodenal or biliary obstruction involving the annular ventral segment.     

Promising results with chemoradiation in patients with sinonasal undifferentiated carcinoma

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is an uncommon malignancy associated with poor prognosis. The optimal treatment approach for SNUC has not been established was performed. METHODS: A retrospective review of all patients with SNUC seen at the Peter MacCallum Cancer Centre over a 12-year period. RESULTS: Ten patients with SNUC were identified, with nine having locally advanced disease (T4). Seven were treated with three cycles of platinum and 5-fluorouracil followed by radiation with two cycles of concurrent platinum. In these seven patients, the 2-year progress on-free survival was 43% (95% CI, 11% to 82%) and 2-year overall survival was 64% (95% CI, 23% to 91%). One patient with a T1N0 nasal cavity tumor treated with radiation alone has not relapsed. Two patients who were treated with initial surgical resection, prior to referral to our institution, received postoperative radiation, but they subsequently had relapses and died. CONCLUSION: Induction chemotherapy followed by concurrent chemoradiation is promising treatment strategy for SNUC.     

Preoperative chemoradiation in the management of adenocarcinoma of the body of the pancreas

Adenocarcinoma of the body of the pancreas has been traditionally associated with low resectability and poor prognosis. We reviewed 30 consecutive cases of pancreatic body adenocarcinoma presenting between 1988 and 2001. Twenty-six (87%) patients received preoperative chemotherapy (either 5-fluorouracil with or without mitomycin C or gemcitabine) plus radiation therapy (50.4 Gy), and four patients received chemoradiation postoperatively. During or shortly after chemoradiation 16 (53%) patients developed distant metastasis (n = 12), tumor progression (n = 2), or fatal septic complications (n = 2). Fourteen patients underwent surgical resection with curative intent. Resections performed included distal subtotal pancreatectomies (n = 6), extended pancreaticoduodenectomies (n = 6), and total pancreatectomies (n = 2). Ten patients (71%) required vascular reconstruction as a result of involvement of the portal vein or the superior mesenteric, hepatic arterial, or celiac vessels. Median overall survival was 34 months (range 8-152) for the resected group as compared with 8 months (range 1-14) in the unresected group (P = 0.005). Five-year actuarial overall survival is projected at 45 per cent for the resected group. In this poor-prognostic subset of patients with pancreatic cancer preoperative chemoradiation followed by an aggressive surgical approach was associated with resectability and long-term survival of a significant minority of patients.     

Predicting the node-negative mesorectum after preoperative chemoradiation for locally advanced rectal carcinoma

Preoperative chemoradiation therapy (CRT) in patients with locally advanced rectal cancer allows for radical surgery with sphincter preservation in many patients. To determine whether patients downsized with preoperative CRT may be potential candidates for local excision, we investigated residual disease patterns after neoadjuvant treatment. A retrospective analysis was carried out of patients with T3 or T4 rectal adenocarcinoma who were treated with neoadjuvant CRT. Clinical and pathologic data were analyzed to (1) determine the response rates to preoperative CRT in the tumor bed and regional nodal basin and (2) identify the incidence of residual disease in the mesorectum in patients downsized to ≤T2. A total of 219 patients met the inclusion criteria. Preoperatively 193 patients (88%) were staged as T3, and 99 patients (47%) had clinical N1 disease. The pathologic complete response rate was 20% (43 of 219 patients). T stage was downsized in 64% of the patients (140 of 219), and 69% (67 of 97) of the patients with clinical N1 disease were rendered node negative. Seventeen percent (21 of 122) of patients downsized to ≤T2 had residual disease in the mesentery. With a median follow-up of 40 months, 182 patients (83%) remain alive and free of disease. Nine patients (4.1%) have had a local recurrence. Although tumor response rates to preoperative CRT within the bowel wall and lymph node basin are similar, one in six patients with pT0-2 tumors will have residual disease in the rectal mesentery and nodes. Despite a substantial reduction in tumor volume with neoadjuvant CRT, local excision should be recommended with caution in patients with locally advanced rectal cancer. Presented at Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 18–21, 2003 (oral presentation).     

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.     

Long-term survival of resectable subset after induction chemotherapy in patients with locally advanced head and neck cancer

BACKGROUND: Although meta-analysis showed that survival improved with concurrent chemoradiation in locally advanced head and neck cancer, neoadjuvant chemotherapy is still unique, because it renders curative surgery feasible for marginally resectable head and neck cancer patients. METHODS: We reviewed patients with locally advanced head and neck cancer, who had been treated with neoadjuvant chemotherapy between June 1984 and February 2001 at the Seoul National University Hospital. RESULTS: A total of 167 patients were included. After 2 to 3 chemotherapy cycles, either surgery (38 patients) or radiation (104 patients) was conducted. Those who received surgery exhibited better survival than those who received radiation [median survival: not reached vs 33.6 months (95% CI: 22.6-44.7), p = .006]. The 5-year and 10-year survival rates of surgery group were 63.2% and 59.8%. CONCLUSION: The potential benefit of neoadjuvant chemotherapy with surgery in patients with locally advanced head and neck cancers merits further evaluation in future clinical trials.     

Staging of pancreatic cancer before and after neoadjuvant chemoradiation

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine theutilityof staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT. Presented at the 2001 Americas Congress of the American Hepatopancreatobiliary Association, Miami, Fla., February 25, 200l.