INTRODUCTION More than 37,000 people develop pancreatic adenocarcinoma (cancer of the exocrine pancreas) each year in the United States, and almost all are expected to die from the disease . Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Furthermore, prognosis is poor, even for those undergoing complete (R0) resection. Reported five-year survival rates following pancreaticoduodenectomy for node-negative and node-positive disease are 25 to 30, and 10 percent, respectively . Outcomes may be improving over time, possibly related to an increase in the proportion of patients undergoing surgery at teaching hospitals, lower perioperative mortality rates, better patient selection, and/or greater use of adjuvant therapy. As an example, in a report of 396 Medicare patients residing in one of 11 SEER (Surveillance, Epidemiology, and End Results) registries who underwent curative intent surgery for pancreatic cancer between 1991 and 1996, the three-year survival rate was 34 percent . Nevertheless, these patients still have a relatively poor prognosis overall. Systemic chemotherapy, radiation therapy (RT), or a combination of both modalities (chemoradiotherapy) have been used following surgical resection (adjuvant therapy) and even prior to resection (neoadjuvant therapy) in an effort to improve cure rates. Although the benefit of adjuvant therapy has become more apparent in recent years, the optimal choice of treatment modality (chemotherapy with or without RT) remains intensely controversial. Cancer of the ampulla of Vater is uncommon, but it often presents as a periampullary tumor that may be indistinguishable preoperatively from adenocarcinoma of the pancreatic head. These patients are treated in a similar manner to those with pancreatic cancer, and adjuvant therapy is often considered following pancreaticoduodenectomy although outcomes for patients with ampullary cancer are better than for routine pancreatic adenocarcinomas. Adjuvant and neoadjuvant therapies for pancreatic and ampullary adenocarcinomas will be reviewed here. Surgical management of localized pancreatic and ampullary adenocarcinoma, treatment of locally advanced tumors, and chemotherapy for advanced disease are discussed separately. ADJUVANT THERAPY FOR PANCREATIC CANCER Systemic chemotherapy, RT or a combination of chemotherapy and RT have all been applied following surgery in an effort to improve outcome in patients undergoing potentially curative (R0) resection. The rationale for combined modality therapy is provided by the failure pattern following surgical resection; more than one-half of patients develop locoregional recurrence without evidence of distant metastases . An important point is that over the last 25 years, three major trends have impacted our ability to evaluate the effectiveness of various therapies, and makes the comparison of studies across this time paeriod very difficult.
Chemoradiotherapy The Gastrointestinal Tumor Study Group (GITSG) initially demonstrated improved survival when external beam RT was combined with concurrent 5-fluorouracil (5-FU) chemotherapy compared to RT alone in patients with locally advanced unresectable pancreatic cancer . This combined modality regimen was subsequently applied to patients who had undergone an R0 resection in an attempt to improve the surgical cure rate. However, despite the publication of several randomized trials evaluating postoperative chemoradiotherapy or a combination of preoperative plus postoperative combined modality therapy in patients with resected pancreatic cancer, its true benefit remains controversial. GITSG study In a study conducted in the late 1970s and early 1980s by GITSG, patients were randomly assigned to either observation or external beam RT (EBRT, 40 Gy) plus concurrent bolus 5-FU (500 mg/m2 per day on the first three and last three days of RT), followed by maintenance chemotherapy (5-FU 500 mg/m2 per day for three days monthly) for two years or until disease progression . The study was terminated after eight years due to poor patient accrual. As a result, only 43 patients were available for analysis. Despite the relatively low RT dose, small number of patients, and the fact that 25 percent of the patients on the treatment arm did not begin postoperative treatment until more than 10 weeks following resection, patients receiving postoperative chemoradiotherapy had significantly longer median overall survival (20 versus 11 months) and a doubling of the two-year survival rate (20 versus 10 percent). Following closure of the study, an additional 32 patients were registered on the combined modality arm, and a subsequent report that included these and the original 43 patients confirmed the initial survival benefit . EORTC study In an effort to reproduce these findings, a study sponsored by the European Organization for Research and Treatment of Cancer (EORTC) randomly assigned 114 patients with resected pancreatic cancer to postoperative concurrent 5-FU (25 mg/kg per day by continuous infusion) plus EBRT (40 Gy in split courses) or observation . In contrast to the GITSG findings, postoperative chemoradiotherapy did not significantly improve median overall survival or two-year survival (26 versus 34 percent for control and treated patients, respectively, However, like the GITSG trial, this study was also criticized for several reasons: RT was delivered in a split-course manner (potentially allowing for tumor repopulation between courses), the dose was suboptimal, there was no prospective assessment of the completeness of surgical margins. Furthermore, 20 percent of patients randomized to treatment never received it. However, since the trial did show a trend towards benefit of adjuvant therapy and was considered underpowered, some investigators viewed this study as supporting the conclusions of the GITSG trial. ESPAC-1 trial An ambitious second trial sponsored by European investigators, the ESPAC-1 trial, initially set out to randomize patients to a 2x2 factorial design in which the relative benefits of adjuvant chemotherapy, chemoradiotherapy, or chemoradiotherapy followed by chemotherapy would be compared to observation alone. However, fear of poor accrual led the investigators to permit physicians to choose from this or two other randomization schemes (described below). The final results were presented in two separate publications, one that pooled the results from the three parallel randomized trials , and a later report that focused on the 289 patients randomized to the four-arm study . The pooled analysis included 541 patients (including those with positive margins) who were randomly assigned to postoperative treatment following resection of pancreatic adenocarcinoma in the following three parallel studies :
In the initial report of the pooled analysis, there was no survival difference when the 175 patients receiving postoperative chemoradiotherapy were compared to the 178 who did not receive it (median overall survival 15.5 versus 16.1 months, respectively). In contrast, there was a significant survival benefit for adjuvant chemotherapy alone when 238 patients who received it were compared to 235 who did not receive it (median survival 19.7 versus 14 months, respectively). This analysis was criticized for the following reasons:
Some (but not all) of these concerns were addressed in a subsequent report that included only the 289 patients randomized to the four arm study . In an intent-to treat analysis, there was no significant benefit for chemoradiotherapy in the two groups that received it, and the data in fact suggested a trend toward worse survival for this group (two and five-year survival rates were 29 versus 41 percent, and 10 versus 20 percent for the chemoradiotherapy and no chemoradiotherapy groups, respectively). There were no significant imbalances for known prognostic factors (nodal positivity, resection margin status, histologic grade) in the two arms that could have contributed to these results. Local recurrence rates were similar in both groups, but there were more recurrences overall (84 versus 74) in the chemoradiotherapy group and a shorter recurrence-free interval (10.7 versus 15.2 months, respectively). In contrast to these results, both the two-year (40 versus 30 percent) and five-year (21 versus 8 percent) survival rates were significantly greater among patients randomized to postoperative chemotherapy alone compared to those who did not receive it, despite the fact that 33 percent of those assigned to adjuvant chemotherapy did not complete all six courses, and 17 percent received no chemotherapy at all. The median survival for patients treated with chemotherapy versus no chemotherapy was 20.1 versus 15.5 months, respectively. The authors postulated that the delay in the administration of systemic chemotherapy in patients undergoing chemoradiotherapy might explain the inferior outcomes seen in this group. Although the trial was underpowered to perform statistical comparisons of the four individual treatment groups, patients in both chemoradiotherapy groups had an inferior median overall survival (13.9 and 14.2 months for chemoradiotherapy alone or chemoradiotherapy plus chemotherapy) as compared to those undergoing observation alone (16.9 months). These data suggest that treatment-related toxicity might account for some of the differences. In summary, it is difficult to draw firm conclusions regarding the benefit of chemoradiotherapy from the ESPAC-1 trial. Although there are no large contemporary randomized trials that confirm the GITSG data, it should be noted that in other gastrointestinal cancers where local failure is a common problem (eg, gastric and rectal cancer), a survival benefit has been shown in large randomized trials for patients receiving a combination of adjuvant chemoradiation and chemotherapy. Uncontrolled series Other investigators have reported retrospective data that suggest benefit for postoperative chemoradiotherapy in pancreatic cancer
� Standard therapy was chosen by 99 patients. It consisted of EBRT to the pancreatic bed (40 to 45 Gy) plus two 3-day courses of 5-FU concurrent with the start and finish of RT, followed by weekly bolus 5-FU (500 mg/m2 per dose) for four months. � Intensive therapy was chosen by 21 patients. It consisted of EBRT to the pancreatic bed (50.4 to 57.6 Gy) plus prophylactic hepatic irradiation (23.4 to 27 Gy) given with and followed by infusional 5-FU (200 mg/m2 per day) plus leucovorin (5 mg/m2 per day) for five of seven days every week for four months. � The remaining 53 patients
declined any postoperative therapy. Compared to no postoperative therapy, any postoperative adjuvant chemoradiotherapy was associated with a significantly better median survival (20 versus 14 months). More intensive therapy was not associated with a survival advantage when compared to standard dose therapy.
The results were striking. At a mean follow-up duration of 32 months, 67 percent of patients remained alive, and the actuarial two, three, and five-year survival rates were 64, 64, and 55 percent, respectively. Although these survival results compare favorably with historical control series, the toxicity of this regimen was substantial. Seventy percent of patients had moderate to severe treatment-related toxicity (predominantly gastrointestinal), with 42 percent requiring hospitalization at some point. Confirmatory trials are needed, which are underway at the MD Anderson Cancer Center, and within the American College of Surgeons Oncology Group (ACOSOG). Because the above data are not from prospectively randomized trials, they must therefore be interpreted with caution. However, these findings provide some support for the potential survival benefit of standard dose adjuvant chemoradiation therapy for patients undergoing complete resection for pancreatic cancer. Gemcitabine-based approaches Preliminary data support the tolerability and favorable short-term outcomes of regimens that use gemcitabine as a radiation sensitizer but no trials have compared this approach to chemoradiotherapy using 5-FU as the radiation sensitizer, at least in the postoperative setting. A slightly different approach, adjuvant gemcitabine monotherapy both before and after concomitant 5-FU-based chemoradiotherapy, was directly compared to 5-FU-based chemoradiotherapy in which 5-FU was given before, during, and after RT in a United States Intergroup study (Radiation Therapy Oncology Group [RTOG] 9740) . Patients who had undergone gross total resections for T1-4, N0-1 pancreatic adenocarcinoma, and who were taking in at least 1500 calories daily postoperatively were randomly assigned to one of the following two treatment arms:
The study was sufficiently powered to separately analyze results according to the primary site (head versus body/tail). In a preliminary report, patients with pancreatic head tumors (n = 380) had a significantly better median (20.6 versus 16.9 months) and three-year survival (32 versus 21 percent) with gemcitabine-based adjuvant therapy, although there was no significant difference between the two groups in either the population as a whole, or in those with body/tail tumors (n = 62). Compared to the all 5-FU treatment, the gemcitabine group had similar rates of nonhematologic grade 3 or 4 toxicity, and febrile neutropenia despite significantly more grade 4 hematologic toxicity (14 versus 2 percent). Chemotherapy alone At least three randomized controlled clinical trials and a meta-analysis suggest a significant disease-free or overall survival benefit from chemotherapy alone without RT following resection of a pancreatic cancer. This approach is commonly used outside of the United States. 5-FU based regimens Despite its methodologic problems, the results of the ESPAC-1 trial, discussed above, demonstrated a survival benefit from six months of postoperative leucovorin-modulated 5-FU in patients with resected pancreatic cancer, compared to those receiving no adjuvant chemotherapy (median overall survival 19.7 versus 14 months, respectively) Comparable results were noted in a Norwegian trial that randomly assigned 61 patients with curatively resected pancreatic cancer to six cycles of 5-FU, doxorubicin, plus mitomycin (FAM) or observation. Like the ESPAC-1 trial, chemotherapy was associated with a significantly longer median survival (23 versus 11 months). However, long-term survival was similar at both three (30 versus 27 percent) and five years (8 versus 4 percent). Gemcitabine � The efficacy of gemcitabine was evaluated in the multinational European CONKO trial of 368 patients with grossly complete (R0 or R1) surgical resection and a preoperative CA 19-9 level <2.5 times the upper limit of normal. The patients were randomly assigned to gemcitabine (1000 mg/m2 days 1,8, and 15 every four weeks for six months) or no treatment after surgery. Patients were stratified by resection margins (which were positive in about 17 percent of patients) and tumor (T) and nodal (N) status; the primary end point was disease-free survival (DFS). At a median follow-up of 53 months, adjuvant gemcitabine was associated with a significantly longer median DFS (13.4 versus 6.9 months), which was evident in those with negative (24.8 versus 10.4 months) and positive nodes (12.1 versus 6.4 months), as well as those with negative (13.1 versus 7.3 months) or positive margins (15.8 versus 5.5 months). There was a nonsignificant trend toward improved overall survival with gemcitabine (median 22.1 versus 20.2 months, p = 0.06). The pattern of recurrence did not differ between the two groups. Local recurrence was a component of failure in 34 and 41 percent of the relapsing patients in the gemcitabine and observation groups, respectively. These data suggest that gemcitabine delayed rather than prevented the development of recurrent disease after resection of pancreatic cancer. Radiation therapy Adjuvant EBRT after potentially curative surgery reduces local recurrence rates but does not improve overall survival. In contrast, some but not all studies suggest a potential survival benefit from the use of intraoperative RT (IORT) in conjunction with surgical resection . IORT permits the delivery of high-dose RT directly to areas at highest risk of local recurrence, while minimizing toxicity to adjacent normal tissues. Most trials have combined IORT with preoperative EBRT and chemotherapy (see below). Summary There is no consensus regarding the optimal management of patients following resection of pancreatic cancer, and the approach is different in Europe and in the United States. The European approach emphasizes the weaknesses of the early GITSG study, and the lack of data demonstrating a significant survival benefit with chemoradiotherapy in the EORTC and ESPAC-1 trials. Most European clinicians support the conclusions of the ESPAC-1 trial (ie, that chemotherapy prolongs survival and chemoradiotherapy may actually worsen survival). The benefit of adjuvant chemotherapy alone is further supported by the German CONKO trial . The American approach to adjuvant therapy differs with regard to the benefit of chemoradiotherapy, and emphasizes the following points:
In the opinion of the authors and the National Comprehensive Cancer Network (NCCN [43] ), patients who have undergone resection of a pancreatic adenocarcinoma should be encouraged to enroll in clinical trials evaluating the potential benefits of chemotherapy and/or chemoradiotherapy as well as new therapies. Off protocol, NCCN guidelines suggest 5-FU-based chemoradiation with or without additional gemcitabine, or chemotherapy alone (5-FU or gemcitabine). At least until the results of the ongoing European ESPAC-3 trial (observation, leucovorin-modulated 5-FU, or gemcitabine after resection) become available, the authors suggest chemoradiotherapy with concurrent infusional 5-FU following resection of a pancreatic adenocarcinoma. The early results from RTOG 9704 combined with the results from the CONKO trial provide support for adding gemcitabine adjuvant chemotherapy to chemoradiotherapy, at least for patients with pancreatic head tumors. The benefit of this approach is unproven for body/tail lesions, but we tend to treat these patients similarly. The optimal way to sequence 5-FU-based chemoradiotherapy and gemcitabine alone is unclear. An acceptable regimen is that used in RTOG 9704, which consists of three weekly doses of gemcitabine alone (1000 mg/m2 per week), followed by chemoradiotherapy with concurrent infusional 5-FU (250 mg/m2 daily), and, starting three to five weeks later, three months of single agent gemcitabine (1000 mg/m2 weekly for three of every four weeks). However, based upon logistical concerns as well as postoperative morbidity, clinicians may sequence chemoradiotherapy and gemcitabine differently than in the RTOG study. NEOADJUVANT THERAPY FOR POTENTIALLY RESECTABLE TUMORS The low rate of resectability and the poor long-term outcomes following pancreaticoduodenectomy have led to the investigation of preoperative chemoradiotherapy or a combination of preoperative and postoperative therapies in an attempt to improve both resectability and long-term outcomes. The following sections will review the efficacy of these approaches in patients with operable (potentially resectable) disease. Neoadjuvant approaches for patients with locally advanced (ie, unresectable) disease are discussed elsewhere. 5 FU-based therapy Although initial reports of preoperative radiation therapy (RT) with or without concurrent 5-FU demonstrated that this approach did not worsen perioperative morbidity and mortality, there was no obvious improvement in either resectability or overall survival . A possible limitation of these initial studies is that most used single agent 5-FU. Subsequent studies have focused upon improving the treatment regimen by increasing the RT dose, adding intraoperative RT (IORT), and optimizing the chemotherapy regimen. These newer approaches appear to be tolerable, with low rates of hepatic toxicity and biliary stent-related complications . However, their efficacy remains uncertain:
Gemcitabine-based approaches Gemcitabine-based chemoradiotherapy may provide an enhanced local effect, although with the potential for more toxicity than 5-FU-based regimens. Several early reports are available:
Nineteen patients completed therapy without interruption, and there was one grade 3 gastrointestinal toxicity. Seventeen patients underwent resection, 16 complete, and there was one pathologic complete response. With a median follow-up of 18 months, the median and two-year survival rates were 26 months and 61 percent, respectively. Adjuvant versus neoadjuvant therapy Whether preoperative therapy is better than postoperative therapy is uncertain. There are no randomized trials comparing the two approaches. One advantage of preoperative therapy is that it avoids the morbidity of pancreaticoduodenectomy in patients who have occult, micrometastatic disease that becomes clinically evident during therapy. A second advantage in patients undergoing pancreaticoduodenectomy is that prolonged recovery prevents the delivery of postoperative adjuvant chemotherapy in about one-fourth of patients . This can be avoided with the neoadjuvant approach. Summary Neoadjuvant chemoradiotherapy can be safely delivered to patients with localized pancreatic cancer without adversely influencing perioperative morbidity or mortality. However, no study has clearly demonstrated improved resectability or survival compared to patients treated with surgery alone, and it remains unclear whether this approach provides benefit compared to adjuvant (postoperative) therapy. ADJUVANT THERAPY FOR RESECTED AMPULLARY CANCER Cancer of the ampulla of Vater is uncommon, and often presents as a periampullary tumor that may be indistinguishable preoperatively from adenocarcinoma of the pancreatic head, a primary duodenal cancer, or a distal cholangiocarcinoma. Patients with potentially resectable disease are usually treated with pancreaticoduodenectomy. (See "Ampullary carcinoma"). The outcome of resected ampullary cancer depends mainly upon the status of the surgical margins, the presence or absence of lymph node metastases, and the extent of local invasion . As an example, in one series of 171 patients, the five-year survival by stage was as follows:
These survival data are better than similar presentations for pancreatic cancer, particularly for those with node-positive disease. It is unclear whether this represents a true difference in biology or earlier presentation of ampullary cancers due to earlier biliary obstruction. There are few published data to guide the use of adjuvant therapy in patients with resected ampullary cancer. A potential benefit for postoperative chemoradiotherapy in patients with completely resected disease has been suggested in several uncontrolled series :
The only phase III randomized trial that includes a substantial number of patients with ampullary carcinoma failed to show a benefit for postoperative chemoradiotherapy. In the postoperative adjuvant EORTC study described above, 218 patients with resected pancreatic or other periampullary cancers were randomly assigned to postoperative RT (40 Gy in split courses) plus concurrent 5-FU (25 mg/kg per day by continuous infusion) or observation. For the 104 periampullary cancers, there was no difference in the 2-year survival rate (67 versus 63 percent) or in the incidence of locoregional recurrence in the treated patients compared to controls. Summary There is no consensus regarding the optimal management of patients after resection of an ampullary cancer. National Comprehensive Cancer Network (NCCN) guidelines for treatment of ampullary cancer are not available. We treat these patients in a manner similar to those with resected pancreatic adenocarcinoma. At least until the results of the ongoing European ESPAC-3 trial (observation, leucovorin-modulated 5-FU, or gemcitabine after resection) become available, the authors suggest concurrent chemoradiotherapy with infusional 5-FU. The early results from RTOG 9704 combined with those from the German CONKO trial provide support for adding gemcitabine adjuvant chemotherapy to chemoradiotherapy, although this approach remains unproven for resected ampullary tumors. As with pancreatic cancer, the optimal way to sequence chemoradiotherapy and gemcitabine alone is unclear. An acceptable regimen is that used in RTOG 9704, which consists of three weekly doses of gemcitabine alone (1000 mg/m2 per week), followed by chemoradiotherapy with concurrent infusional 5-FU (250 mg/m2 daily), and, starting three to five weeks later, three months of single agent gemcitabine (1000 mg/m2 weekly for three of every four weeks). Initial 5-FU-based chemoradiotherapy followed by four months of gemcitabine alone is an acceptable alternative. SUMMARY AND RECOMMENDATION Cancer of the exocrine pancreas is associated with a poor prognosis, even if a complete (R0) resection can be accomplished. Systemic chemotherapy, radiation therapy (RT), and a combination of chemotherapy and RT have all been applied following surgery in an effort to improve cure rates. Although the benefit of adjuvant therapy has become more clear in recent years, the optimal choice of treatment modality (chemotherapy with or without RT) remains intensely controversial. There are scant data to guide adjuvant treatment decisions for patients with ampullary cancer, and the true benefit of adjuvant therapy remains uncertain. Nevertheless, most clinicians treat these patients in a similar manner to those with resected pancreatic head adenocarcinomas. There is no consensus regarding the optimal management of patients after resection of a pancreatic or ampullary adenocarcinoma, and the approach is different in Europe and in the United States. Based upon the ESPAC-1 trial, which showed that 5-FU-containing chemotherapy prolongs survival, and the preliminary results of the German CONKO trial showing a survival benefit from adjuvant gemcitabine , most European clinicians use chemotherapy alone after resection of a pancreatic or ampullary neoplasm. The American approach more often includes chemoradiotherapy as well as adjuvant chemotherapy. Guidelines from the National Comprehensive Cancer Network support either approach The following represents our approach to patients with resected pancreatic or ampullary tumors.
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