Epidemiology

In 2010 there were an estimated 43,140 new cases of pancreatic carcinoma in the United States, with slightly more cases in women than in men.² In the same year the number of deaths due to carcinoma of the pancreas was estimated to be 36,800. It was anticipated that carcinoma of the pancreas would be the 10th most frequently diagnosed new cancer in men and women, but the 4th leading cause of cancer death (after lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women). Internationally, incidence rates are highest in Western and industrialized countries.

Most patients with pancreatic cancer present with advanced disease. Incidence rates increase with age, and most cases occur in patients older than 60 years of age. Approximately 68% of cases will be diagnosed in patients 65 years of age or older. In the absence of overt metastatic disease, patients undergoing pancreatic resection have a clear survival advantage as compared with patients not undergoing resection. The 1-, 2-, and 3-year overall survival (OS) rates for patients undergoing resection as compared with those not undergoing resection are 48% versus 23%, 24% versus 9%, and 17% versus 6%, respectively.³

Etiology

Pancreatic cancer is clearly associated with cigarette smoking, diet (higher risk with higher percentages of fat and meat in the diet), obesity,⁴ chronic diabetes mellitus, and chronic pancreatitis. Of these, the strongest association is with cigarette smoking. There is also an occupational association with the manufacture of 2-naphthylamine and benzidine and with those working with gasoline derivatives.⁵ Although coffee consumption has sometimes been implicated in the occurrence of carcinoma of the pancreas, a review failed to confirm this association.⁶

There is an increased risk of developing pancreatic cancer, as well as other intra-abdominal malignancies, after radiation therapy (RT) to the abdomen for management of testicular malignancy, either seminoma or nonseminoma (the observed to expected frequency is 2.30).⁷ The risk is noted as early as 10 years after management and continues to increase with time.

An important development in our understanding of the etiology of pancreatic cancer is the recognition of familial pancreatic cancer.⁸ Familial pancreatic cancer may occur in the absence of a recognizable clinical syndrome, and as many as 10% of pancreatic cancers may be familial. Data from the National Familial Pancreas Tumor Registry have shown that the risk of cancer is 18-fold greater in first-degree relatives of familial pancreatic cancer cases (at least two first-degree relatives with pancreatic cancer in the family) than it is in first-degree relatives of sporadic pancreatic cancer cases (families in which there has been only one member with pancreatic cancer).⁹ In addition, there are associations with other known syndromes such as the familial breast, ovarian, pancreas cancer syndrome associated with BRCA2, the familial pancreas cancer syndrome associated with CDKN2A abnormalities, the Peutz-Jeghers polyposis gastrointestinal malignancy syndrome associated with mismatched repair genes, LKB1/STK11, and the hereditary nonpolyposis colon cancer (HNPCC) syndrome. Current understanding of familial pancreatic cancer has been reviewed by Shi and associates¹⁰ and is regularly updated at the webpage of the Johns Hopkins National Familial Pancreatic Tumor registry (pathology.jhu.edu/pancreas/PartNFPTR.php).¹¹

Pathology

Infiltrating ductal adenocarcinomas are the most common histologic type of malignant tumors of the exocrine pancreas, as shown in Figure 46-2. These malignant epithelial neoplasms show glandular or ductal differentiation, with most arising in the periampullary region of the pancreas.³⁴ Although ductal adenocarcinoma is the most common primary malignancy of the pancreas, accounting for approximately 75% of all primary nonendocrine cancers in this organ, there are a number of other important epithelial malignancies arising in the pancreas that should be recognized because of their variant presentations and prognostic implications.³⁵ Recent reports have nicely summarized the progression of pancreatic intraepithelial neoplasia to invasive ductal carcinoma and also described the molecular and prognostic correlates associated with less common pancreatic tumors.^36,37

Figure 46-2 Pancreatic adenocarcinoma. When viewed under the microscope, cancerous cells can be seen that form small ducts. These cancers often cause scarring and inflammation (arrow).

Courtesy Johns Hopkins Hospital Department of Pathology.

Adenosquamous carcinoma is a rare histology that disseminates to lymphatics, perineural and perivascular pathways, and lymph nodes in the peritoneum, much the same as is seen with standard adenocarcinoma of the pancreas. It may be seen after prior treatment with chemotherapy and RT.

Acinar cell carcinoma is also a rare histology in which 20% of cases may be associated with subcutaneous fat necrosis, a rash similar to erythema nodosum, peripheral eosinophilia, and polyarthralgias. These associated phenomena are a result of release of large amounts of lipase by the tumor.³⁸ These tumors typically present with large size and average dimension of 11 cm and occur in the head, body, and tail of the pancreas with frequencies of 60%, 30%, and 10%, respectively. Survival is not significantly superior to that seen with standard adenocarcinoma of the pancreas. Those patients presenting with large amounts of lipase production may have a less than average prognosis.

Giant cell carcinoma is a histology that accounts for approximately 5% of nonendocrine pancreatic cancers. These tumors also present with large size, with an average of 11-cm diameter. These are very aggressive carcinomas with poor average survival and no 5-year survivors. Giant cell carcinoma with osteoclast-like giant cells is an extremely rare variant with an improved prognosis compared with giant cell carcinomas. These giant cells resemble the osteoclasts of resorbing bone.

The primary cystic, nonendocrine epithelial tumors are another type of pancreatic neoplasm. Only 5% to 15% of pancreatic cystic lesions are actually neoplastic, with the remaining non-neoplastic lesions including pseudocysts, congenital cysts, and retention cysts. The cystic neoplasms of the pancreas include serous and mucinous neoplasms. Most serous cystic neoplasms are serous cystadenomas, also known as microcystic adenomas and glycogen-rich cystadenomas. They occur more commonly in women, with average age at presentation in the seventh decade.³⁹ These lesions may be large, and patients with von Hippel-Lindau syndrome (familial cancer syndrome associated with clear cell renal cancer, cerebellar and spinal hemangioblastomas, pancreatic islet cell cancers, and other tumors) may be predisposed to develop pancreatic serous cystadenomas. Most serous cystic neoplasms of the pancreas are benign.

In contrast, mucinous cystic neoplasms are more frequently malignant. These are also more common in women and are typically diagnosed in the fifth decade of life. Histologically, these lesions contain a mucin-positive, cloudy fluid and do not communicate with the main pancreatic duct.⁴⁰ Microscopic analysis reveals three types of mucinous cystic neoplasms: mucinous cystadenomas, borderline mucinous cystic neoplasms, and mucinous cystadenocarcinoma. It is generally thought that mucinous cystadenomas and borderline cystic neoplasms have the potential for progressing to overt malignancy and should be completely resected. Interestingly, mucinous cystadenocarcinomas are associated with a better prognosis than typical adenocarcinoma of the pancreas, with roughly 50% of patients surviving 5 years.

Intraductal papillary mucinous neoplasms communicate with the main pancreatic duct system and are typically diagnosed in the seventh decade. They are associated with a good prognosis compared with more typical pancreatic malignancies.⁴¹ A more aggressive variant is the papillary mucinous carcinoma in which the histology displays significant cytologic and architectural atypia and/or overt invasion.

Solid and cystic papillary neoplasms are also known as Hamoudi tumors, occurring primarily in women in the third decade of life. Patients present with distention, discomfort, and/or pain. Typically, these tumors range in size from 5 to 15 cm in diameter. With surgical resection, most patients survive for many years, with metastases occurring rarely.

Other neoplasms that can be seen in the pancreas include pancreatoblastoma, a malignancy of childhood, acinar cyst adenocarcinoma (a rare variant of acinar cell carcinoma), and primary mesenteric mesenchymal tumors. Malignancies metastatic to the pancreas include primary tumors of the breast, lung, colon/rectum, and stomach and melanoma. Finally, lymphomas may comprise 1% to 2% of all primary pancreatic neoplasms, with the most common type being diffuse large B-cell tumors.

It has been well known that a precursor histology of intraepithelial neoplasia (IN) can be described in sites such as colon, cervix, and prostate. The precursor histology for pancreatic adenocarcinoma (PanIN) has also been well described.⁴² These lesions have been named PanIN-1A and 1B, PanIN-2, and PanIN-3. They are often seen in association with invasive adenocarcinoma and have occasionally been observed to progress into invasive adenocarcinoma.

Pathways of Spread

The pancreas is a retroperitoneal organ that lies in close anatomic relationship to the stomach, duodenum, jejunum, kidneys, spleen, celiac trunk, superior mesenteric artery and vein, common bile duct, and portal vein (see Fig. 46-1). The main pancreatic duct is known as the duct of Wirsung, and the accessory pancreatic duct is known as the duct of Santorini. At the time of diagnosis, more than 85% of pancreas tumors will have extended into adjacent organs, lymph nodes, fat, or soft tissue, allowing early metastasis to regional and distant lymph nodes.⁴³

Patterns of involvement in the regional lymphatics have long been well recognized. Frequently involved nodal sites include the posterior pancreaticoduodenum, superior pancreatic head, inferior pancreatic head, superior pancreatic body, and porta hepatis.44,45 There is also a relationship between para-aortic lymph node involvement and involvement of posterior pancreaticoduodenal nodes by direct interlymphatic communication⁴⁶ (Fig. 46-3). Venous drainage of the pancreas is to the liver via the portal vein.

Figure 46-3 Classification of regional lymph nodes of the pancreas. Inset, subdivision of area 14. ACM, medial colic artery; AJ, jejunal artery; AMS, superior mesenteric artery; APDI, inferior pancreaticoduodenal artery.

From Cubilla AL, Fortner J, Fitzgerald PJ: Lymph node involvement in carcinoma of the head of the pancreas area, Cancer 41:880, 1978.

Patterns of failure after resection have been described, with local recurrence, peritoneal relapse, and hepatic metastases occurring in 50%, 42%, and 62% of patients, respectively.47,48–50 Although it is likely that the peripancreatic burden of disease has multiple direct lymphatic pathways to hepatic tissues, hepatic involvement has been taken as a sign of systemic metastasis. The lung is the most frequently involved extra-abdominal organ.⁴³

Recent reports confirm that these patterns of failure have not changed appreciably over time and also emphasize the effect of the retroperitoneal margin, poor differentiation, and lymph node involvement in determining relapse risk, especially locally.51,52 In addition, rapid autopsy results from Johns Hopkins Hospital studies indicate that local recurrence may be associated with alterations in SMAD4 and that local recurrence may be the cause of death in up to 30% of patients with overt metastatic disease.⁵³

Patient Evaluation

Assessment is guided by the patient’s presenting symptoms, findings on history and physical examination, and initial laboratory results (Fig. 46-4). Ultrasonography, CT, and ERCP are often included in the evaluation of patients with obstructive jaundice. With current spiral CT techniques combined with enhancement after oral and intravenous administration of contrast, pancreatic masses, pancreatic duct dilatation, local invasion, liver metastases, and vascular invasion of the great vessels are readily identified. EUS has improved staging of pancreatic cancer. It is especially effective in detecting vascular invasion of pancreatic cancer when CT is equivocal, which is imperative in determining resectability.⁵⁷ ERCP is frequently used to obtain biopsy specimens, decompress the biliary tree, and localize the source of obstruction. Biliary obstruction can also be relieved by percutaneous and transhepatic cholangiography. Visceral angiography is selectively used based on concern regarding vascular invasion leading to unresectability. PET may be useful in identifying otherwise occult metastases. A study of 82 patients staged with either CT alone or PET/CT showed that the addition of PET increased sensitivity for the detection of distant metastases and would have changed management in 11% of the patients.⁵⁸ Laparoscopy is used in some institutions as a prelude to exploration and has been found to increase the detection of intraperitoneal metastases in patients with locally advanced pancreatic cancer. It appears that a tissue diagnosis by FNA before laparotomy is not necessary.⁵⁹

Figure 46-4 Diagnostic algorithm for pancreatic tumors.

Staging

The seventh edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic cancer is shown in Table 46-2. There were no changes between the AJCC sixth and seventh editions, except that the seventh edition now includes neuroendocrine tumors. Treatment and prognosis are defined by resectability (T < T4) and presence of distant metastatic disease, which most commonly involves the liver, peritoneum, or both.⁶⁰

TABLE 46-2 American Joint Committee on Cancer TNM Staging for Pancreas Cancer

From Edge SB, Byrd DR, Compton C, et al, editors: AJCC Cancer Staging Manual, ed 7, New York, 2010, Springer.

Pancreatic tumors staged as T1, T2, or T3 are generally considered to be resectable. Unresectable pancreatic tumors are those in which the tumor cannot be separated from the adjacent large arterial structures (celiac axis or superior mesenteric artery). The extent of resection also carries prognostic significance. A patient who has undergone an R0 complete resection with negative margins will have a better prognosis compared with a patient who has undergone an R1 or R2 resection with microscopic (R) or grossly positive margins (R2). Furthermore, recent data suggest that margins greater than 1.5 mm are needed to optimize locoregional control, and the extent of clear margins in R0 resections may potentially be used to estimate risk of locoregional failure.⁶¹ Borderline resectable tumors, which are at high risk for a margin-positive resection, are discussed later in this chapter.

Surgery

The classic operation for resection of a carcinoma of the head of the pancreas is a pancreaticoduodenectomy, also known as a Whipple procedure. In this operation the gallbladder, common bile duct, second through fourth portions of the duodenum, and the head of the pancreas are resected along with the postpyloric duodenum (pylorus-preserving pancreaticoduodenectomy) or the resection is continued proximally to include the distal stomach (classic pancreaticoduodenectomy). The regional lymph nodes are also resected. It appears well established that the pylorus-preserving pancreaticoduodenectomy improves gastrointestinal function without compromise of oncologic management.^62–64 Figure 46-5 illustrates these two variants of surgical resection.⁶⁵ Within the past two decades, the mortality of this operation has declined from approximately 20% to between 1% and 3% in major centers.^66–68 (A video of this operation may be observed at www.orlive.com/umm/videos/whipple-procedure-for-pancreatic-cancer.)

Figure 46-5 Classic pancreaticoduodenectomy (A) and pylorus-preserving pancreaticoduodenectomy (B), showing the resected specimens, the structures retained, and one method of reconstruction by way of pancreaticojejunostomy and gastrojejunostomy.

From Yeo CJ, Cameron JL: The pancreas. In Hardy JD, editor: Hardy’s textbook of surgery, ed 2, Philadelphia, 1988, JB Lippincott, pp 717-718.

It is important that the radiation oncologist understand the postsurgical anatomy after pancreaticoduodenectomy. Examples of various types of anatomic connections are shown in

web-only Figure 46-2, available on the Expert Consult website

.⁶⁹ As illustrated, gastrointestinal reconstruction after pancreaticoduodenectomy requires enteric, biliary, and pancreatic anastomoses. Although postoperative mortality is less than 3% at high-volume centers, the morbidity of pancreaticoduodenectomy remains high, with pancreatic leak and infection, delayed gastric emptying, and pancreatic fistula among the most common complications.⁷⁰ Based on large-volume, single-institution experience the dramatic improvements in postoperative morbidity and mortality reported in the 1990s have not shown further improvement.⁷¹

Web-Only Figure 46-2 A, Pancreaticogastrostomy. B, End-to-end pancreaticojejunostomy. C, End-to-side pancreaticojejunostomy. The inset details the location of the posterior gastrostomy.

From Yeo CJ, Cameron JL, Maher MM, et al: A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. Ann Surg 222:580, 1995.

Surgical management of carcinoma of the body or tail of the pancreas requires a different orientation. Presenting symptoms such as jaundice or pain typically occur with larger and more locally advanced masses or evidence of overt metastatic disease. Even when explored, most patients at major centers are deemed as having unresectable disease when presenting with adenocarcinoma in the body or tail of the pancreas. If the tumor is resectable, the operation performed is classically a distal pancreatectomy with en bloc splenectomy.

Adjuvant Chemotherapy and Irradiation after Resection, Randomized Data

In 1974, the Gastrointestinal Tumor Study Group (GITSG) undertook a prospective, randomized trial of adjuvant 5-FU–based chemoradiation compared with no adjuvant treatment.83,84 This was a well-designed trial that attempted to recruit patients with histologically negative margins of resection between 4 and 10 weeks postoperatively. However, only 49 patients were randomized into the study over an 8-year interval; moreover, 5 withdrew without being treated. The external beam irradiation (EBRT) was given as two courses of 20 Gy in 10 fractions, each with a planned 2-week rest. Treatment fields did not exceed 20 × 20 cm and were given anterior-posterior/posterior-anterior. Shaping of fields was optional, and 5-FU chemotherapy was given on the first 3 days of each half of the RT at a dose of 500 mg/m² as an IV bolus. Thirty-five percent of patients had tumor confined to the pancreas, 37% had contiguous invasion resected to clear margins, and 28% had nodal involvement.

Results showed that patients treated with combined chemoradiation had improved survival (p = .03) compared with patients treated with surgery alone, with a median survival in the treatment group of 20 months versus 11 months in the control arm (Table 46-4). Two-year OS was 42% versus 15%, respectively, and 5-year OS was 19% versus 5%. Prognostic factors including age, sex, type of resection, degree of cellular differentiation, initial performance status, location of tumor, and extent of tumor were evaluated. Performance status and extent of tumor were the only independently significant prognostic variables. The study was terminated prematurely because of poor accrual in spite of the long period of time during which it was open.

In an effort to address concerns due to poor accrual, the GITSG registered an additional 30 patients in a nonrandomized fashion to receive the same adjuvant therapy. Results in these 30 patients recapitulated the results of the treatment arm in the previous randomized study.⁸⁴ It was of interest to note that, although the treatment produced relatively little toxicity, the local recurrence rate was between 30% and 50% in all patients regardless of whether they received adjuvant treatment and the incidence of hepatic metastases was between 40% and 50%. These results, although strongly suggesting a treatment effect, imply that the dose of radiation, coupled with the 2-week break, was too low to deal with the regional burden of disease and the efficacy of 5-FU alone was inadequate to sterilize disease outside the treatment fields for most patients.

The European Organization for Research and Treatment of Cancer (EORTC) performed a multi-institutional, randomized trial in which 218 patients with periampullary cancers, including pancreatic adenocarcinoma, were randomized to receive surgery alone or surgery plus postoperative 5-FU–based chemoradiation.⁸⁵ The radiation dose and fractionation were the same as in the GITSG trial (40 Gy in split-course fashion over 6 weeks). There were two differences in the delivery of 5-FU compared with the GITSG study. Concurrent 5-FU during RT was administered by continuous intravenous infusion, rather than bolus, during the first 3 days of each treatment sequence. Furthermore, no 5-FU was given after the concurrent chemoradiation. In the subset of 114 patients with pancreatic adenocarcinoma, patients in the chemoradiation arm (n = 60) had a median survival of 17.1 months versus 12.6 months in the pancreatectomy alone arm (n = 54). The 2-year OS for the two trial arms were 37% versus 23%, respectively, and 5-year OS was 20% versus 10% (p = .099). There were no differences in locoregional recurrence rates, which were high with both surgery alone (37 of 103, 36% of patients at risk) and postoperative chemoradiation (34 of 104, 33% of patients at risk). The EORTC concluded that there was no demonstrable benefit from postoperative chemoradiation for the total group of patients but that survival trends favored adjuvant postoperative chemoradiation for the 114 patients with pancreatic cancer.

However, several aspects of the EORTC trial design, analysis, and interpretation warrant comment. Patients with T3 lesions were excluded, and the pathologic basis for distinguishing between and including pancreatic and nonpancreatic periampullary lesions (which have different natural histories and prognoses than do pancreatic adenocarcinomas) was not made clear. Additionally, the adequacy of the retroperitoneal margin was not independently assessed, perhaps influencing the frequency of locoregional recurrence. Moreover, 20% of patients assigned to the chemoradiation trial arm never received that treatment (because of patient refusal, poor postoperative performance status, disease progression, etc.) but they were analyzed by intent-to-treat principles. Although this approach is statistically correct, one needs to consider that the chemoradiation group includes a sizable minority of patients who did not receive postoperative chemoradiation. Furthermore, unlike the GITSG trial, no chemotherapy was given after chemoradiation. Moreover, many have criticized the use of a two-sided log-rank test, and demonstrated that if a one-sided test had been used, the survival benefit of chemoradiation would have reached significance.⁸⁶ Finally, the study lacked sufficient patient numbers to exclude a clinically significant 10% to 15% benefit from the addition of adjuvant chemoradiation to surgery. Thus some investigators consider the EORTC trial to be an underpowered study that provides additional circumstantial evidence to support a role for postoperative chemoradiation. However, the trial was updated in 2007 and continued to show no statistical survival advantage after a median follow-up of 11.7 years.⁸⁷ Although this trial is used as evidence against chemoradiation, it has several methodologic flaws, as just listed.

An important trial for radiation oncologists to be aware of is the ESPAC-1 study,⁸⁸ which had a complex design (three separate but concurrent phase III trials) and was initiated to evaluate the independent effects of adjuvant chemotherapy and chemoradiation in 541 patients with grossly resected pancreas cancer. This included a subset of 285 patients who underwent randomization with a 2 × 2 factorial design as follows: (1) observation; (2) concomitant chemoradiation alone (20 Gy in 10 fractions over 2 weeks with 500 mg/m² 5-FU IV bolus during the first 3 days of RT and then repeated after a planned 2-week break) followed by no additional chemotherapy; (3) chemotherapy alone (leucovorin 20 mg/m² bolus followed by 5-FU 425 mg/m² administered for 5 consecutive days repeated every 28 days for six cycles); and (4) chemoradiation followed by six cycles of adjuvant 5-FU/leucovorin. Investigators were also allowed to randomize patients into two separate but concurrent trials testing one of the main treatment comparisons (adjuvant chemotherapy vs. none: 188 patients; adjuvant concurrent chemoradiation vs. none: 68 patients). Background therapy was allowed before patients were entered into the latter two trials, and RT was performed according to the standard of the individual institutions in all three trials. In the initial analysis, a survival advantage for adjuvant chemotherapy was achieved only by merging data from the three separate randomized trials (median survival of 19.7 months in the 238 patients randomized to receive adjuvant chemotherapy vs. median survival rate of 14 months in the 235 patients randomized to no adjuvant chemotherapy, p = .005).⁸⁹ The latest analysis of the ESPAC-1 trial analyzed only the patients randomized to the 2 × 2 factorial design (n = 289; no background therapy allowed). Patients randomized to receive adjuvant chemotherapy (two of the four arms, n = 147) had a survival advantage (2-year, 40% vs. 30%; 5-year, 21% vs. 8%; p = .009).⁸⁸ Local recurrence was a component of relapse in 99 patients (34% of the 289 patients at risk, 63% of patients with relapse).

As noted in 2001 by Abrams and associates,⁹⁰ major concerns regarding the design and execution of this trial include more than one randomization scheme (three separate but concurrent phase III trials), patients were allowed to receive “background” therapy in addition to protocol therapy in two of the three trials, patients did not have their disease restaged after resection and before adjuvant therapy, and there were no quality assurance guidelines for the delivery of radiation (i.e., no section in the protocol on appropriate field design, no central audit of radiation fields), which is contrary to the routine in North American cooperative group trials. ESPAC-1 was a trial of varying patient populations, and the nature of the differences in the patients cannot be known. Thus the validity of this analysis should be regarded with concern.

RTOG 97-04, a randomized phase III trial,⁹¹ evaluated whether gemcitabine before and after 5-FU–based chemoradiation would provide superior outcome to 5-FU before and after 5-FU–based chemoradiation. In this study, 518 patients with resected pancreatic cancer were treated with postoperative 5-FU–based chemoradiation (50.4 Gy in 28 fractions over 5.5 weeks plus concurrent protracted venous infusion of 5-FU). Patients were randomized to receive either 5-FU (250 mg/m²/day) given as continuous infusion over 3 to 4 weeks or gemcitabine (1000 mg/m²/wk) given for 3 of 4 weeks. Chemotherapy was given for a total of three cycles: one before chemoradiation and two cycles after chemoradiation. On subset analysis of patients with pancreatic head tumors, median survival and 3-year OS were 20.5 vs. 16.9 months and 31% versus 22% for the gemcitabine and 5-FU trial arms, respectively. These results neared statistical significance overall (p = .09) and reached significance on multivariate analysis (p = .05). Although the grade 4 neutropenia rate was higher in the gemcitabine trial arm (14% vs. 1%), there was no difference in febrile neutropenia or in the ability to complete chemotherapy or RT.⁹¹

Retrospective and Prospective Adjuvant Chemoradiation Studies, Nonrandomized

Although the available randomized trials have generated conflicting results, the majority of nonrandomized studies have suggested a benefit for adjuvant chemoradiation in pancreatic cancer. The following is a review of the results of the nonrandomized trials that have sought to answer the still unclear debate over the most beneficial adjuvant therapy in resected pancreatic cancer.

The retrospective data of Whittington and colleagues⁹² lent credence to the need for combined modality adjuvant therapy. They reported on a series of 72 patients with pancreatic cancer managed surgically with curative intent between 1981 and 1989 at the Hospital of the University of Pennsylvania in three sequential treatment groups. The first group received surgery alone, while the second group received postoperative RT, with some of these patients receiving bolus 5-FU on the first 3 days of RT and at the beginning of the fifth week. The last 20 patients reported received RT with 96-hour infusions of 5-FU on the first and fifth weeks of treatment. They observed a decrease in local recurrence from 85% in the patients treated with surgery only to 25% in the patients treated with irradiation and infusional 5-FU (see Table 46-4). Inferior survival was noted with positive surgical margins. Among patients with negative resection margins, the 2-year survival was 41% for surgery alone, 33% for surgery plus RT with or without bolus 5-FU, and 59% for surgery plus RT with infusional 5-FU. More impressively, the 3-year survival was 22% for surgery alone, 11% for surgery plus RT with or without bolus 5-FU, and 47% for patients receiving postoperative RT with infusional 5-FU. Their work also emphasized the importance of nutritional support and the value of CT-based treatment planning.

The Johns Hopkins Hospital published results of a single-institution prospective but nonrandomized trial that was designed to evaluate survival benefit in patients with pancreatic cancer after surgical resection.⁹³ This report, involving 174 patients, demonstrated that patients receiving GITSG-style chemoradiation with maintenance 5-FU truncated at 6 months (rather than 2 years) or a more intensive regimen (involving higher doses of irradiation as well as hepatic irradiation administered without interruption and with continuous infusion 5-FU chemotherapy augmented with leucovorin) did better than patients receiving no postsurgical therapy. The median survival for the more standard regimen was 21 months, with 1- and 2-year survivals of 80% and 44% (see Table 46-4). For the intensive regimen, the median survival was 17.5 months with 1- and 2-year survivals at 70% and 22%. For the control arm, the median survival was 13.5 months with survival at 1 and 2 years of 54% and 30% (Fig. 46-6). The intensive therapy had no survival advantage compared with the standard therapy group, but there was a statistically significant difference between the standard arm versus control (p <.0002). Multivariate analysis confirmed that prognostic factors for disease relapse included margin and lymph node status, tumor size

Figure 46-6 Tumor-specific actual 5-year survival curves for the cohort of 242 patients treated by pancreaticoduodenectomy for periampullary adenocarcinoma.

From Yeo CJ, Cameron JL, Sohn TA, et al: Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s. Pathology, complications, and outcomes, Ann Surg 226:248, 1997.

(see web-only Fig. 46-3 on the Expert Consult website), and degree of differentiation.

Web-Only Figure 46-3 Actuarial survival curves for Johns Hopkins Hospital patients undergoing pancreaticoduodenectomy comparing patients receiving adjuvant therapy (n = 120) with those declining adjuvant therapy (n = 53; p = .003).

Investigators at Johns Hopkins Hospital have updated their prospectively collected cohort of 616 patients who underwent resection of proximal pancreatic cancer between 1993 and 2005.⁹⁴ The patients receiving chemoradiation were significantly younger and less likely to present with comorbid disease, but they were more likely to have positive margins. Chemoradiation patients had improved median, 2-year, and 5-year OS compared with patients with no chemoradiation (median 21.2 vs. 14.4 months, 2-year OS 44% vs. 20%, 5-year OS 32% vs. 15%; p <.001). Importantly, this survival advantage persisted even after controlling for age, medical comorbidities, and surgical complications.⁹⁴

A similar retrospective analysis from Mayo Clinic Rochester of 472 patients with R0 resection treated over three decades demonstrated comparable findings.⁹⁵ Despite having significantly more adverse prognostic factors, patients undergoing adjuvant postoperative chemoradiation had improved median, 2-year, and 5-year OS than patients having surgery alone (median 2.1 vs. 1.6 years; 2-year OS 50% vs. 29%, 5-year OS 28% vs. 17%, p = .001).

Subsequently a Johns Hopkins Hospital–Mayo Clinic collaborative analysis was performed in patients who had pancreaticoduodenectomy for pancreatic adenocarcinoma at Johns Hopkins Hospital and Mayo Clinic Rochester.⁹⁶ The study consisted of 1092 patients treated with curative intent (n = 618 JHH, n = 474 Mayo), with 583 receiving adjuvant 5-FU–based chemoradiation (median RT dose 50.4 Gy). Propensity score and matched-pair analyses were performed to account for biases associated with nonrandom allocation of patients to adjuvant chemoradiation or surgery alone. Overall survival was significantly longer among patients who received adjuvant chemoradiation versus pancreaticoduodenectomy alone (median 21.1 vs. 15.5 months, p <.001; 2-year OS 44.7% vs. 34.6%, 5-year OS 22.3% vs. 16.1%, p <.001). In propensity score analysis, adjuvant CRT improved survival compared with surgery alone for all patients (relative risk [RR] = 0.67, p <.001) and stratified by age, margin, node, and T stage (RR = 0.57 to 0.75, p <.05), after adjusting for covariates. Matched-pair analysis demonstrated overall survival was longer with adjuvant chemoradiation versus pancreaticoduodenectomy alone (median 21.9 vs. 14.3 months, 2-year OS 45.5% vs. 31.4%, 5-year OS 25.4% vs. 12.2%, p <.001).⁹⁶

Adjuvant Chemotherapy

In the past few decades, while the emphasis in adjuvant therapy for pancreatic cancer has focused on both chemotherapy and irradiation in the United States, much of the focus in Europe has been on adjuvant chemotherapy alone, based on the results of ESPAC-1. A few large randomized trials have been published in the past few years, further establishing adjuvant chemotherapy as an important part of the curative paradigm for pancreatic cancer, but have not addressed the role of RT. Although historically 5-FU–based chemotherapy has been most commonly used in pancreatic cancer, a series of paradigm-shifting studies over the past several years has pushed gemcitabine to the forefront.

First, a randomized trial in patients with symptomatic advanced pancreatic cancer (to be discussed later) showed improvement in symptoms and longer median survival in patients treated with gemcitabine versus those treated with 5-FU.⁹⁷ As is often the case, success in the advanced setting led to trials exploring the role of gemcitabine in the adjuvant setting. In the CONKO-001 trial conducted in Europe, patients with postoperative CA19-9 values less than or equal to 2.5 times the upper limit of normal and with R0 or R1 resections for pancreatic cancer were randomized to six cycles of gemcitabine (1000 mg/m² weekly, 3 of every 4 weeks) versus observation. At first publication, the use of gemcitabine significantly improved disease-free survival from 6.9 to 13.9 months (p <.001) and trended toward an improvement in overall survival.⁹⁸ An update with longer follow-up showed significant improvement in median survival (22.8 vs. 20.2 months, p = .005), as well as improvements in 5-year overall survival (21.0% vs. 9.0%).⁹⁹ These important results have solidified adjuvant gemcitabine as an important part of adjuvant treatment of pancreatic cancer. However, the lack of a chemoradiation trial arm means the value of RT (either concurrent or sequential) must still be elucidated. In addition the applicability of these results to patients with higher postoperative CA19-9 levels is uncertain.

There has been strong interest in finding a second drug to add to gemcitabine to enhance the benefit of chemotherapy. Unfortunately, in the context of metastatic and locally advanced disease, multiple “doublet” trials (gemcitabine + X) have not demonstrated superiority to gemcitabine alone when “X” has been 5-FU, cisplatin, oxaliplatin, irinotecan, exactecan, and capecitabine. A statistically significant, small improvement in median survival and 1-year survival has been seen with the combination of gemcitabine and erlotinib as compared with gemcitabine alone.100,101

Although gemcitabine is commonly held to be more effective in the adjuvant setting than 5-FU alone based on its superiority in the advanced stage setting, the largest trial comparing adjuvant 5-FU/leucovorin to adjuvant gemcitabine in resected pancreatic cancer shows no benefit. ESPAC-3 was a multicenter trial that randomized 1088 patients after R0 or R1 resections to either 5-FU/leucovorin or gemcitabine for 6 months.¹⁰² In this trial there was no difference in median survival for the 5-FU/leucovorin or gemcitabine groups (23.0 vs. 23.6 months, respectively, p = .39). There was also no significant difference in effect of treatment across subgroups according to extent of resection (R0 or R1).

Newer Chemoradiation Regimens

Although the historic trials previously discussed used 5-FU–based chemoradiation in the adjuvant setting, new systemic agents have been coupled with RT over the past decade. Many feasibility studies have shown that these regimens can be given safely, and now randomized trials are needed to see if they lead to improved results.

Present Status of Adjuvant Therapy for Pancreatic Cancer

A great deal remains unresolved regarding adjuvant therapy for pancreatic cancer after resection with curative intent. Clearly, surgery with curative intent does not accomplish cure with sufficient frequency to be satisfactory for patients, their families, or their physicians. The most convincing level I data currently available are from the CONKO-001 trial, which has clearly established a role for gemcitabine as an adjuvant after surgery. The CONKO-001 trial does not address whether RT has a role to play in this context. Each currently published phase III trial that has included RT is either subject to serious criticism (i.e., GITSG, EORTC, ESPAC-1) or has not directly addressed the question of what the role of RT ought to be in this context (i.e., RTOG 97-04). Current practice and current guidelines reflect this unresolved state of affairs. National Comprehensive Cancer Network guidelines for pancreatic cancer (available online at www.nccn.org) include chemotherapy (gemcitabine, capecitabine, 5-FU) or chemotherapy followed by chemoradiation. However, the highest recommendation goes to a clinical trial.

Designing randomized, phase III adjuvant therapy trials for pancreatic cancer that include RT has proven to be incredibly difficult. Large randomized trials require both consensus and equipoise around the question(s) asked. In addition, it is clear that there are potentially confounding variables other than the therapies in an adjuvant trial in this context. These potentially include the surgery done, numerous identified pathologic variables, and possibly the extent to which RT is designed and delivered as requested by protocol specification.¹¹⁵ Finally, the anticipated difference in therapeutic benefit must be sufficiently large to allow the power calculation to result in realistic and achievable accrual requirements.

In late 2009, the RTOG in cooperation with the Southwest Oncology Group (SWOG) and the EORTC opened RTOG 08-48, a randomized phase III trial designed to ask two questions. The first is whether gemcitabine plus erlotinib produces superior survival results to gemcitabine alone. The second is whether the addition of RT in combination with 5-FU or capecitabine enhances survival for patients remaining disease free after chemotherapy. The trial stratifies for known prognostic variables, includes a surgical quality assurance component as well as real-time, online quality assurance to ensure RT guideline adherence, and will require the enrollment of more than 900 patients over 4 years to answer these two important questions.¹¹⁶ For trial schema, please see Figure 46-7.

Figure 46-7 Schema to RTOG 08-48. See text and also the Expert Consult website for supplemental information and results.

Neoadjuvant Strategies

In the mid to late 1980s, a number of institutions began considering the use of RT or chemotherapy as a planned, preoperative approach (neoadjuvant) for patients with apparently resectable, biopsy-proven adenocarcinoma of the pancreas. Theoretical advantages of this sequencing include superior radiobiologic effect with improved blood flow, avoiding omission of chemoradiation secondary to postoperative recovery, and allowing patients destined to fail treatment early systemically to declare themselves to avert futile surgery. In the early to mid 1990s, these results began to mature and a number of authors have described results in this context. Ishikawa and colleagues¹¹⁷ reported on 54 consecutive patients, with tumors judged to be resectable, who either went directly to surgery (n = 31) or received 50 Gy EBRT to the region of the pancreatic head (n = 23). They found no difference in resectability, 3-year OS, or 5-year OS. There was a slight advantage to 1-year OS for patients treated with preoperative RT. There was a decrease in the incidence of regional relapse during the first 1.5 postoperative years for patients undergoing preoperative RT.

Investigators at the Fox Chase Cancer Center in Philadelphia have also published a series of papers regarding neoadjuvant chemoradiation for periampullary malignancy, most recently in 2004. Their approach originally consisted of 50.4 Gy conventionally fractionated with 4-day infusions of 5-FU at 1000 mg/m²/day and bolus infusion of mitomycin C, 10 mg/m² on the second day. In a report published in 1993, they described their initial experience with 31 patients, of whom 24 had carcinoma of the head of the pancreas, 2 had carcinoma of the body of the pancreas, and 5 had carcinoma of the duodenum. They found the toxicity to be acceptable, with one death from biliary sepsis and a resectability rate of 38% for pancreatic carcinoma.¹¹⁸ At first update, this group reported on 34 patients with localized pancreatic cancer receiving the same treatment as already described. Twenty-five of these patients underwent laparotomy, and 14 were deemed to have unresectable disease owing to the extent of the primary tumor, hepatic metastases, or peritoneal dissemination. Therefore only 11 underwent surgery with curative intent, with 1 patient dying in the perioperative period. With a median follow-up of 33 months, the median survival was 45 months and median DFS was 27 months in patients who underwent potentially curative resection. In 1998, these workers reported on a comparison of their preoperative studies to 23 patients who were accrued sequentially after closure of their preoperative protocol.¹¹⁹ These patients were treated with postoperative chemoradiation, using the same irradiation and chemotherapy dosing and scheduling as the preoperative regimen. These researchers found that there was no difference in intraoperative management or length of postoperative stay. With preoperative therapy, there were fewer involved nodes and more patients with negative resection margins. After a median follow-up of 44 months, median survival was 20 months versus 25 months in the preoperative group compared with the postoperative group, respectively. Local failure either alone or as a component of overall failure was the same in both groups at 16%. It was concluded that both treatments were similar with respect to toxicity and benefit, but 22% of patients did not receive their intended postoperative therapy. Most recently, in 2004, this group updated their results from 1986 through 2003, an experience including 152 patients, with more than 60 more recent patients treated with gemcitabine-based preoperative treatment. Overall, in their retrospective analysis they did not find improvement in outcomes with the use of gemcitabine instead of 5-FU and they did not find improved median overall survival or disease-free survival in patients treated preoperatively versus those treated postoperatively. However, the patients treated preoperatively tended to have more advanced tumors than those treated postoperatively and to be more marginal surgical candidates to begin with, so the similar overall survival and disease-free survival may still favor the use of preoperative treatment in certain subsets of patients.¹²⁰ Of note, the Eastern Cooperative Oncology Group (ECOG) experience with 41 patients treated with a similar approach as the Fox Chase Cancer Center were not encouraging, with only 24 of 53 patients undergoing curative resection. Among these patients who underwent resection, median survival was 15.7 months.¹²¹

Investigators have also used RT concurrent with gemcitabine neoadjuvantly for resectable pancreatic cancer. Talamonti and associates¹²² reported on 20 patients with potentially resectable pancreatic cancer treated neoadjuvantly with full-dose gemcitabine (1000 mg/m² IV) concurrent with RT during the second cycle (36 Gy in 2.4-Gy fractions). Because of the high doses of concurrent gemcitabine, RT was given without prophylactic nodal irradiation. Of the 20 patients, 95% completed treatment without interruption. Radiographically, 80% of patients had stable disease, 15% had partial response, and 5% had progressive disease. Seventeen (85%) patients underwent curative resection with a 94% rate of R0 resection and a 65% rate of negative lymph nodes. Preliminary survival data with median follow-up of 18 months were promising in resected patients (median survival 26 months, 2-year OS 61%), with 41% of the patients alive with no evidence of disease. In 2008, researchers at the M.D. Anderson Cancer Center also reported on a slightly different gemcitabine-based preoperative chemoradiation, with 7 weekly doses (400 mg/m²) concurrent with RT to 30 Gy in 10 fractions, including prophylactic nodal irradiation.¹²³ Of the 86 patients enrolled, 13 did not undergo surgery because of progressive disease or worsening performance status and 9 who did have surgery did not undergo resection because of extrapancreatic disease. Overall, 64 of 86 patients underwent resection (74%), and these patients had excellent survival numbers (median survival, 34 months; 5-year OS, 36%). Promising early survival results were also found by Small and associates¹²⁴ in patients with initially resectable pancreatic cancer treated with three cycles of full-dose gemcitabine concurrent with irradiation to 36 Gy in 2.4-Gy fractions (without prophylactic nodal radiation).

In summary, for patient populations that clearly present with resectable disease it is extremely difficult to try to do direct comparison of neoadjuvant and adjuvant results. In the former context one does not have surgical pathologic staging unmodified by the effects of nonsurgical therapy, and the denominator of who undergoes surgery with these two approaches differs by the selection processes applied. The neoadjuvant approach assures the use of chemotherapy and adjuvant therapy before surgery, provides a window of opportunity for rapidly progressive disease to declare itself prior to surgery, and likely enhances the opportunity for an R0 resection. This approach requires a fully integrated team approach among the involved disciplines, histologic confirmation of diagnosis before therapy, and the ability to manage jaundice nonsurgically. The adjuvant approach provides the greatest opportunity for surgery, which is the core intervention of all curative management and arguably may provide the best anatomic palliation for those not cured while also providing the clearest pathologic staging both with respect to disease site (pancreas, distal common bile duct, ampulla of Vater, and periampullary duodenum) and with respect to tumor grade and nodal involvement. Ultimately, many operations performed with curative intent for pancreatic cancer prove to be not curative in both contexts and the choice between these two approaches remains one of surgeon and/or institutional preference.

GDA, gastroduodenal artery; IVC, inferior vena cava; SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Palliative Surgery

Classically, a discussion of palliative surgery for periampullary carcinoma would imply hepaticojejunostomy, gastrojejunostomy, or both, to relieve biliary obstruction and gastric outlet obstruction. As summarized by Lillemoe and colleagues,¹²⁹ this type of operation can be performed with an in-hospital mortality rate of 2.5%, postoperative non–life-threatening morbidity of 37%, and a mean survival of 7.7 months. Several groups have looked at the role of palliative pancreaticoduodenectomy, that is, pancreaticoduodenectomy performed despite the surgeons’ intraoperative realization that the final margins of resection are likely to be visibly positive. Lillemoe and colleagues¹²⁹ looked at this issue in 64 consecutive patients undergoing surgery between 1986 and 1994 and compared the outcomes to 62 consecutive patients undergoing standard surgical palliation between 1986 and 1991. None of these patients had evidence of hepatic, serosal, or peritoneal dissemination. Patients undergoing palliative pancreaticoduodenectomy fared significantly better than patients undergoing palliative bypass (p <.02) with a 24-month survival of approximately 30% in the pancreaticoduodenectomy patients versus less than 10% in the palliative bypass patients. However, the patients undergoing palliative pancreaticoduodenectomy who received postoperative chemoradiation survived significantly longer than patients undergoing the same operation without adjuvant chemoradiation. Similarly, patients undergoing bypass therapy who received postoperative RT survived significantly longer than patients undergoing bypass therapy without chemoradiation. Similar results have been described by Ouchi and associates.¹³⁰

Chemoradiation for Locoregional Unresectable Disease

For locoregionally unresectable disease, the GITSG has demonstrated that split-course RT to a total dose of 40 to 60 Gy with concurrent 5-FU bolus was superior to RT alone at a dose of 60 Gy (median survival rate from diagnosis at exploratory laparotomy of 5.5 months [60 Gy alone] vs. 8.3 months [40 Gy + 5-FU] and 11.3 months [60 Gy + 5-FU])¹³¹ (Table 46-6). Subsequently, the GITSG demonstrated that combination chemotherapy with an SMF regimen (streptozocin, mitomycin C, 5-FU) produced a significantly inferior survival result for patients with unresectable disease than 5-FU chemoradiation to 54 Gy followed by SMF chemotherapy (median survival 42 vs. 32 weeks; 1-year OS 41% vs. 19%, 2-year OS 18% vs. 0%; advantage to chemoradiation vs. chemotherapy alone at all time points)¹³² (see Table 46-6).

The ability to give combined chemoradiation, with either continuous or split-course EBRT, to doses between 40 and 60 Gy combined with 5-FU, 5-FU/leucovorin, 5-FU/mitomycin C, and 5-FU/cisplatin, with definite but acceptable toxicity has also been confirmed.133–135,136 Conversion to operability was noted to occur rarely (10%), with pain relief occurring in the majority of patients. Treatment toxicity is related to treatment volume, total EBRT dose, EBRT fraction size, and the use or absence of a planned split, as well as to the intensity of the chemotherapy dosing. In patients with adequate nutrition and with hepatic and gastric obstruction absent or surgically relieved, toxicities, such as nausea and mucositis, are generally readily manageable.

As previously discussed, there has been considerable interest in combining EBRT with gemcitabine owing to its potent radiosensitizing properties. Blackstock and colleagues¹³⁷ examined, in a phase I study, gemcitabine (starting at 20 mg/m²) twice weekly in combination with EBRT (total dose 50.4 Gy in 1.8-Gy fractions) in 19 patients with locally advanced pancreatic adenocarcinoma. Thrombocytopenia, neutropenia, and nausea/vomiting were dose-limiting toxicities. Of the 15 patients assessable for response, partial responses were identified in 3. A dose of 40 mg/m² twice weekly in combination with RT to a total dose of 50.4 Gy was subsequently examined by the Cancer and Leukemia Group B (CALGB)¹³⁸ in a phase II study of 39 patients with locally advanced pancreatic cancer. After chemoradiation, patients without disease progression received gemcitabine alone 1000 mg/m² weekly × 3 every 4 weeks for five additional cycles. Grade 3/4 hematologic toxicity was significant and identified in 69% of patients. In addition, grade 3/4 gastrointestinal toxicity was identified in 41% of patients. The median survival was 8.2 months (Table 46-6).

The M.D. Anderson Cancer Center has published a corollary phase I study of 18 patients with locally advanced disease using rapid fractionation EBRT. Patients received dose-escalating gemcitabine from 350 mg/m² to 500 mg/m² weekly × 7 with concurrent rapid fractionation 3000 cGy EBRT during the first 2 weeks of therapy.¹³⁹ Hematologic and nonhematologic toxicities were significant in all three patient cohorts. There were eight responses (four minor and four partial). One of two patients who subsequently underwent surgical exploration had a curative resection. The recommended phase II testing dose of gemcitabine was 350 mg/m².

The University of Michigan¹⁴⁰ has described an alternative approach using standard doses of gemcitabine at 1000 mg/m² weekly × 3 every 4 weeks and administering EBRT as dose escalation beginning at 24 Gy (1.6 Gy in 15 fractions) in 37 patients with locally advanced disease. The majority of patients received additional chemotherapy after chemoradiation at the discretion of the treating physician. Seventy-five percent of patients received at least 85% of planned gemcitabine. Two of six assessable patients experienced dose-limiting toxicity at the final planned radiation dose of 42 Gy in 2.8-Gy fractions. An additional two patients developed late gastrointestinal toxicities at this dose level. Six patients were documented to have a partial response with a complete radiographic response in two patients. In addition, four patients with documented stable disease at the time of initial post-therapy evaluation experienced objective responses (two partial and two complete responses) with additional chemotherapy. Definitive resection was achieved in one of three patients who underwent surgical exploration. With a median follow-up of 22 months, median survival for the entire group was 11.6 months (see Table 46-6).

In a subsequent phase II multi-institutional trial by Small and colleagues, patients were treated with three cycles of full-dose gemcitabine, with concurrent EBRT during the second cycle to 36 Gy in 2.4-Gy fractions. Of the 14 patients with unresectable disease at presentation, 1 ultimately underwent resection and 1-year OS was 47%. This report was one of the first multi-institutional trials showing the safety and efficacy of full-dose gemcitabine with full-dose irradiation in patients with unresectable pancreatic cancer.¹²⁴

An ECOG phase III trial attempted to assess the benefit of RT combined with gemcitabine in the unresectable pancreatic cancer population but was closed early because of poor accrual (only 74 patients). Although only published in abstract form, adding 50.4 Gy of RT to weekly gemcitabine significantly improved median survival compared with weekly gemcitabine alone (11.0 vs. 9.2 months, p = .044). However, grade IV toxicity was also significantly higher in the chemoradiation trial arm.¹⁴¹

(See additional details at the Expert Consult website. )

The ECOG published a phase I study of 7 patients with locally advanced disease using combination chemotherapy consisting of EBRT to a maximum 59.4 Gy in 1.8-Gy fractions. 5-FU (200 mg/m²/day as continuous infusion [CI] throughout RT) was administered with weekly gemcitabine dose escalation beginning at 100 mg/m². The study was closed early due to dose-limiting toxicities, even with lowered doses of gemcitabine.¹⁴²

Gemcitabine has also been combined with cisplatin and RT in published phase I trials, following up on promising preclinical synergistic data. A study based at the Mayo Clinic gave twice-weekly gemcitabine and cisplatin for 3 weeks during EBRT (50.4 Gy in 28 fractions) (see Table 46-6). Dose-limiting toxicities consisted of grade IV nausea and vomiting. The recommended phase II dose was gemcitabine 30 mg/m² and cisplatin 10 mg/m².¹⁴³ Another trial used strictly time-scheduled gemcitabine (dosing on days 2, 5, 26, and 33 after a weekly regimen was too toxic) and cisplatin (days 1 to 5 and 29 to 33) combined with RT, with a recommended phase II dose of 20 mg/m² for cisplatin and 300 mg/m² for gemcitabine.¹⁴⁴ The response to chemoradiation allowed 10 of 30 patient with initially unresectable disease to undergo surgery, with an R0 resection in nine cases and a complete response in two cases.

Because the ESPAC-3 study showed no difference in OS or DFS in patients treated adjuvantly with 5-FU/leucovorin versus gemcitabine, the question of which agent to use in the locally advanced setting is debatable. The M.D. Anderson Cancer Center¹⁴⁵ retrospectively examined its database of 114 patients with locally advanced disease treated with combination EBRT (rapid-fractionation 30 Gy in 10 fractions) with either concurrent continuous infusion 5-FU 200 to 300 mg/m² (61 patients) or gemcitabine 250 to 500 mg/m² weekly for 7 weeks (53 patients). Patients receiving gemcitabine developed significantly higher incidences of severe acute toxicity, defined as toxicity requiring a hospital stay of more than 5 days, mucosal ulceration with bleeding, more than three-dose deletions of gemcitabine, or toxicity resulting in surgical intervention or death compared with those patients receiving 5-FU (23% vs. 2%, p <.0001). Five of 53 patients treated with gemcitabine-based chemoradiation subsequently underwent surgical resection compared with 1 of 61 patients treated with 5-FU–based chemoradiation. However, with short median follow-up, median survival was similar (11 vs. 9 months, p = .19) (see Table 46-6).

Another agent being tested in unresectable pancreatic cancer is bevacizumab (Avastin), an anti–vascular endothelial growth factor (VEGF) inhibitor. It is hypothesized that anti-VEGF inhibitors enhance radiation sensitivity because VEGF, which is induced by RT, appears to be cytoprotective.¹⁴⁶ Early reports combining bevacizumab with RT in unresectable pancreatic cancer showed an alarming rate of duodenal bleeding at the primary site, but this was thought to be because tumors involving the duodenum at presentation were included.¹⁴⁷ RTOG 04-11, which tested RT concurrent with bevacizumab and capecitabine followed by gemcitabine and bevacizumab in unresectable pancreatic cancer, excluded tumors with duodenal invasion. None of the 82 patients tested with the regimen experienced duodenal bleeding. Although the survival was not improved compared with historic controls, this phase II trial showed the tolerability of bevacizumab concurrent with RT for locally advanced pancreatic cancer.¹⁴⁷

Finally, a recent area of study incorporates single-fraction stereotactic body radiation therapy (SBRT) for locally unresectable pancreatic cancer. A report from Stanford University in 2009¹⁴⁸ describes treating gross tumor plus a margin of 2 to 3 mm to 25 Gy in a single fraction for a heterogeneous population of patients (81% locally advanced, 19% metastatic). Most patients (96%) were treated sequentially with a gemcitabine-based chemotherapy regimen. With a median follow-up of 6 months, the overall rate of freedom from local progression at 6 and 12 months was 91% and 84%, respectively. The 12-month actuarial rate of grade 2 or greater late toxicity (mostly intestinal ulceration) was 25%, and the median survival from time of SBRT for the locally advanced patients was only 6.4 months. Although this early experience with SBRT shows potential, the survival achieved from diagnosis (11.5 months) was similar to both historical and contemporary treatment and the retrospective assessment of toxicity may underestimate the true rate of serious side effects.¹⁴⁹ Further study is required to evaluate this technique.

Chemotherapy

Because the benefit of chemoradiation is relatively modest, some oncologists recommend chemotherapy alone for locally advanced disease. Gemcitabine is the most commonly used agent, extrapolating from the metastatic disease setting. This is based on the randomized trial by Burris and colleagues,⁹⁷ in which 26% of the study subjects had locally advanced disease, and showed that gemcitabine ameliorated symptoms and modestly improved survival compared with 5-FU. The results for patients with locally advanced disease were not reported separately. As discussed earlier, an ECOG phase III trial (E4201) comparing gemcitabine/irradiation versus gemcitabine alone opened in April 2003 to examine this issue and closed prematurely for inadequate accrual in December 2005 with 74 patients enrolled.¹⁴¹ Results were analyzed and presented in abstract form in 2008, showing that patients in the chemoradiation trial arm had a median survival of 11.0 months compared with 9.2 months with gemcitabine alone (p = .044, two-sided log-rank).

As mentioned in the prior adjuvant section, there has been considerable interest in finding a second drug to add to gemcitabine to enhance chemotherapy benefit, with little success. Agents that have been tested in the metastatic or locally advanced setting include 5-FU, cisplatin, oxaliplatin, irinotecan, exactecan, and capecitabine. Unfortunately, these trials have not shown survival advantages, with the exception being a statistically significant, small improvement in median survival and 1-year OS seen with the combination of gemcitabine and erlotinib as compared with gemcitabine alone.100,101

Erlotinib added to gemcitabine was tested in advanced pancreatic cancer by Moore and associates¹⁰¹ in a large randomized phase III trial of 569 patients of whom about one fourth (24%) had locally advanced disease. Subgroup analysis did not suggest a greater effect in patients with locally advanced disease than in those with metastatic disease. With the use of an intent-to-treat analysis, survival was improved with the addition of erlotinib, with a hazard ratio of .82 (median survival 6.24 vs. 5.91 months; p = .038). Progression-free survival and 1-year OS were also significantly improved with the addition of erlotinib. Significantly more patients with erlotinib had adverse reactions, but the majority were grade 1 and 2. Further study with this agent coupled with gemcitabine is recommended to assess its value.

Intraoperative Irradiation or Brachytherapy