- Email: [email protected]
The Virginia Mason approach to localized pancreatic cancer
Surg Oncol Clin N Am 13 (2004) 663–674
The Virginia Mason approach to localized pancreatic cancer Vincent J. Picozzi, MD, MMMa*, L. William Traverso, MDb a
Section of Hematology-Oncology, Virginia Mason Medical Center, 1100 9th Avenue, Seattle, WA 98111, USA b Section of General Surgery, Virginia Mason Medical Center, 1100 9th Avenue, Seattle, WA 98111, USA
In 2004, pancreatic cancer represents the fourth most common cause of cancer death for men and women in the United States. More than 30,000 people in this country (and more than 200,000 people worldwide) succumb annually from this disorder [1,2]. According to the National Cancer Database, pancreatic cancer has the worst survival data for any major cancer; 1- and 5-year overall survivals are 20% and 2%, respectively [3]. Various reasons exist for the poor clinical outcomes in pancreatic cancer, including difficulty in disease recognition, frequency of advanced stage at presentation, patient age, patient comorbidity, and pessimism among patients and providers. Pancreatic cancer thus represents one of the supreme challenges to oncologists. Management of pancreatic cancer is equally challenging from the perspective of the surgeon. In the United States, only about 15% of patients with pancreatic cancer are able to undergo surgery with curative intent. Although operative mortality has declined substantially at large-volume centers for pancreaticoduodenectomy over the past several decades, mortality rates in association with this operation remain over 10% at low- and moderatevolume centers [4]. Despite the improvements in operative mortality seen at high-volume centers, median survival after pancreaticoduodenectomy alone for localized disease remains a disappointing 11 to 13 months (Table 1). Furthermore, perioperative morbidity can play a role in the inability to administer adjuvant radiation or chemotherapy to 20% to 30% of resected patients, even in high-volume centers [9]. Thus, many surgical challenges to the management of localized pancreatic cancer remain. * Corresponding author. E-mail address: [email protected] (V.J. Picozzi). 1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2004.06.002
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Table 1 Median and overall survival rates of patients in pancreaticoduodenectomy only arms of phase III trials for localized pancreatic cancer Study
No. of patients
Median survival (mo)
Overall survival (5 y)
GITSG [5] Bakkevold et al [6] EORTC [7] ESPAC [8]
22 31 54 69
11 11 13 17
0% 8% 10% 11%
This article describes the approaches presently employed at Virginia Mason Medical Center for treatment of localized pancreatic cancer, including preoperative staging, operative intervention, incorporation of adjuvant therapy, and supportive care. Preoperative staging At Virginia Mason (as at most institutions), evaluation of a patient with potentially resectable pancreatic cancer begins with computed tomography (CT). In recent years, use of multidetector, triphasic scanning technique with high resolution through the pancreatic bed has added to the accuracy of this technique. The specific scanning technique at Virginia Mason incorporates the following key methodologies:
The use of water (as opposed to dilute barium) for oral contrast The use of high volume and density (eg, 150 cc Optiray 350) Performance of noncontrast images before contrast imaging Dual-phase (arterial and portal venous) scanning High-resolution (ie, 2.5 mm or less) sections through the pancreas during arterial phase imaging
Once a high-quality scan is obtained, the following is examined to assess resectability: Presence or absence of distant metastases (particularly hepatic and/or peritoneal) Presence or absence of anomalous vascular anatomy Description of the patency of the superior mesenteric vein (SMV) and portal vein (PV) as well as the relationship of the cancer to these structures Description of the relationship of the cancer to the superior mesenteric artery (SMA), celiac artery, hepatic artery, and gastroduodenal artery, especially with respect to the presence or absence of a definable tissue plane between the tumor and these structures At Virginia Mason, peripancreatic nodal involvement is also noted but does not represent a contraindication to operation with curative intent.
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Patients who are not candidates for curative surgery based on the above helical scanning criteria are defined as such with virtually complete accuracy. However, patients believed to be surgical candidates based on the above may or may not prove to be resectable at the time of surgery because of the relative inability of CT scanning to detect small hepatic and peritoneal metastases, and to accurately judge vascular involvement [10]. To assist in the definition of operability, other imaging techniques, such as endoscopic ultrasound (EUS) and positive emission tomography (PET scanning), have been employed. EUS has the advantage of being able to be combined with ERCP or biopsy procedures and may be particularly valuable in the detection of small pancreatic neoplasms [11]. Experienced endoscopists report a high degree of accuracy with the use of this technique, even in comparison with CT scanning [12]. This technique is employed at Virginia Mason in patients who are undergoing endoscopy for other reasons (eg, stent placement) or in whom the diagnosis of a pancreatic malignancy is suspected (eg, abdominal pain, high CA 19.9) but no tumor is visualized using other imaging techniques. Lack of tumor visualization by CT is usually due to poor CT technique, and the EUS is therefore uncommonly needed. PET scanning has limitations in the routine evaluation of patients with pancreatic cancer for resectability [13]. These include (1) a lack of specificity in distinguishing cancer from other inflammatory conditions of the pancreas (eg, pancreatitis), (2) the high rate of glucose intolerance among pancreatic cancer patients that may limit radioisotopic uptake and thus limit PET sensitivity for cancer detection, and (3) the limitations of PET in detecting small (ie, less than 1 cm) lesions. For these reasons, PET scanning is not routinely used at Virginia Mason as part of preoperative evaluation of patients with localized pancreatic cancer. Serum CA 19.9 measurements have been reported to be useful in the management of pancreatic cancer in various ways, including diagnosis, staging, and assessment of response to treatment [14]. With respect to resectability, some believe that significantly elevated CA 19.9 values (ie, greater than 500 to 750 U/ml) are associated with a high probability of the cancer not being able to be resected [15]. At Virginia Mason, CA 19.9 determinations are routinely performed at all stages of management of pancreatic cancer, and its usefulness as a staging tool in comparison with CT scanning and the other imaging tests cited above is being evaluated. However, patients are not currently excluded from attempts at resection with curative intent solely on the basis of an elevated CA 19.9. Laparoscopy may also improve the staging accuracy of patients with ostensibly localized pancreas cancer. Routine laparoscopy is not performed on patients deemed resectable by CT criteria, as only about 10% will be found to have distant metastases at time of operation [5]. However, laparoscopic evaluation of patients with locally advanced pancreatic carcinoma by CT criteria seems more important. Laparoscopic examination of these patients (including peritoneal lavage cytology) will sometimes reveal positive
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lavage cytology, and less commonly, small metastases in the liver or peritoneum. In the authors’ experience, outpatient laparoscopy will upstage about one third of patients with CT-determined locally advanced pancreatic cancer (28% of pancreatic head lesions, 53% of pancreatic body or tail lesions) (Liu RC, Traverso LW, unpublished manuscript). These cases with ‘‘unresectable’’ disease by CT because of locally extending disease of the mesenteric vessels and with no distant metastases by CT would normally be candidates for radiotherapy-based treatment. However, laparoscopy enables these patients to avoid this more difficult, and potentially ineffective, approach to their treatment.
Surgery for localized pancreatic cancer Operative exploration with the intent to resect is the next consideration once the patient has been deemed resectable by the optimum CT imaging technique possible and there are no comorbidities to preclude a major surgical procedure. At Virginia Mason, every CT is jointly reviewed by the surgeon and the radiologist rather than simply relying on a dictated CT report. In this way, items on the CT scan that would have been missed by the radiologist or the surgeon (such as involvement of the gastroepiploic veins or the presence of an anomalous mesenteric artery or replaced right or common hepatic artery that might be involved with tumor) are more likely to be found. Patients felt to be appropriate operative candidates will not have tumor extending to any major mesenteric artery or greater than 180 degrees of tumor encroachment around the portal or superior mesenteric vein. Patients with mesenteric venous encroachment precluding surgery may be considered for ‘‘downstaging’’ therapy with subsequent consideration of resection attempt in 6 to 12 months (as described later in this article). All patients are allowed to have their jaundice clear for at least 2 weeks before surgery using endoscopic biliary stents. These stents have not been associated with an increased incidence of infection. Preoperatively, the patient receives an oral mechanical bowel preparation, and preoperative antibiotics are given only with the induction anesthesia medications. No somatostatin-like substances are used. Postoperatively, all patients are managed by way of a critical pathway and are recovered for 1 day in the intensive care unit and the remaining days on the same nursing unit (known as the ‘‘Whipple floor’’ at Virginia Mason). The operative technique involves a pylorus-preserving pancreaticoduodenectomy in 95% of cases unless the tumor is thought to be extending ventrally behind the duodenal bulb. In the latter case, a standard Kausch-Whipple operation with hemigastrectomy is performed. A single, closed-suction drain is placed under the pancreatic and biliary anastomoses. The goal of surgery is to remove the tumor with safe surgery that allows the patient to enter the adjuvant chemotherapy phase of treatment in the
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best possible physical condition. The benchmarks for the important outcomes after the Whipple procedure have recently been reviewed by the authors and are listed in Table 2 [16]. During the postoperative hospitalization period, the patient is visited by (1) a medical oncologist, (2) an oncology nurse familiar with pancreaticobiliary therapy, (3) a nutritionist, and (4) a social worker to begin the process of preparation for adjuvant therapy.
Adjuvant therapy for localized pancreatic cancer: the Virginia Mason approach The approach to adjuvant therapy at Virginia Mason is based on the lessons learned from other major clinical experiences with this disorder. Contemporary thought in this regard began with the work of the Gastrointestinal Tumor Study Group (GITSG) in the mid-1980s [5]. From a total of 73 resected pancreatic cancer patients accrued in two phases, the authors concluded postoperative adjuvant therapy consisting of involved field radiation and bolus intravenous 5-FU produced significant improvement in median (20 months versus 11 months) and overall (2-year 43% versus 18%, 5-year 19% versus 0%) survival. This study was criticized from various perspectives (small patient numbers, slow accrual, low numbers of Table 2 Compared outcomes after single-surgeon pancreaticoduodenectomy Outcome Men Age ASA classification Mortality OR time Estimated blood loss OR/All hospital transfusion Length of stay SD Pancreatic anastomotic leak Clinically relevant Biliary leak Delayed gastric emptying at 10 and 14 days Percutaneous drainage Reoperation Readmission
Virginia Mason 1996–2002a (N = 232) [17]
Literature 1997–2003b (N = 2730)
51% 59.5 y (18–91) I = 0%, II = 56% III = 42%, IV = 2% 0% 450 min (236–951) 382 ml (50–2400) 3.0%/7.3% 11.2 6.1 d (6–79)
56% 63.3 y Not stated 1.9% 431 min (421–531) 1183 ml (982–1600) Not stated 17.8 d
6.5% 0.4% 9.5% and 6.0%
9.9% (0–18) Not stated 13.9% (2.5–22)
5.6% 0.4% 4.3%
Not stated 3.8% (0.8–9) Not stated
Abbreviations: OR, operating room; ASA, American Society of Anesthesiologists; SD, standard deviation. a Any range in this column is the minimum and maximum of actual data. b Any range in this column is the range of reported means.
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node-positive and margin-positive patients, and delays in initiation of chemoradiation). However, the work of the GITSG became the standard of care for patients with localized pancreatic cancer, at least in the United States. A number of single-institution and phase-II experiences from centers in the United States seemed to support the GITSG experience. The collected experience from Johns Hopkins in over 600 patients with resected pancreatic cancer, most of whom underwent various 5-FU–based chemoradation protocols, showed results almost identical to those in the GITSG trial [17]. Again, however, criticisms emerged from the results, owing to issues related to single-institution nonrandomized experience and the still high (30% to 50%) rate of local recurrence reported in many series. Based on the above (and further reinforced by the subsequent results of the EORTC and ESPAC-1 trials), investigators at Virginia Mason drew the following conclusions about the treatment of localized pancreatic cancer and the role of adjuvant therapy [7,8,18]: Pancreatic cancer is a systemic disease in virtually all patients with pancreatic cancer, including at least 90% of those who appear resected. As a result, surgery is a necessary but insufficient therapy for the treatment of pancreatic cancer with curative intent. Pancreaticoduodenectomy only for localized pancreatic cancer results in median survival of only about 12 months, and long-term survival for only about 10% of patients with localized pancreatic cancer. Given the systemic nature of localized pancreatic cancer, it is not a question of if systemic therapy should be given, but how. Trials using chemotherapy after pancreaticoduodenectomy do seem to show a survival benefit over pancreaticoduoudenctomy only, irrespective of how chemotherapy is given. Although the benefit of radiation therapy in the adjuvant therapy of pancreatic cancer is uncertain, radiation therapy and chemotherapy can be given safely together, with careful planning. Based on the above conclusions, Virginia Mason began in 1995 a phase II trial for the adjuvant therapy of pancreas cancer that added cisplatin and alpha-interferon to 5-FU during chemoradiation. It should be remembered that, at the time, agents such as gemcitabine, capecitabine, and oxaliplatin were investigational and not generally available for use in pancreatic cancer. Cisplatin and alpha-interferon had the advantages of (1) radiosensitization properties and (2) biochemical synergy with 5-FU and each other [19–23]. The hope was that these three agents would form a ‘‘combination radiosensitizer’’ analogous to chemotherapy used in combination. These agents were combined into a dose-dense program together with radiation therapy in an attempt to maximize antitumor effect and minimize toxicity. Two 6-week courses of infusion 5-FU completed the adjuvant regimen (Box 1).
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Box 1. The initial Virginia Mason adjuvant chemoradiation regimen for pancreatic cancer Chemoradiotherapy XRT 50cGy in 2.0 cGy fractions (Monday through Friday, weeks 1 through 5) Cisplatin 30 mg/m2 on days 1, 8, 15, 22, and 29 during XRT Ifn-alpha 2b 3,000,000 U sq every other day on days 1 through 35 during XRT 5-FU 200 mg/m2 intravenous continuous infusion (IVCI) days 1 through 35 during XRT Post-XRT chemotherapy 5-FU 200 mg/m2 IVCI days 1 through 42 (weeks 10 through 15) 5-FU 200 mg/m2 IVCI days 1 through 42 (weeks 18 through 23)
A total of 53 patients were entered into this phase II trial between 1995 and 2002. From these 53 patients, 43 (representing those undergoing pancreaticoduodenectomy at Virginia Mason as opposed to distal pancreatectomy or operation elsewhere) were reported as a group in 2003 after an initial report of the first 17 such patients in 2000 [24,25]. These patients (approximate average age 65) had stage III or higher disease at operation 86% of the time (36 of 43 patients) using AJCC staging criteria; 84% (35 of 43 patients) had positive lymph nodes (average 3.2) by standard histological sectioning. Nineteen percent (8 of 43 patients) were histologially positive at surgical or specimen margins. Treatment details reveal 95% (41 of 43) of patients received full radiation dose. Ninety-three percent (40 of 43) of patients received greater than 85% of intended 5-FU dose during chemoradiation; 72% (31 of 43) received greater than 80% of intended cisplatin dose. Seventy percent (30 of 43) of patients received greater than 85% of intended chemoradiation dose during the postchemoradiation period. Toxicity during chemoradiation was moderate to severe. Seventy percent of patients (30 of 43) experienced CTC (common toxicity criteria) grade 3 or higher (90% grade 3) toxicity during treatment. Virtually all significant toxicity was of gastrointestinal origin (anorexia, nausea or vomiting, mucositis, diarrhea or hypovolemia). These complications necessitated a delay in treatment in the above patents. Hospitalization was required for toxicity in 42% (18 of 43) of patients owing to one or more of the following symptoms: nausea/vomiting/dehydration (n = 10), diarrhea (n = 9), mucositis (n = 2), gastrointestinal bleeding (n = 2), or bleeding due to
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Candida esophagitis (n = 1). There were no treatment fatalities; all patients returned to full functional status posttreatment. The survival status for these patients was reverified for the purpose of the current report as of the end of December 2003. With a median follow-up of 4 years (48 months), the 1-year, 2-year, and 5-year overall survival statistics are 90%, 58%, and 45%, respectively. Median survivorship of this group is 44 months. These survival data are compared with other major series (Table 3). Of interest is the pattern of recurrence seen in the Virginia Mason experience with respect to space and time. Typical local recurrence rates using standard chemoradiation (ie, radiation and 5-FU) are 30% to 60% [7,8]. However, the overall local recurrence rate in the authors’ experience was only 12% (5 of 43 patients); only two of 43 patients (5%) had only local recurrence of their cancer. With respect to time of recurrence, all recurrences except one took place within 2 years of surgery. This accounts for the relative similarity of the 2- and 5-year survival statistics in the Virginia Mason experience, again rather unique from the other experiences cited. To improve upon the aforementioned results, one would ideally wish to reduce therapeutic toxicity and recurrence rates, particularly with respect to systemic recurrence. With respect to therapeutic toxicity, various steps have been undertaken. First, nutrition and social services were involved as the vanguard of a large group of dedicated support staff (including nursing, radiation therapy, and psychological and pastoral services). This is designed to help support patients through the perioperative period to optimize their physical and psychological condition in anticipation of subsequent adjuvant therapy. Supportive care plans for chemoradiation are constructed even while the patient is still hospitalized following pancreaticoduodenectomy. Using this approach, virtually all patients at Virginia Mason are able to undergo some form of adjuvant therapy following curative resection for pancreatic cancer, usually within 8 weeks of pancreaticoduodenectomy. Second, patients are followed intensely during chemoradiation. Their attending physicians see patients at the beginning of each treatment week, with toxicities carefully monitored. Nursing staff also sees them almost daily. A supportive care pathway exists for virtually every symptom
Table 3 Comparison of adjuvant chemoradiation results, resected pancreas cancer Author
Median survival (mo)
2-y overall survival (%)
5-y overall survival (%)
GITSG 1987 [5] EORTC 1999 [7] Johns Hopkins 2000 [18] ESPAC 2004 [8] Virginia Mason 2004
21 17 21 16 44
43 37 39 29 58
19 16 19 10 45
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occurrence (eg, dehydration, nausea, and depression) with the emphasis on symptom prevention. Patients are instructed to stay close by the institution during chemoradiation, and family members are instructed carefully in symptom monitoring and supportive care measures. Third, the radiation and chemotherapy elements of the protocol have been modified slightly following our initial phase II trial in an attempt to reduce toxicity during chemoradiation. Remembering the low rate of local recurrence seen in the above patients, the daily radiation fraction was reduced slightly (from 200 to 180 cGy) while keeping the total 5040 radiation cGy dose the same. Perhaps more importantly, the size of the radiation field was reduced in an attempt to ease gastointestinal toxicity. The daily dose of 5-FU given by way of continuous infusion during radiation has been reduced for the same reason. The treatment modifications cited have all been incorporated into the American College of Surgeons Oncology Group (ACOSOG) trial (ACOSOG Z05031) that attempts to recapitulate the Virginia Mason experience in a multicenter, phase II trial in approximately 100 patients. Other centers, including M.D. Anderson (Houston, Texas) and Washington University (St. Louis, Missouri) have also launched their own phase II trials based on the Virginia Mason experience. A positive outcome from these trials could identify this therapeutic approach as a potential new standard for the care of resected pancreatic cancer.
Combined modality therapy for localized pancreatic cancer at Virginia Mason—future studies In considering additional therapy to surgery for the treatment of localized pancreatic cancer, four approaches suggest themselves beyond the standard 5-FU-based chemoradiation that has become the standard of care in the United States. These include (1) the use of neoadjuvant therapy (as has been tested at M.D. Anderson and Fox Chase), (2) the use of chemotherapy as a sole therapeutic modality (such as is being done in the ESPAC-3 trial), (3) alteration of chemoradiation (as described above), or (4) alteration of chemotherapy given pre- or postchemoradiation [26,27]. This final approach was the theme of the RTOG 9704 trial for adjuvant pancreatic cancer, in which the use of intravenous bolus gemcitabine was randomized against continuous infusion intravenous 5-FU pre-and postchemoradiation. The use of novel chemotherapy pre-and or postchemoradiation is also an ongoing interest at Virginia Mason, particularly given the proliferation of systemic agents believed effective in the treatment of pancreatic cancer and the enthusiasm for gemcitabine-based combination chemotherapy in advanced stage disease. The authors’ preference has been for the combination of gemcitabine and docetaxel, a combination with an approximate 30%
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response rate and acceptable toxicity [28]. This combination has the additional advantage of differing mechanisms of action and nonoverlapping toxicities from the three-drug combination used in conjunction with radiation. Preliminary investigation is underway exploring the use of these drugs postchemoradiation. Of even greater potential importance would be to extend the potential for curative therapy in pancreatic cancer to more than the 15% of patients with localized disease presently able to undergo curative resection. In particular, a major therapeutic goal would be to approach some fraction of the approximately 50% of patients with locally advanced, unresectable pancreatic cancer with a therapeutic design that is potentially curative. To this end, the authors have begun to experiment with neoadjuvant chemotherapy in patients with limited vascular involvement (ie, individuals with noncircumferential, nonocclusive vascular involvement) in attempt to downstage them to the point of operability, and then approach them as if they had presented de novo with more localized disease. Based on preliminary results, as many as one-half of patients treated in this fashion may be able to be approached with definitive local therapy. Summary Pancreatic cancer remains a disease of great frustration and difficulty for all cancer providers. Given its propensity for local and systemic recurrence, and given the limitations of current therapy, it is a disease in which no single therapeutic modality can produce success. A true team approach to the complex needs of the pancreatic cancer patient by physicians and support staff is needed for optimum success. Fortunately, the pancreaticobiliary surgeon is increasingly able to accurately define the anatomy of disease extent. This ability (by therapeutic exclusion), coupled with improved multimodality therapeutic and supportive care measures, offers the surgeon a greater degree of therapeutic appropriateness and effectiveness than ever before.
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[26] Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson III AB. Phase II trial of preoperative radiation therapy and chemotherapy or patients with localized, resectable, adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1998;16:317–23. [27] Wayne JD, Abdalla ED, Wolff RA, et al. Localized adenocarcinoma of the pancreas: the rationale for preoperative chemoradiation. Oncologist 2002;7:34–45. [28] Jacobs AD, Otero H, Picozzi VJ, Aboulafia D, Weiden P. Docetaxel and gemcitabine in metastatic pancreas cancer: results of a phase II trial. Proc American Society of Clinical Oncology 2000;19:265.
The Virginia Mason approach to localized pancreatic cancer Vincent J. Picozzi, MD, MMMa*, L. William Traverso, MDb a
Section of Hematology-Oncology, Virginia Mason Medical Center, 1100 9th Avenue, Seattle, WA 98111, USA b Section of General Surgery, Virginia Mason Medical Center, 1100 9th Avenue, Seattle, WA 98111, USA
In 2004, pancreatic cancer represents the fourth most common cause of cancer death for men and women in the United States. More than 30,000 people in this country (and more than 200,000 people worldwide) succumb annually from this disorder [1,2]. According to the National Cancer Database, pancreatic cancer has the worst survival data for any major cancer; 1- and 5-year overall survivals are 20% and 2%, respectively [3]. Various reasons exist for the poor clinical outcomes in pancreatic cancer, including difficulty in disease recognition, frequency of advanced stage at presentation, patient age, patient comorbidity, and pessimism among patients and providers. Pancreatic cancer thus represents one of the supreme challenges to oncologists. Management of pancreatic cancer is equally challenging from the perspective of the surgeon. In the United States, only about 15% of patients with pancreatic cancer are able to undergo surgery with curative intent. Although operative mortality has declined substantially at large-volume centers for pancreaticoduodenectomy over the past several decades, mortality rates in association with this operation remain over 10% at low- and moderatevolume centers [4]. Despite the improvements in operative mortality seen at high-volume centers, median survival after pancreaticoduodenectomy alone for localized disease remains a disappointing 11 to 13 months (Table 1). Furthermore, perioperative morbidity can play a role in the inability to administer adjuvant radiation or chemotherapy to 20% to 30% of resected patients, even in high-volume centers [9]. Thus, many surgical challenges to the management of localized pancreatic cancer remain. * Corresponding author. E-mail address: [email protected] (V.J. Picozzi). 1055-3207/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2004.06.002
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Table 1 Median and overall survival rates of patients in pancreaticoduodenectomy only arms of phase III trials for localized pancreatic cancer Study
No. of patients
Median survival (mo)
Overall survival (5 y)
GITSG [5] Bakkevold et al [6] EORTC [7] ESPAC [8]
22 31 54 69
11 11 13 17
0% 8% 10% 11%
This article describes the approaches presently employed at Virginia Mason Medical Center for treatment of localized pancreatic cancer, including preoperative staging, operative intervention, incorporation of adjuvant therapy, and supportive care. Preoperative staging At Virginia Mason (as at most institutions), evaluation of a patient with potentially resectable pancreatic cancer begins with computed tomography (CT). In recent years, use of multidetector, triphasic scanning technique with high resolution through the pancreatic bed has added to the accuracy of this technique. The specific scanning technique at Virginia Mason incorporates the following key methodologies:
The use of water (as opposed to dilute barium) for oral contrast The use of high volume and density (eg, 150 cc Optiray 350) Performance of noncontrast images before contrast imaging Dual-phase (arterial and portal venous) scanning High-resolution (ie, 2.5 mm or less) sections through the pancreas during arterial phase imaging
Once a high-quality scan is obtained, the following is examined to assess resectability: Presence or absence of distant metastases (particularly hepatic and/or peritoneal) Presence or absence of anomalous vascular anatomy Description of the patency of the superior mesenteric vein (SMV) and portal vein (PV) as well as the relationship of the cancer to these structures Description of the relationship of the cancer to the superior mesenteric artery (SMA), celiac artery, hepatic artery, and gastroduodenal artery, especially with respect to the presence or absence of a definable tissue plane between the tumor and these structures At Virginia Mason, peripancreatic nodal involvement is also noted but does not represent a contraindication to operation with curative intent.
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Patients who are not candidates for curative surgery based on the above helical scanning criteria are defined as such with virtually complete accuracy. However, patients believed to be surgical candidates based on the above may or may not prove to be resectable at the time of surgery because of the relative inability of CT scanning to detect small hepatic and peritoneal metastases, and to accurately judge vascular involvement [10]. To assist in the definition of operability, other imaging techniques, such as endoscopic ultrasound (EUS) and positive emission tomography (PET scanning), have been employed. EUS has the advantage of being able to be combined with ERCP or biopsy procedures and may be particularly valuable in the detection of small pancreatic neoplasms [11]. Experienced endoscopists report a high degree of accuracy with the use of this technique, even in comparison with CT scanning [12]. This technique is employed at Virginia Mason in patients who are undergoing endoscopy for other reasons (eg, stent placement) or in whom the diagnosis of a pancreatic malignancy is suspected (eg, abdominal pain, high CA 19.9) but no tumor is visualized using other imaging techniques. Lack of tumor visualization by CT is usually due to poor CT technique, and the EUS is therefore uncommonly needed. PET scanning has limitations in the routine evaluation of patients with pancreatic cancer for resectability [13]. These include (1) a lack of specificity in distinguishing cancer from other inflammatory conditions of the pancreas (eg, pancreatitis), (2) the high rate of glucose intolerance among pancreatic cancer patients that may limit radioisotopic uptake and thus limit PET sensitivity for cancer detection, and (3) the limitations of PET in detecting small (ie, less than 1 cm) lesions. For these reasons, PET scanning is not routinely used at Virginia Mason as part of preoperative evaluation of patients with localized pancreatic cancer. Serum CA 19.9 measurements have been reported to be useful in the management of pancreatic cancer in various ways, including diagnosis, staging, and assessment of response to treatment [14]. With respect to resectability, some believe that significantly elevated CA 19.9 values (ie, greater than 500 to 750 U/ml) are associated with a high probability of the cancer not being able to be resected [15]. At Virginia Mason, CA 19.9 determinations are routinely performed at all stages of management of pancreatic cancer, and its usefulness as a staging tool in comparison with CT scanning and the other imaging tests cited above is being evaluated. However, patients are not currently excluded from attempts at resection with curative intent solely on the basis of an elevated CA 19.9. Laparoscopy may also improve the staging accuracy of patients with ostensibly localized pancreas cancer. Routine laparoscopy is not performed on patients deemed resectable by CT criteria, as only about 10% will be found to have distant metastases at time of operation [5]. However, laparoscopic evaluation of patients with locally advanced pancreatic carcinoma by CT criteria seems more important. Laparoscopic examination of these patients (including peritoneal lavage cytology) will sometimes reveal positive
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lavage cytology, and less commonly, small metastases in the liver or peritoneum. In the authors’ experience, outpatient laparoscopy will upstage about one third of patients with CT-determined locally advanced pancreatic cancer (28% of pancreatic head lesions, 53% of pancreatic body or tail lesions) (Liu RC, Traverso LW, unpublished manuscript). These cases with ‘‘unresectable’’ disease by CT because of locally extending disease of the mesenteric vessels and with no distant metastases by CT would normally be candidates for radiotherapy-based treatment. However, laparoscopy enables these patients to avoid this more difficult, and potentially ineffective, approach to their treatment.
Surgery for localized pancreatic cancer Operative exploration with the intent to resect is the next consideration once the patient has been deemed resectable by the optimum CT imaging technique possible and there are no comorbidities to preclude a major surgical procedure. At Virginia Mason, every CT is jointly reviewed by the surgeon and the radiologist rather than simply relying on a dictated CT report. In this way, items on the CT scan that would have been missed by the radiologist or the surgeon (such as involvement of the gastroepiploic veins or the presence of an anomalous mesenteric artery or replaced right or common hepatic artery that might be involved with tumor) are more likely to be found. Patients felt to be appropriate operative candidates will not have tumor extending to any major mesenteric artery or greater than 180 degrees of tumor encroachment around the portal or superior mesenteric vein. Patients with mesenteric venous encroachment precluding surgery may be considered for ‘‘downstaging’’ therapy with subsequent consideration of resection attempt in 6 to 12 months (as described later in this article). All patients are allowed to have their jaundice clear for at least 2 weeks before surgery using endoscopic biliary stents. These stents have not been associated with an increased incidence of infection. Preoperatively, the patient receives an oral mechanical bowel preparation, and preoperative antibiotics are given only with the induction anesthesia medications. No somatostatin-like substances are used. Postoperatively, all patients are managed by way of a critical pathway and are recovered for 1 day in the intensive care unit and the remaining days on the same nursing unit (known as the ‘‘Whipple floor’’ at Virginia Mason). The operative technique involves a pylorus-preserving pancreaticoduodenectomy in 95% of cases unless the tumor is thought to be extending ventrally behind the duodenal bulb. In the latter case, a standard Kausch-Whipple operation with hemigastrectomy is performed. A single, closed-suction drain is placed under the pancreatic and biliary anastomoses. The goal of surgery is to remove the tumor with safe surgery that allows the patient to enter the adjuvant chemotherapy phase of treatment in the
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best possible physical condition. The benchmarks for the important outcomes after the Whipple procedure have recently been reviewed by the authors and are listed in Table 2 [16]. During the postoperative hospitalization period, the patient is visited by (1) a medical oncologist, (2) an oncology nurse familiar with pancreaticobiliary therapy, (3) a nutritionist, and (4) a social worker to begin the process of preparation for adjuvant therapy.
Adjuvant therapy for localized pancreatic cancer: the Virginia Mason approach The approach to adjuvant therapy at Virginia Mason is based on the lessons learned from other major clinical experiences with this disorder. Contemporary thought in this regard began with the work of the Gastrointestinal Tumor Study Group (GITSG) in the mid-1980s [5]. From a total of 73 resected pancreatic cancer patients accrued in two phases, the authors concluded postoperative adjuvant therapy consisting of involved field radiation and bolus intravenous 5-FU produced significant improvement in median (20 months versus 11 months) and overall (2-year 43% versus 18%, 5-year 19% versus 0%) survival. This study was criticized from various perspectives (small patient numbers, slow accrual, low numbers of Table 2 Compared outcomes after single-surgeon pancreaticoduodenectomy Outcome Men Age ASA classification Mortality OR time Estimated blood loss OR/All hospital transfusion Length of stay SD Pancreatic anastomotic leak Clinically relevant Biliary leak Delayed gastric emptying at 10 and 14 days Percutaneous drainage Reoperation Readmission
Virginia Mason 1996–2002a (N = 232) [17]
Literature 1997–2003b (N = 2730)
51% 59.5 y (18–91) I = 0%, II = 56% III = 42%, IV = 2% 0% 450 min (236–951) 382 ml (50–2400) 3.0%/7.3% 11.2 6.1 d (6–79)
56% 63.3 y Not stated 1.9% 431 min (421–531) 1183 ml (982–1600) Not stated 17.8 d
6.5% 0.4% 9.5% and 6.0%
9.9% (0–18) Not stated 13.9% (2.5–22)
5.6% 0.4% 4.3%
Not stated 3.8% (0.8–9) Not stated
Abbreviations: OR, operating room; ASA, American Society of Anesthesiologists; SD, standard deviation. a Any range in this column is the minimum and maximum of actual data. b Any range in this column is the range of reported means.
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node-positive and margin-positive patients, and delays in initiation of chemoradiation). However, the work of the GITSG became the standard of care for patients with localized pancreatic cancer, at least in the United States. A number of single-institution and phase-II experiences from centers in the United States seemed to support the GITSG experience. The collected experience from Johns Hopkins in over 600 patients with resected pancreatic cancer, most of whom underwent various 5-FU–based chemoradation protocols, showed results almost identical to those in the GITSG trial [17]. Again, however, criticisms emerged from the results, owing to issues related to single-institution nonrandomized experience and the still high (30% to 50%) rate of local recurrence reported in many series. Based on the above (and further reinforced by the subsequent results of the EORTC and ESPAC-1 trials), investigators at Virginia Mason drew the following conclusions about the treatment of localized pancreatic cancer and the role of adjuvant therapy [7,8,18]: Pancreatic cancer is a systemic disease in virtually all patients with pancreatic cancer, including at least 90% of those who appear resected. As a result, surgery is a necessary but insufficient therapy for the treatment of pancreatic cancer with curative intent. Pancreaticoduodenectomy only for localized pancreatic cancer results in median survival of only about 12 months, and long-term survival for only about 10% of patients with localized pancreatic cancer. Given the systemic nature of localized pancreatic cancer, it is not a question of if systemic therapy should be given, but how. Trials using chemotherapy after pancreaticoduodenectomy do seem to show a survival benefit over pancreaticoduoudenctomy only, irrespective of how chemotherapy is given. Although the benefit of radiation therapy in the adjuvant therapy of pancreatic cancer is uncertain, radiation therapy and chemotherapy can be given safely together, with careful planning. Based on the above conclusions, Virginia Mason began in 1995 a phase II trial for the adjuvant therapy of pancreas cancer that added cisplatin and alpha-interferon to 5-FU during chemoradiation. It should be remembered that, at the time, agents such as gemcitabine, capecitabine, and oxaliplatin were investigational and not generally available for use in pancreatic cancer. Cisplatin and alpha-interferon had the advantages of (1) radiosensitization properties and (2) biochemical synergy with 5-FU and each other [19–23]. The hope was that these three agents would form a ‘‘combination radiosensitizer’’ analogous to chemotherapy used in combination. These agents were combined into a dose-dense program together with radiation therapy in an attempt to maximize antitumor effect and minimize toxicity. Two 6-week courses of infusion 5-FU completed the adjuvant regimen (Box 1).
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Box 1. The initial Virginia Mason adjuvant chemoradiation regimen for pancreatic cancer Chemoradiotherapy XRT 50cGy in 2.0 cGy fractions (Monday through Friday, weeks 1 through 5) Cisplatin 30 mg/m2 on days 1, 8, 15, 22, and 29 during XRT Ifn-alpha 2b 3,000,000 U sq every other day on days 1 through 35 during XRT 5-FU 200 mg/m2 intravenous continuous infusion (IVCI) days 1 through 35 during XRT Post-XRT chemotherapy 5-FU 200 mg/m2 IVCI days 1 through 42 (weeks 10 through 15) 5-FU 200 mg/m2 IVCI days 1 through 42 (weeks 18 through 23)
A total of 53 patients were entered into this phase II trial between 1995 and 2002. From these 53 patients, 43 (representing those undergoing pancreaticoduodenectomy at Virginia Mason as opposed to distal pancreatectomy or operation elsewhere) were reported as a group in 2003 after an initial report of the first 17 such patients in 2000 [24,25]. These patients (approximate average age 65) had stage III or higher disease at operation 86% of the time (36 of 43 patients) using AJCC staging criteria; 84% (35 of 43 patients) had positive lymph nodes (average 3.2) by standard histological sectioning. Nineteen percent (8 of 43 patients) were histologially positive at surgical or specimen margins. Treatment details reveal 95% (41 of 43) of patients received full radiation dose. Ninety-three percent (40 of 43) of patients received greater than 85% of intended 5-FU dose during chemoradiation; 72% (31 of 43) received greater than 80% of intended cisplatin dose. Seventy percent (30 of 43) of patients received greater than 85% of intended chemoradiation dose during the postchemoradiation period. Toxicity during chemoradiation was moderate to severe. Seventy percent of patients (30 of 43) experienced CTC (common toxicity criteria) grade 3 or higher (90% grade 3) toxicity during treatment. Virtually all significant toxicity was of gastrointestinal origin (anorexia, nausea or vomiting, mucositis, diarrhea or hypovolemia). These complications necessitated a delay in treatment in the above patents. Hospitalization was required for toxicity in 42% (18 of 43) of patients owing to one or more of the following symptoms: nausea/vomiting/dehydration (n = 10), diarrhea (n = 9), mucositis (n = 2), gastrointestinal bleeding (n = 2), or bleeding due to
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Candida esophagitis (n = 1). There were no treatment fatalities; all patients returned to full functional status posttreatment. The survival status for these patients was reverified for the purpose of the current report as of the end of December 2003. With a median follow-up of 4 years (48 months), the 1-year, 2-year, and 5-year overall survival statistics are 90%, 58%, and 45%, respectively. Median survivorship of this group is 44 months. These survival data are compared with other major series (Table 3). Of interest is the pattern of recurrence seen in the Virginia Mason experience with respect to space and time. Typical local recurrence rates using standard chemoradiation (ie, radiation and 5-FU) are 30% to 60% [7,8]. However, the overall local recurrence rate in the authors’ experience was only 12% (5 of 43 patients); only two of 43 patients (5%) had only local recurrence of their cancer. With respect to time of recurrence, all recurrences except one took place within 2 years of surgery. This accounts for the relative similarity of the 2- and 5-year survival statistics in the Virginia Mason experience, again rather unique from the other experiences cited. To improve upon the aforementioned results, one would ideally wish to reduce therapeutic toxicity and recurrence rates, particularly with respect to systemic recurrence. With respect to therapeutic toxicity, various steps have been undertaken. First, nutrition and social services were involved as the vanguard of a large group of dedicated support staff (including nursing, radiation therapy, and psychological and pastoral services). This is designed to help support patients through the perioperative period to optimize their physical and psychological condition in anticipation of subsequent adjuvant therapy. Supportive care plans for chemoradiation are constructed even while the patient is still hospitalized following pancreaticoduodenectomy. Using this approach, virtually all patients at Virginia Mason are able to undergo some form of adjuvant therapy following curative resection for pancreatic cancer, usually within 8 weeks of pancreaticoduodenectomy. Second, patients are followed intensely during chemoradiation. Their attending physicians see patients at the beginning of each treatment week, with toxicities carefully monitored. Nursing staff also sees them almost daily. A supportive care pathway exists for virtually every symptom
Table 3 Comparison of adjuvant chemoradiation results, resected pancreas cancer Author
Median survival (mo)
2-y overall survival (%)
5-y overall survival (%)
GITSG 1987 [5] EORTC 1999 [7] Johns Hopkins 2000 [18] ESPAC 2004 [8] Virginia Mason 2004
21 17 21 16 44
43 37 39 29 58
19 16 19 10 45
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occurrence (eg, dehydration, nausea, and depression) with the emphasis on symptom prevention. Patients are instructed to stay close by the institution during chemoradiation, and family members are instructed carefully in symptom monitoring and supportive care measures. Third, the radiation and chemotherapy elements of the protocol have been modified slightly following our initial phase II trial in an attempt to reduce toxicity during chemoradiation. Remembering the low rate of local recurrence seen in the above patients, the daily radiation fraction was reduced slightly (from 200 to 180 cGy) while keeping the total 5040 radiation cGy dose the same. Perhaps more importantly, the size of the radiation field was reduced in an attempt to ease gastointestinal toxicity. The daily dose of 5-FU given by way of continuous infusion during radiation has been reduced for the same reason. The treatment modifications cited have all been incorporated into the American College of Surgeons Oncology Group (ACOSOG) trial (ACOSOG Z05031) that attempts to recapitulate the Virginia Mason experience in a multicenter, phase II trial in approximately 100 patients. Other centers, including M.D. Anderson (Houston, Texas) and Washington University (St. Louis, Missouri) have also launched their own phase II trials based on the Virginia Mason experience. A positive outcome from these trials could identify this therapeutic approach as a potential new standard for the care of resected pancreatic cancer.
Combined modality therapy for localized pancreatic cancer at Virginia Mason—future studies In considering additional therapy to surgery for the treatment of localized pancreatic cancer, four approaches suggest themselves beyond the standard 5-FU-based chemoradiation that has become the standard of care in the United States. These include (1) the use of neoadjuvant therapy (as has been tested at M.D. Anderson and Fox Chase), (2) the use of chemotherapy as a sole therapeutic modality (such as is being done in the ESPAC-3 trial), (3) alteration of chemoradiation (as described above), or (4) alteration of chemotherapy given pre- or postchemoradiation [26,27]. This final approach was the theme of the RTOG 9704 trial for adjuvant pancreatic cancer, in which the use of intravenous bolus gemcitabine was randomized against continuous infusion intravenous 5-FU pre-and postchemoradiation. The use of novel chemotherapy pre-and or postchemoradiation is also an ongoing interest at Virginia Mason, particularly given the proliferation of systemic agents believed effective in the treatment of pancreatic cancer and the enthusiasm for gemcitabine-based combination chemotherapy in advanced stage disease. The authors’ preference has been for the combination of gemcitabine and docetaxel, a combination with an approximate 30%
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response rate and acceptable toxicity [28]. This combination has the additional advantage of differing mechanisms of action and nonoverlapping toxicities from the three-drug combination used in conjunction with radiation. Preliminary investigation is underway exploring the use of these drugs postchemoradiation. Of even greater potential importance would be to extend the potential for curative therapy in pancreatic cancer to more than the 15% of patients with localized disease presently able to undergo curative resection. In particular, a major therapeutic goal would be to approach some fraction of the approximately 50% of patients with locally advanced, unresectable pancreatic cancer with a therapeutic design that is potentially curative. To this end, the authors have begun to experiment with neoadjuvant chemotherapy in patients with limited vascular involvement (ie, individuals with noncircumferential, nonocclusive vascular involvement) in attempt to downstage them to the point of operability, and then approach them as if they had presented de novo with more localized disease. Based on preliminary results, as many as one-half of patients treated in this fashion may be able to be approached with definitive local therapy. Summary Pancreatic cancer remains a disease of great frustration and difficulty for all cancer providers. Given its propensity for local and systemic recurrence, and given the limitations of current therapy, it is a disease in which no single therapeutic modality can produce success. A true team approach to the complex needs of the pancreatic cancer patient by physicians and support staff is needed for optimum success. Fortunately, the pancreaticobiliary surgeon is increasingly able to accurately define the anatomy of disease extent. This ability (by therapeutic exclusion), coupled with improved multimodality therapeutic and supportive care measures, offers the surgeon a greater degree of therapeutic appropriateness and effectiveness than ever before.
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