TREATMENT OF LOCALLY ADVANCED DISEASE
CHEMORADIATION

A pilot trial of 5-FU and supervoltage radiation therapy in patients with locally advanced adenocarcinoma of the pancreas served as the foundation for a subsequent study of 5-FU-based chemoradiation by the GITSG. All patients were surgically staged; only patients with disease confined to the pancreas and peripancreatic organs, regional lymph nodes, and regional peritoneum were eligible for treatment. The entire area of malignant disease had to be encompassed within a 400-cm2 area. Radiation therapy was delivered as a split course with 20 Gy given over 2 weeks followed by a 2-week rest. Patients received a total of either 40 or 60 Gy. 5-FU was delivered intravenously at a bolus dose of 500 mg/m2 /d for the first 3 days of each 20-Gy cycle and given weekly (500 mg/m2 ) following the completion of chemoradiation. Patients were randomized to receive 40 Gy plus 5-FU, 60 Gy plus 5-FU, or 60 Gy without chemotherapy. Median survival was 10 months in each of the chemoradiation groups and 6 months for patients who received 60 Gy without 5-FU. These data supported the original double-blind study by Moertel and colleagues that compared 35 to 40 Gy of radiation plus 5-FU to radiation alone. Mean survival was 10.4 months in the chemoradiation group and 6.3 months in the group that received radiation alone. Clinically matched, untreated patients with locally advanced pancreatic cancer (retrospectively reviewed from the Mayo Clinic) were also found to have a median survival of approximately 6 months.

All patients were entered in the GITSG studies following laparotomy, at which time the disease was deemed unresectable by the operating surgeon. Chemoradiation was reasonably well tolerated following major surgery. Approximately 80% of patients completed chemoradiation, and the two fatal septic events were believed not to be treatment related. The most frequent toxic effects were nausea and vomiting, which were seldom severe. The significant morbidity reported with palliative pancreatic surgery suggests that only patients with a high performance status could have recovered rapidly enough to be eligible for these studies. Thus, although surgical staging made for a more uniform study population, it also introduced significant selection bias: only rapidly recovering patients were considered for treatment. Comparison of future studies to these data must account for this selection bias. In subsequent GITSG studies, neither doxorubicin (Adriamycin) used as a radiation potentiator nor multidrug chemotherapy (SMF: streptozocin, mitomycin, and 5-FU) alone or continued after chemoradiation was found superior to 5-FU chemoradiation. Additional chemotherapy beyond 5-FU-based chemoradiation increased toxicity without apparent therapeutic benefit.

EXTERNAL-BEAM RADIATION THERAPY

Treatment planning using high-quality CT allows precise definition of the volume to be treated, enabling the delivery of high-dose EBRT to restricted tumor volumes. The EBRT treatment field encompasses the primary tumor and regional lymph nodes including the celiac axis and the SMA origin. Although these important structures cannot be visualized directly at simulation, their radiographic location is usually at the pedicle of the T12 vertebral body (contrary to the commonly accepted location of the celiac axis at the T12-L1 interspace). In one study, the SMA was found by angiography to arise at the level of the top of L1 in 83% of patients and below the pedicle of L1 in 21%; it arose below the L1-2 interspace in no patients. Because of this anatomic variability, EBRT planning must be individualized by using information from CT, magnetic resonance imaging, or angiographic evaluations. With external irradiation, the isodose lines typically contract in from the superior and inferior field edges, and because of variation in daily treatment set-up, external radiation fields must not encompass T12 or L1 tightly because this risks under-treating the regional lymph nodes.

Treatment simulation is carried out by placing the patient in an arms-up position to avoid an exit dose to the arms. The dose to the primary tumor and regional lymphatics can be specified to the 95% isodose line as a tumor minimum or as an isocentric dose. The limits of normal tissue toxicity guide EBRT to doses of 50.4 Gy (tumor minimum) using fields that rarely exceed 12 × 12 cm. This treatment is usually given in 28 fractions over 5.5 weeks using a four-field technique with anterior-posterior and two lateral fields. Rapid-fractionation irradiation, which delivers 30 Gy (isocenter dose) in 10 fractions over 2 weeks offers the advantages of decreased treatment time, toxicity, and cost. Hyperfractionated irradiation (1.2 Gy twice daily) has also been used for the treatment of unresectable pancreatic cancer, but no improvement in either local tumor control or time to recurrence was found compared with conventional treatment schedules.

Additional data regarding the potential benefit of postoperative adjuvant therapy will come from the European Organization for Research and Treatment of Cancer (EORTC) and the European Study Group for Pancreatic Cancer (ESPCA). The EORTC initiated a study in 1987 comparing adjuvant 5-FU-based chemoradiation following pancreatectomy with surgery alone. More than 150 patients have been entered; results are not yet available. In 1994, a study was initiated by the ESPCA randomizing patients following pancreatectomy to one of four treatment groups: (1) no adjuvant therapy; (2) 5-FU-based chemoradiation; (3) 5-FU-based chemoradiation followed by systemic 5-FU and leucovorin; and (4) 5-FU and leucovorin without EBRT.

The risk of delaying adjuvant therapy, combined with small published experiences of successful pancreatic resection following EBRT, prompted many institutions to initiate studies in which chemoradiation was given before pancreaticoduodenectomy for patients with potentially resectable (or locally advanced) adenocarcinoma of the pancreas. The preoperative use of chemoradiation is supported by the following considerations:

Radiation therapy is more effective on well-oxygenated cells that have not been devascularized by surgery.
Peritoneal tumor cell implantation due to the manipulation of surgery may be prevented by preoperative chemoradiation.
The high frequency of positive-margin resections recently reported supports the concern that the retroperitoneal margin of excision, even when negative, may be only a few millimeters; surgery alone may therefore be an inadequate strategy for local tumor control.
Patients with disseminated disease evident on restaging studies after chemoradiation will not be subjected to laparotomy.
Because radiation therapy and chemotherapy will be given first, delayed postoperative recovery will have no effect on the delivery of multimodality therapy, a frequent problem in adjuvant therapy studies.

In patients who receive chemoradiation before surgery, a repeat staging CT scan after chemoradiation reveals liver metastases in 25%. If these patients had undergone pancreaticoduodenectomy at the time of diagnosis, it is probable that the liver metastases would have been subclinical; these patients would therefore have undergone a major surgical procedure only to have liver metastases found soon after surgery. In the MDACC trial, patients who were found to have disease progression at the time of restaging had a median survival of only 6.7 months. The avoidance of a lengthy recovery period and the potential morbidity of pancreaticoduodenectomy in patients with such a short expected survival duration represent distinct advantages of preoperative over postoperative chemoradiation. When delivering multimodality therapy for any disease, it is beneficial, when possible, to deliver the most toxic therapy last, thereby avoiding morbidity in patients who experience rapid disease progression not amenable to currently available therapies.
The survival advantage for the combination of chemoradiation and surgery compared with surgery alone likely results from improved local-regional tumor control. Because of the poor rates of response to 5-FU-based systemic therapy in patients with measurable metastatic disease, it is unlikely that current chemoradiation regimens significantly impact the development of distant metastatic disease. Recent data from Staley and colleagues at MDACC support this belief. Thirty-nine patients received preoperative 5-FU-based chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for adenocarcinoma of the pancreatic head. Thirty-eight of them were evaluable for patterns of treatment failure; there was one perioperative death. Overall, there were 38 recurrences in 29 patients: 8 (21%) were local-regional (pancreatic bed or peritoneal cavity or both), and 30 (79%) were distant (lung, liver, or bone). The liver was the most frequent site of tumor recurrence, and liver metastases were a component of treatment failure in 53% of patients (69% of all patients who had recurrences). Fourteen patients (37% of all patients; 48% of patients who had recurrences) had liver metastases as their only site of recurrence. Isolated local or peritoneal recurrences were documented in only four patients (11%). This improvement in local-regional control was seen despite the fact that 14 of 38 evaluable patients had undergone laparotomy with tumor manipulation and biopsy before referral for chemoradiation and reoperation. If these 14 patients were excluded, only two patients (8%) would have experienced local or peritoneal recurrence as any component of treatment failure. However, because of the large percentage of patients who developed distant metastatic disease, predominantly in the liver, improved local-regional tumor control translated into only a small improvement in median survival compared with that in other recently published studies. Therefore, in the absence of effective systemic therapy, the goal of chemoradiation (preoperative or postoperative) and pancreatectomy should be to maximize local-regional tumor control while minimizing treatment-related toxicity and cost.

TUMORS OF THE PANCREATIC BODY AND TAIL

Because adenocarcinomas of the pancreatic body and tail do not cause obstruction of the intrapancreatic portion of the common bile duct, early diagnosis is rare; virtually all patients have locally advanced or metastatic disease at the time of diagnosis. CT provides an excellent assessment of the relationship of the tumor to the celiac axis and the SMA origin. Arterial encasement is present in most patients, except for the anecdotal patient who presents with upper gastrointestinal hemorrhage resulting from sinistral hypertension secondary to splenic vein occlusion by a small tumor. In the rare patient who appears to have resectable disease (no arterial encasement and no extrapancreatic disease), laparoscopy before laparotomy is a logical approach because peritoneal metastases are frequently found. The scant data available regarding surgical resection confirm the short survival and poor prognosis in this subgroup of patients. Further, the high 30-day hospital mortality rate (43%; 6 of 14 patients with adenocarcinoma) reported in a study from the Department of Veterans Affairs hospitals suggests that many of the patients taken to surgery have advanced disease and a poor performance status. Accurate preoperative imaging and a selective approach to surgical therapy will minimize treatment-related morbidity and mortality and maximize the length and quality of patient survival.

TREATMENT OF POTENTIALLY RESECTABLE DISEASE

PREOPERATIVE AND POSTOPERATIVE CHEMORADIATION

External-beam radiation therapy (EBRT) and concomitant 5-FU chemotherapy (chemoradiation) were shown to prolong survival in patients with locally advanced adenocarcinoma of the pancreas. Those data were the foundation for a prospective randomized study of adjuvant chemoradiation (500 mg/m2 /d 5-FU for 6 days and 40 Gy of radiation) following pancreaticoduodenectomy conducted by the Gastrointestinal Tumor Study Group (GITSG); that trial also demonstrated a survival advantage from multimodality therapy compared with resection alone. However, because of a prolonged recovery, 5 (24%) of the 21 patients in the adjuvant chemoradiation arm could not begin chemoradiation until more than 10 weeks after pancreaticoduodenectomy.

Further, published studies advocating postoperative adjuvant chemoradiation are prone to selection bias; the patients likely to be considered for protocol entry are those who recover rapidly from surgery and have a good performance status.

The slow patient accrual of postoperative adjuvant therapy studies and the positive correlation of survival with performance status in the GITSG trial validate this concern. A similar selection bias is likely in effect when attempts are made to retrospectively compare patients who received postoperative adjuvant chemoradiation with patients who were treated only with pancreaticoduodenectomy. However, recently reported data from Yeo and colleagues at Johns Hopkins University add further support to the use of multimodality therapy. Those investigators reviewed all patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head during a 4-year period. Fifty-six patients received adjuvant chemoradiation, and 22 underwent pancreaticoduodenectomy alone. Despite the chemoradiation group containing a larger percentage of patients with aneuploid tumors, median survival for that group was 20 months compared with 12 months for the group who received surgery alone.

A survival advantage was also demonstrated for patients treated with adjuvant combination chemotherapy alone (5-FU, doxorubicin, mitomycin C) after pancreatectomy. Median survival was 23 months in the 30 patients randomized to receive adjuvant therapy compared with 11 months in the 31 patients treated with surgery alone. Forty-six additional patients were ineligible following surgery, attesting to the difficulty in performing multiinstitution protocol-based research following a complex surgical procedure such as pancreaticoduodenectomy. The toxicity of the surgery and chemotherapy was significant; only 24 of 30 patients received chemotherapy, and only 13 of these received all 6 planned courses of chemotherapy. A previous pilot study of adjuvant 5-FU, doxorubicin, and mitomycin C, using a different schedule of administration, found similar toxicity and therefore questioned the use of adjuvant combination chemotherapy, of even moderate toxicity, after pancreatectomy.

NATURAL HISTORY AND PATTERNS OF TREATMENT FAILURE

Rational anticancer therapy for solid malignancies is based on an accurate knowledge of the natural history and patterns of treatment failure for each tumor type. Pancreatic cancer spreads early to regional lymph nodes, and subclinical liver metastases are present in the majority of patients at the time of diagnosis, even when findings from imaging studies are normal. Patient survival depends on the extent of disease and performance status at diagnosis. Extent of disease is best categorized as resectable, locally advanced, or metastatic. Patients who undergo surgical resection for localized nonmetastatic adenocarcinoma of the pancreatic head have a long-term survival rate of approximately 20% and a median survival of 15 to 19 months (Table 32.4-2) (Table Not Available) . As will be discussed, survival is clearly maximized by combining surgery with either preoperative or postoperative 5-fluorouracil (5-FU)-based chemotherapy and radiation therapy (chemoradiation). However, disease recurrence following a potentially curative pancreaticoduodenectomy remains common. Local recurrence occurs in up to 85% of patients who undergo surgery alone; local-regional tumor control is maximized with combined-modality therapy in the form of chemoradiation and surgery. With improved local-regional disease control, liver metastases become the dominant form of tumor recurrence and occur in 50% to 70% of patients following potentially curative combined-modality treatment.
Patients with locally advanced, nonmetastatic disease have a median survival of 6 to 10 months. A survival advantage has been demonstrated for patients with locally advanced disease treated with 5-FU-based chemoradiation compared with no treatment or radiation therapy alone. Patients with metastatic disease have a short survival (3 to 6 months), the length of which depends on the extent of disease and performance status.

Knowledge of the prognosis and patterns of treatment failure associated with adenocarcinoma of the pancreas leads to the following basic treatment principles:

The treatment must not be worse than the disease. The low cure rate and modest median survival following pancreatectomy mandate that treatment-related morbidity be low and treatment-related death be rare.

2.Improvements in patient survival and quality of life will result from the development of innovative treatment strategies directed at the known sites of tumor recurrence. Data to date have clearly demonstrated that as local-regional treatment becomes more effective, the dominant site of failure has shifted to hepatic metastases.

Therefore, future improvements in survival duration will result either from effective systemic or regional therapy directed at subclinical liver metastases or from strategies for screening and early diagnosis directed at increasing the number of patients eligible for potentially curative surgery. Future improvements in the quality of patient survival will result from the application of innovative multimodality therapy to carefully selected (staged) patients and the avoidance of unnecessary patient morbidity due to the inappropriate use of surgery, radiation, or chemotherapy or any combination thereof in poorly selected (advanced disease) patients.

Pancreatic cancer accounts for approximately 27,000 deaths per year in the United States and 50,000 deaths per year in Europe (excluding the former USSR). Only 1% to 4% of patients with adenocarcinoma of the pancreas will be alive 5 years after diagnosis. Thus, incidence rates are virtually identical to mortality rates. In the United States in 1995, pancreatic cancer was be the fifth leading cause of adult deaths from cancer (after lung, colorectal, breast, and prostate cancers) and was responsible for close to 5% of all cancer-related deaths.

EPIDEMIOLOGY

The incidence of pancreatic cancer declined slightly from 1973 to 1991, with 26,300 new cases (2% of all cancer diagnoses) estimated in 2006. Studies evaluating this trend suggest that the decreased incidence is due to a steady decline in the rate for white men, which peaked during the period 1970 to 1974. By contrast, rates for white women, black men, and black women have not fallen. In Japan, the incidence of cancer of the pancreas has increased sharply from 1.8/100,000 in 1960 to 5.3 in 100,000 in 1985. Overall, incidence in mortality statistics are very similar for the United States and Western Europe. Between 1989 and 1991, mortality rates for pancreatic cancer in the United States were 10 in 100,000 for men, and 7.2 in 100,000 for women. Although overall mortality rates in industrialized societies appear similar, geographically and ethnically dissimilar populations show considerable differences in mortality rates from pancreatic cancer.
The risk of developing pancreatic cancer is low in the first three to four decades of life but increases sharply after age 50, with most patients between ages 65 and 80 at diagnosis. The male to female ratio has ranged from 1.7:1.0 in older series to 1.3:1.0 in a more contemporary series. Historically, the male to female ratio was reported to decrease with age; however, this trend was not observed in a recent series from Memorial Sloan-Kettering Cancer Center. Interestingly, in several animal models of pancreatic cancer, tumors are more reproducibly induced in male animals.
Racial differences in mortality rates for pancreatic cancer have also been observed. Pancreatic cancer mortality rates for American blacks are higher than for any other ethnic group in the United States and are considerably higher than the rates observed for African blacks, suggesting an environmental contribution to this increased risk.

These broad epidemiologic categories do little to identify persons at high risk for pancreatic cancer. To define high-risk groups, we must consider the contribution of specific etiologic factors.