Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

15. Pancreas

Usama Mahmood • Edgar Ben-Josef • Christopher H. Crane

Pancreatic Cancer – Highlights

Key Studies and Guidelines

Yovino et al. (IJROBP 2011 and IJROBP 2012) showed that IMRT improved acute gastrointestinal toxicity in patients treated with concurrent chemoradiation while not associated with increased local recurrences with adjuvant IMRT. (PMID 20399035 and 22285684)

Normal Tissue Constraints

Spinal cord < 45 Gy.

70% of liver < 30 Gy.

Equivalent of 1 kidney < 20 Gy.

Limit small bowel/stomach receiving to 45–50 Gy.

Goodman et al. (IJROBP 2012) developed new RTOG consensus guidelines for stepwise contouring. (PMID 22483737)

New IMRT Treatment Options

FIGURE 15-5. Representative IMRT plan for unresectable pancreatic cancer, including axial radiation dose distributions.

(Left panel from Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012.)

1. INTRODUCTION

• Pancreatic adenocarcinoma remains one of the most deadly cancers, with nearly equal incidence and mortality rates. Surgical resection remains the only curative treatment for pancreatic cancer, although even patients who are able to undergo surgery have a poor prognosis. Adjuvant therapy (typically chemotherapy and radiation) modestly improves outcomes in this setting. Unresectable pancreatic cancer is typically treated with definitive chemotherapy and radiation. The utility of intensity-modulated radiation therapy (IMRT) for the treatment of pancreatic cancer is a subject of ongoing research, although given its ability to improve conformality while minimizing radiation dose to critical structures, it may play a role in improving the therapeutic index for treatment of pancreatic cancer in both the adjuvant and definitive settings. This chapter summarizes the anatomy, epidemiology, natural history, diagnosis/staging, prognosis, management, and role of IMRT in pancreatic cancer.

2. ANATOMY

• The pancreas lies in the retroperitoneal space of the upper abdomen, typically at the level of the first two lumbar vertebrae (Fig. 15-1).

• It lies in close vicinity to a number of critical organs, including the stomach, duodenum, jejunum, liver, kidneys, and spleen, as well as major blood vessels, including the celiac artery, superior mesenteric artery/vein (SMA/SMV), splenic artery/vein, portal vein, abdominal aorta, and inferior vena cava.

• The pancreas is divided into four parts—the head (including uncinate process), neck, body, and tail—based on its relation to nearby structures.

FIGURE 15-1. Anatomy of the pancreas and upper abdomen. The pancreas is conventionally divided into 5 sections based on its relationship to surrounding anatomic structures: the uncinate process, head, neck, body, and tail. (From Agur AMR, Dalley AF, eds. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009, with permission.)

3. EPIDEMIOLOGY

3.1. The U.S. Incidence/Mortality

• In the United States, pancreatic cancer is the ninth most common type of cancer but fourth most common cause of cancer-related deaths.1 Unfortunately, most people diagnosed with pancreatic cancer ultimately succumb to the disease. In 2010, about 43,140 patients were diagnosed with pancreatic cancer, while 36,800 patients died as a result of pancreatic cancer.

3.2. Risk Factors

• Risk factors for pancreatic cancer (with varying degrees of association) include increasing age, male gender, African American race, family history/genetic predisposition (especially among those with Ashkenazi Jewish heritage), tobacco use, obesity/physical inactivity, diet, environmental exposures, chronic pancreatitis, and diabetes mellitus.

4. NATURAL HISTORY

4.1. Histopathologic Differentiation

• The pancreas can give rise to various benign and malignant neoplasms.

• Exocrine pancreatic neoplasms include all tumors that are related to the pancreatic ductal and acinar cells (95% of pancreatic tumors), while endocrine pancreatic neoplasms arise in the endocrine tissues of the pancreas (5% of pancreatic tumors).

• The term “pancreatic cancer” typically refers to exocrine pancreatic adenocarcinomas arising from the ductal epithelium, which represent the vast majority (85%) of pancreatic tumors and is the primary subject of this chapter.

4.2. Patterns of Spread

• Cancer most commonly arises from the pancreatic head, where it typically causes obstruction of biliary drainage. Cancers of the pancreatic head, neck, or body may invade the duodenum, whereas tumors of the pancreatic tail may invade the spleen.

• Primary lymph node drainage includes the superior and inferior pancreaticoduodenal, porta hepatic, celiac, superior mesenteric, and pancreaticosplenic lymph nodes (particularly for tumors of the body/tail). The para-aortic lymph nodes may be involved with more advanced disease.

• The most common sites of distant metastasis include the liver, peritoneum, lungs, and bone.

• In total, approximately 10% have local disease, 30% have regional disease, and 60% have metastatic disease at initial presentation.1

5. DIAGNOSIS AND STAGING SYSTEM

5.1. Symptoms

• The median age of diagnosis in the United States is 72 years. No effective screening methods have as yet been identified.

• The most common symptoms associated with pancreatic cancer include pain (typically along the upper abdomen, the precise location of which relates to tumor location, and potentially radiating to the back), jaundice (including pruritus, acholic stools, and dark urine), and weight loss (with associated anorexia and early satiety). Moreover, patients may have symptoms due to gastric outlet obstruction, pancreatic exocrine insufficiency (resulting in steatorrhea), pancreatic endocrine insufficiency (resulting in new-onset diabetes), pancreatitis, or migratory thrombophlebitis (Trousseau sign). Also, patients may present with a variety of symptoms as a result of metastatic disease to distant organs.

• Clinical symptoms vary according to tumor location. Tumors in the head of the pancreas more often present with jaundice due to early obstruction of biliary flow, whereas tumors in the pancreatic body/tail more commonly present with pain and weight loss. Due to the nonspecific nature of the symptoms associated with tumors of the pancreatic body/tail, cancers in these locations more often present with locally advanced/metastatic disease. Differences between tumors of the pancreatic head and body/tail are summarized in Table 15-1.

5.2. Physical Examination

• The most common abnormal physical findings are secondary to jaundice, which result in abnormal skin color, scleral icterus, and possibly cutaneous excoriations due to pruritis. More rarely, patients may display subcutaneous areas of nodular fat necrosis (pancreatic panniculitis). On abdominal examination, pancreatic cancer may result in an abdominal mass, ascites, or a nontender but palpable gallbladder (Courvoisier sign). Also, one should carefully inspect the liver for signs of involvement, including hepatomegaly or nodularity. In more advanced cases, patients may exhibit signs of cachexia. Other signs of distant spread include left supraclavicular lymphadenopathy (Virchow node), axillary adenopathy (Irish node), periumbilical lymphadenopathy (Sister Mary Joseph node), or a palpable rectal shelf (Blumer shelf), all of which can also be seen as a result of other gastrointestinal malignancies.

5.3. Imaging

• The goal of imaging is to diagnose the tumor, determine the extent of disease spread, and identify patients who may be the candidates for curative surgical resection. Diagnostic evaluation via imaging should precede operative resection/exploration.

• Computed Tomography Scan: Contrast-enhanced, multiphase, multidetector helical computed tomography (CT) scanning with three-dimensional reconstruction of the upper abdomen is the preferred imaging modality for diagnosing/staging pancreatic cancer. Typical CT characteristics of pancreatic cancer include a hypoattenuating mass along with possible secondary signs, such as pancreatic/common bile duct dilation or pancreatic atrophy (Fig. 15-2). Comprehensive CT imaging of the pancreas includes both arterial and venous phase scans to allow assessment of vessel involvement. The lack of major vessel involvement on CT scans is associated with a resectability rate of >90%, whereas partial involvement of major vessels is associated with a 10% to 50% resectability rate.2 CT scans of the abdomen allow for assessment of the size, location, and invasion of the primary tumor as well as, to a lesser degree, regional lymph nodes, and also help to rule out metastasis to common intra-abdominal sites (the liver and peritoneum). CT scans of the chest and pelvis can be obtained to rule out more distant metastasis. Of note, CT of the abdomen is best performed prior to biopsy and biliary stent placement given the difficulty in visualizing pancreatic tumors in the setting of inflammation and metallic artifacts.

• Ultrasound: The initial study in patients who present with jaundice is often transcutaneous abdominal ultrasound. Signs of a pancreatic tumor include dilated bile ducts or the presence of a mass in the head of the pancreas. Endoscopic ultrasound (EUS), on the other hand, may complement CT scanning in terms of assessment of local/regional tumor invasion. It is particularly helpful for assessing local T- and N-staging and for predicting vascular invasion. Moreover, EUS-guided fine-needle aspiration is often the best modality for obtaining a tissue diagnosis, particularly if the tumor is poorly visualized by other imaging modalities. Both transcutaneous ultrasound and EUS are, however, subject to the expertise of the ultrasonographer.

FIGURE 15-2. Axial (A) and coronal (B) computed tomography images of pancreatic cancer. Note hypoattenuating mass in head of pancreas (arrow) with distal pancreatic ductal dilation. Biliary stent is in place.

• Endoscopic Retrograde Cholangiopancreatography: Endoscopic retrograde cholangiopancreatography (ERCP) was once widely used as a diagnostic tool in the past but has since been largely superseded by EUS. Moreover, ERCP is associated with a number of severe complications including pancreatitis, bleeding, and perforation. ERCP may, nonetheless, be indicated should there be equivocal findings on other studies or for therapeutic purposes, as it allows for stent placement in patients who present with cholangitis or who require relief of biliary obstruction.

• Magnetic Resonance Imaging/Magnetic Resonance Cholangiopancreatography: Although magnetic resonance imaging can also detect pancreatic cancer, for the most part, it offers no significant advantage over CT scans.3Magnetic resonance cholangiopancreatography, on the other hand, may be a useful adjunct to other imaging studies as it allows for better definition of the entire biliary tree and can also identify intrahepatic lesions. Unlike ERCP, it does not require contrast injection and, moreover, it allows for imaging the biliary tree in the setting of disruption/obstruction.

• Positron Emission Tomography: The utility of 18-fluorodeoxyglucose positron emission tomography (PET) in the staging evaluation of suspected pancreatic cancer remains unsettled. In particular, as demonstrated in a previous meta-analysis, it is unclear whether PET offers a benefit beyond that of whole body CT scanning.4 Of note, more recent studies have investigated the utility of integrated PET/CT, which appears more promising.5

• Radiographic Criteria for Resectability/Borderline Resectability: Assessment of resectability is most commonly made based on preoperative CT scans, although findings based on other imaging modalities or at the time of laparoscopy/laparotomy may also be of assistance. Tumors considered to be resectable include those with clear fat planes around the celiac axis, hepatic artery, and SMA, but without evidence of distance metastasis or SMV/portal vein abutment/distortion/thrombus/encasement.6 Although the definition of the “borderline resectable” varies, according to the National Comprehensive Cancer Network7the criteria for borderline resectable tumors of the head or body include severe unilateral/bilateral SMV/portal vein infringement, less than 180° tumor abutment on the SMA, reconstructible abutment/encasement of the hepatic artery, or short segment SMV occlusion if there is adequate vein above and below the site of tumor involvement to allow for resection and reconstruction, while borderline resectable tumors of the tail include those with less than 180° tumor abutment on the SMA/celiac artery.

5.4. Laboratory Studies

• Routine laboratory tests may reveal a rise in the serum bilirubin (and, with significant liver damage, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) or prothrombin time (PT)/partial thromboplastin time (PTT)), elevation in alkaline phosphatase activity (due to liver dysfunction or bone turnover from metastasis), mild-to-moderate hyperglycemia, anemia, or hypoalbuminemia.

• Several serum markers for pancreatic cancer have been evaluated, however the most clinically useful is carbohydrate antigen 19-9 (CA 19-9). Of note, the ability to produce CA 19-9 requires the expression of Lewis blood antigen and, therefore, this tumor marker is not useful among patients who are Lewis-antigen negative (approximately 10% of the population).8 The reported sensitivity and specificity of CA 19-9 for pancreatic cancer are 80% to 90%.9,10Given its limited specificity with frequent elevation due to benign pancreaticobiliary disorders, CA 19-9 is not recommended as a screening test.11 Nonetheless, the degree of elevation of CA 19-9 is associated with long-term prognosis and can be used as an early indicator of recurrent disease (in either the nonoperative or operative settings).1114 Moreover, it can predict the presence of occult metastatic disease among patients undergoing surgery.15

5.5. Biopsy

• Preoperative biopsy of a pancreatic mass can be performed either percutaneously (under CT or ultrasound guidance) or endoscopically (via EUS or ERCP). The former may not be possible if the lesion is not seen on CT and, moreover, is associated with severe, although rare, complications along with at least a theoretical concern of tumor dissemination along the needle path (however, studies suggest the actual risk of this is quite low).16 Whether the addition of molecular genetic analysis to cytologic examination can improve the sensitivity of biopsy is a subject of ongoing research.

• Although biopsy is generally felt to be indicated to confirm diagnosis in the setting of metastatic or unresectable/borderline resectable disease or those who are medically inoperable, the need for preoperative biopsy in a medically fit patient with a potentially resectable, suspicious pancreatic mass is controversial as a negative biopsy does not completely exclude the presence of malignancy. It should be recognized, however, that such an approach is associated with a small risk of radical resection in the setting of a benign lesion, although, of note, the benign process (pancreatitis) most commonly mistaken for pancreatic cancer on the basis of imaging is often suspected based on clinical history.

5.6. Laparoscopy/Cytology

• Although current imaging techniques are accurate in predicting unresectable disease, they are less accurate in predicting resectable disease, due to limited sensitivity to detect small-volume disease (specifically, hepatic or peritoneal lesions measuring less than 1 cm). Staging laparoscopy, with or without laparoscopic ultrasound, may potentially visualize such lesions and therefore reduce the risk of unnecessary laparotomy. Recent studies show that nearly a third of patients thought to be resectable on preoperative imaging will be found to have unresectable disease based on laparoscopic findings.17,18Nonetheless, the routine use of staging laparoscopy is not universally accepted, with some instead suggesting that it be used in those most likely to harbor occult metastatic disease (patients with tumors measuring >2 cm, tumors in the body/tail, equivocal findings for metastasis on CT, ascites, or subtle clinical or laboratory findings suggestive of metastatic disease).19

• Similarly, the importance of obtaining peritoneal cytology at the time of laparoscopy is a matter of debate. Although most patients with positive peritoneal washings have other findings of metastatic disease, whether positive peritoneal washings as an isolated finding adversely impacts prognosis has not been confirmed.20,21 Of note, the American Joint Committee on Cancer (AJCC) staging system designates positive peritoneal washings as M1 disease.22

5.7. Staging

• Tumors are staged according to the 7th edition of AJCC staging system for carcinoma of the pancreas.22 Tumors are generally classified as resectable (stage I, II), unresectable (stage III), or metastatic (stage IV). Recently, borderline resectable tumors have also been defined radiographically (see above).

• Of note, for patients undergoing surgery, it is prudent to repeat staging studies prior to embarking on potentially toxic adjuvant therapies.

6. PROGNOSTIC FACTORS

• Stage: T- and N-stages are significant predictors of outcome. Estimated 5-year and median survival according to the AJCC stage groupings is shown in Table 15-2.23

• Surgical Margins: Data suggest that, if taken to surgery, patients with positive resection margins do worse.24 Moreover, in patients with negative surgical margins, the width of the surgical margin may be prognostic, as well.25 It is important to examine not only the pancreatic resection margin but also the retroperitoneal margin as this is often positive, as well.

• Number of Negative Lymph Nodes: Similar to other gastrointestinal disease sites, an increasing number of pathologically examined but histologically negative lymph nodes is a predictor of improved outcome.26,27

• Tumor Grade: As might be expected, patients with higher grade have worse outcomes.28

• Tumor Markers: Elevated CA 19-9 levels in either the operative or nonoperative settings are associated with inferior outcomes.1214

7. GENERAL MANAGEMENT

7.1. Resectable

7.1.1. Surgery

• Surgical resection remains the only potentially curative treatment for pancreatic cancer, however, due to late presentation of the disease, only 15% to 20% of patients are candidates for curative surgery. Unfortunately, even in patients who are found to be candidates for surgical resection, the prognosis remains poor, with 5-year survival rates of 25% to 30% for those found to be node-negative and 10% for those found to be node-positive.

• The necessity of preoperative biliary drainage in patients who are jaundiced at presentation is a matter of debate. Although multiple prospective trials have been conducted, the results of such studies are conflicting, with one of the most recent and largest studies suggesting a trend toward increased complications with preoperative biliary drainage.29

• The standard operation for resectable pancreatic cancer of the head or uncinate process is a pancreaticoduodenectomy (Whipple procedure), which includes removal of the pancreatic head, duodenum, first 15 cm of jejunum, common bile duct, gallbladder, and the distal stomach along with pancreatic and biliary anastomoses (Fig. 15-3). The perioperative mortality associated with such surgery appear to have improved in more modern series (from 15% to <5%), likely due to the greater experience of the limited number of surgeons who perform this procedure in high-volume centers.30

FIGURE 15-3. Whipple procedure including six steps for pancreaticoduodenectomy (A) and four steps of reconstruction (B). (From DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology, 8th ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2008.)

• Modifications of the standard Whipple procedure have also been introduced. Some attempt to minimize morbidity by limiting the amount of resection, while others attempt to improve cancer outcomes by extending the amount of resection. An example of the former includes the increasingly performed pylorus-preserving Whipple procedure, although the precise benefit of this procedure on gastrointestinal function is unclear. Examples of the latter include total pancreatectomy, regional pancreatectomy, retroperitoneal lymphadenectomy, and vascular resection with or without reconstruction. None of these procedures have been demonstrated to improve survival and, moreover, many have been associated with increased morbidity and mortality.

• The standard operation for resectable pancreatic cancer of the body or tail typically includes a distal subtotal pancreatectomy, usually with splenectomy. Although the data for such tumors are scant, the limited experience that is available suggests that outcomes for these patients is poor.2,31,32

7.1.2. Adjuvant Therapy

• Surgical resection alone is associated with a high rate of both local and distant failure. Given the poor outcomes of patients undergoing surgical resection for pancreatic cancer, chemotherapy, with or without radiation therapy, is used after (or sometimes before) surgery in an effort to improve survival.7 The optimal choice of adjuvant treatment remains controversial. In general, the preferred approach in the United States includes adjuvant chemotherapy and radiation (our preference is initial gemcitabine-based chemotherapy, with 5-Fluorouracil-based chemoradiation reserved for those who remain free of metastatic disease). Adjuvant radiation alone has not been felt to be effective. Neoadjuvant chemoradiation, which offers the potential benefits of improved tolerability and the avoidance of surgery in patients who have occult metastatic disease that becomes evident during therapy, is a subject of ongoing research, but is otherwise generally reserved for those tumors that are unresectable/borderline resectable at initial presentation. Whenever possible, patients should be enrolled on prospective studies evaluating the benefit of adjuvant therapies. Below, we summarize key randomized, prospective, and retrospective studies evaluating adjuvant therapy. A summary of randomized trials exploring adjuvant therapy is provided in Table 15-3.

• Between 1974 and 1982, the GITSG performed a study evaluating observation versus 5-FU-based, split-course chemoradiation followed by maintenance 5-FU chemotherapy in patients with completely resected pancreatic cancer.33 A total of 43 eligible patients were enrolled before the study was closed early due to poor accrual. The authors noted a significantly improved median survival of 20 versus 11 months in favor of the chemoradiation arm.

• In an effort to reproduce the findings of the above GITSG study, the EORTC performed a study in which they randomized 207 eligible patients with resected periampullary/pancreatic cancer to observation versus 5-FU-based, split course chemoradiation (however, without maintenance chemotherapy).34 In 114 patients with pancreatic cancer, the authors noted a trend toward improved median survival of 17.1 versus 12.6 months in favor of the chemoradiation arm, although this difference did not reach statistical significance (P = 0.099).

• In another European trial conducted between 1994 and 2000, the ESPAC-1, 286 eligible patients with pancreatic cancer were randomized to one of four types of adjuvant therapy using a 2 × 2 factorial design: observation; 5-FU-based chemotherapy (six cycles); 5-FU-based, split-course chemoradiation; or 5-FU-based chemoradiation followed by chemotherapy.35 Although this study ultimately demonstrated a significant benefit to adjuvant chemotherapy and a significant detriment to adjuvant chemoradiation, the results of this study are difficult to interpret given concerns regarding trial design, most importantly the ability of enrolling physicians to employ “background treatment” despite randomization.

• Several retrospective series have demonstrated improved survival outcomes with use of adjuvant chemoradiation. The largest of these, a combined analysis of pooled data from Johns Hopkins Hospital and the Mayo Clinic from 1985 to 2005, included 1,092 patients who underwent surgical resection followed by either observation or 5-FU-based chemoradiation.36 The authors noted a significantly improved median survival of 21.1 versus 15.5 months in patients receiving adjuvant chemoradiation.

• Researchers from the Virginia Mason Medical Center performed a phase II study of 43 patients with resected pancreatic cancer who received adjuvant interferon-modulated 5-FU, cisplatin, and radiotherapy, followed by additional 5-FU alone and demonstrated an impressive 5-year survival of 55% (although at a mean follow-up of 32 months).37 This regimen, however, was associated with substantial toxicity. Nonetheless, a multicenter confirmatory trial was carried out by the ACOSOG, for which long-term follow-up is currently awaited.38

• RTOG 9704 was a phase III randomized trial comparing 5-FU versus gemcitabine chemotherapy before and after 5-FU-based chemoradiation, which enrolled a total of 451 eligible, postoperative patients with pancreatic cancer between 1998 and 2002. Although initial results demonstrated significantly improved survival in the gemcitabine arm, with further follow-up, this difference was no longer significant (20.5 vs. 17.1 months, P = 0.08).39

• The efficacy of adjuvant gemcitabine chemotherapy was supported by the European CONKO 001 trial, which enrolled 354 eligible patients with pancreatic cancer status, post surgery between 1998 and 2004 and randomized them to observation versus six cycles of gemcitabine chemotherapy. Initially, the authors demonstrated a significant disease-free survival benefit with adjuvant gemcitabine, however, with further follow-up, they noted a significant overall survival benefit, as well (22.8 vs. 20.2 months).40

• The ESPAC-3 trial, which enrolled 1,084 eligible postoperative patients with pancreatic cancer between 2000 and 2007, randomized patients to 6 months of 5-FU versus gemcitabine chemotherapy.41Although they failed to show a survival difference, 5-FU led to higher G3/4 stomatitis and diarrhea and, ultimately, more treatment-related hospitalizations.

• RTOG 0848 is a currently accruing, phase III randomized trial examining the benefit of the addition of erlotinib to adjuvant gemcitabine with or without 5-FU-based chemoradiation in patients with resected pancreatic cancer.

7.2. Borderline Resectable

• In patients found to have borderline resectable disease (as defined above), it is reasonable to consider upfront chemotherapy and/or radiation prior to restaging and surgical reevaluation, keeping in mind that surgical resection is a key component of curative treatment for pancreatic cancer.

• The available data utilizing neoadjuvant therapy in patients with borderline resectable disease consist of single-institution series. In the largest of such series, researchers from the MD Anderson Cancer Center reported 160 patients who were classified as having borderline resectable pancreatic cancer on the basis of tumor abutment of the visceral arteries, short segment occlusion of the SMV, findings suggestive but not diagnostic of metastatic disease, or marginal performance status.42 Of these, 125 were able to complete neoadjuvant therapy (chemoradiation in the majority). Ultimately, 66 patients were resected of which 62 patients had negative margins. The 5-year survival was 36% among this cohort.

7.3. Unresectable

• The optimal management of unresectable pancreatic cancer also remains unsettled. Options include chemotherapy with or without radiation treatment. Our preference is upfront chemotherapy followed by chemoradiation in those who remain free of metastatic disease. Although a rare occurrence, patients with frankly unresectable (i.e., not borderline resectable) disease that becomes resectable with initial treatment should be considered for surgical resection. Below, we summarize key randomized, prospective, and retrospective studies evaluating treatment of unresectable pancreatic cancer. A summary of randomized trials exploring treatment of unresectable pancreatic cancer is provided in Table 15-4.

• External beam radiation alone is considered inadequate treatment for unresectable pancreatic cancer given high local and distant failure rates with such treatment. Although not demonstrated in a later ECOG trial,43 the GITSG found improved survival with the addition of chemotherapy to radiation treatment in patients with unresectable pancreatic cancer.44 In this study, 194 eligible patients with unresectable pancreatic cancer were randomized to one of three treatment arms: high-dose radiation alone to 60 Gy, moderate-dose radiation to 40 Gy along with concurrent 5-FU chemotherapy, or high-dose radiation with the same chemotherapy. The radiation-alone arm was ultimately closed early given significantly worse survival compared to the chemoradiation arms (median survival 22.9 vs. 42.2 and 40.3 weeks in the moderate- and high-dose chemoradiation arms, respectively). A benefit to the addition of 5-FU chemotherapy was also demonstrated in an older trial from the Mayo Clinic.45

• A few trials have compared chemotherapy alone to combined chemoradiation, two of which demonstrated a survival benefit for combined modality treatment,46,47 and three of which showed no benefit.4850In the most recent of these studies, the ECOG randomized patients with unresectable pancreatic cancer to gemcitabine chemotherapy with or without radiation therapy.47 Although the study was terminated due to poor accrual after enrolling 71 eligible patients, the authors noted a significant survival benefit in favor of combined modality therapy (11.1 vs. 9.2 months).

• The above data refer to conventionally fractionated radiation treatment. Recently, investigators have studied the possibility of applying stereotactic body radiation therapy (SBRT) to unresectable pancreatic cancers; however, the benefit of such treatment remains uncertain as survival outcomes appear no better than conventionally fractionated radiation treatment and toxicity may, in fact, be worse. In a study from Stanford, for instance, 77 patients with unresectable pancreatic cancer were treated with single-fraction Cyber Knife-based SBRT to 25 Gy.51 Median survival was 6.7 months and a quarter of patients experienced grade 2 toxicity at 1 year.

7.4. Metastatic/Palliative

• Patients with metastatic disease at presentation are treated primarily with chemotherapy and/or supportive care. The current standard is either a gemcitabine or 5-FU-based regimen (including the recently validated FOLFIRINOX regimen).

• Appropriate selection of palliative treatment in the setting of pancreatic cancer depends on the site and symptoms to be palliated. Options include radiation therapy with or without chemotherapy, biliary stenting, gastrointestinal stenting, celiac plexus blocking, and surgical biliary or gastric bypass.

8. INTENSITY-MODULATED RADIATION THERAPY IN PANCREATIC CANCER

8.1. Simulation Technique

• CT simulation with immobilization is strongly recommended to optimize delivery of radiation to the regions of interest while respecting normal tissue dose constraints. Patients are simulated in the supine position, with their arms above their heads. Oral contrast assists with visualization of the bowel, whereas intravenous contrast assists with visualization of the vasculature. Four-dimensional CT or fluoroscopy is useful to evaluate target and normal tissue movement during respiration. Radiation delivery using respiratory gating or abdominal compression may be beneficial in these cases. In patients with suspected/known pancreatic cancer who are anticipating surgery, consideration should be given to preoperative simulation in the treatment position to assist with later target volume delineation. At a minimum, preoperative diagnostic imaging along with operative findings should be used for this purpose.

8.2. Target Volume/Doses

8.2.1. Resectable

• Lesions of the pancreatic head, the pancreaticoduodenal, suprapancreatic, celiac, porta hepatic, superior mesenteric and para-aortic lymph nodes, pancreatic remnant, surgical anastamoses, and the tumor bed with a 2 cm margin are typically treated to 45 Gy in 1.8 Gy/fraction. This is often followed by a 5.4 Gy in 1.8 Gy/fraction boost to the tumor bed with a 2 cm margin.

• Lesions of the pancreatic body/tail, the pancreaticoduodenal, suprapancreatic, celiac, superior mesenteric, para-aortic, splenic lymph nodes (the porta hepatic lymph nodes can be excluded), pancreatic remnant, surgical anastamoses, and the tumor bed with a 2 cm margin are similarly treated to 45 Gy in 1.8 Gy/fraction, followed by a 5.4 Gy in 1.8 Gy/fraction boost to the tumor bed with a 2 cm margin.

• A consensus committee from the RTOG developed a helpful, stepwise contouring approach based on identifiable regions of interest and margin expansions (which cover the postoperative bed and nodal regions at risk) that is also available via the RTOG website.52 An example of the stepwise contouring approach is depicted in Figure 15-4.

8.2.2. Unresectable

• Treatment planning for unresectable pancreatic cancer is made difficult by the sometimes bulky nature of the primary tumor compounded by the fact that patients are receiving concurrent chemotherapy (particularly, gemcitabine). A previous phase I study, for instance, attempted to escalate doses of concurrent IMRT (which included the regional lymph nodes) and gemcitabine for the treatment of unresectable pancreatic cancer, but was closed due to excessive toxicity.53 A subsequent study, on the other hand, was able to successfully escalate IMRT dose in the setting of concurrent full-dose gemcitabine, albeit without prophylactic coverage of the regional lymph nodes.54 In this setting, therefore, one may consider omission of draining lymph node coverage and instead treat the gross tumor with a smaller, 1 cm margin (after accounting for respiratory movement) to 54 to 59.4 Gy in 1.8 Gy/fraction (depending on normal tissue tolerance).

8.3. Normal Tissue Dose Constraints

• Limit spinal cord to <45 Gy.

• Limit 70% of liver to <30 Gy.

• Limit the equivalent of 1 kidney to <20 Gy. A renal scan should be considered to further adjust dose constraints to individual kidneys in order to minimize the risk of renal failure.

• Limit amount of small bowel/stomach receiving to 45–50 Gy.

8.4. Intensity-Modulated Radiation Therapy Results

• The utility of IMRT for the treatment of pancreatic cancer is a subject of ongoing research. Given its ability to improve conformality of the high-dose radiation to the target while minimizing delivery of radiation to nearby critical structures (Fig. 15-5), it may play a role in improving the therapeutic index for radiation treatment of pancreatic cancer.

• A number of dosimetric analysis have been performed that suggest that, as compared to three-dimensional conformal radiation therapy (3DCRT), IMRT results in reduced radiation doses to normal tissue structures and, in the setting of unresectable pancreatic cancer, can potentially allow for dose escalation.5557

• In the setting of resectable pancreatic cancer, IMRT may improve the side-effect profile of adjuvant radiation. Researchers from the University of Maryland compared acute toxicity rates from RTOG 9704 (on which patients were treated with concurrent chemotherapy and 3DCRT) and 46 patients with pancreatic/ampullary cancer treated at their institution with concurrent chemotherapy and IMRT.58 They found significantly lower rates of G3/4 nausea vomiting (0% vs. 11%) along with G3/4 diarrhea (3% vs. 18%) among their patients treated with IMRT.

FIGURE 15-4. Sample ROI//target volume delineation in postoperative setting shown in serial axial images (A) final clinical target volume (CTV) and planning target volume (PTV) shown in coronal (B) and sagittal planes (C). (From: Goodman KA, Regine WF, Dawson LA, et al. Radiation Therapy Oncology Group consensus panel guidelines for the delineation of the clinical target volume in the postoperative treatment of pancreatic head cancer. Int J Radiat Oncol Biol Phys 2012;83(3):901–908, with permission.)

• In the setting of unresectable pancreatic cancer, IMRT may provide the ability to escalate radiation doses and, thereby, improve outcomes. Clinically, the ability to escalate radiation dose using IMRT was demonstrated by researchers from the University of Michigan.54 These researchers accrued 50 patients with unresectable pancreatic cancer who were treated with full systemic doses of gemcitabine along with escalating doses of IMRT (50–60 Gy in 25 fractions to the gross tumor volume (GTV) plus 1 cm margin only). The majority of patients were treated with active breathing control to reduce/eliminate breathing motion. At the recommended dose of 55 Gy, the probability of dose limiting toxicity (DLT) (gastrointestinal toxicity G ≥3, neutropenic fever, or deterioration in performance status (PS) to ≥3 developing during IMRT or in the 13 weeks following completion of IMRT) was 24%. The median and 2-year overall survival were 14.8 months (95% CI: 12.6–22.2) and 30% (95% CI: 17–45). The 2-year freedom from local progression (FFLP) was 59% (95% CI: 32–79). These results were statistically significantly better than the University of Michigan’s historic controls treated to 36 Gy in 15 fractions, the maximum feasible with 3D techniques. Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Intriguingly, five of these patients (42%) had a major pathological response (two complete responses (CR) and three near-CR). Thus, these results show that high-dose radiotherapy (with concurrent full-dose gemcitabine) can be delivered safely when IMRT and breath-hold techniques are utilized and that this therapy yields encouraging outcomes.

9. CONCLUSION

• In conclusion, pancreatic adenocarcinoma unfortunately remains one of the deadliest cancers. Surgery with adjuvant chemotherapy/radiation remains the standard for resectable patients, whereas unresectable patients are typically treated with definitive chemotherapy and radiation. IMRT may play a role in both the adjuvant and definitive settings, where it may help to reduce radiation doses to normal tissues and/or allow for dose escalation. Further studies are, nonetheless, needed to confirm its efficacy and potential benefits.

FIGURE 15-5. Representative IMRT plan for unresectable pancreatic cancer, including beam arrangement (A), axial (B) and coronal (C) radiation dose distributions, and associated dose–volume histogram (D).

REFERENCES

1. Jemal A, Siegel R, Xu JQ, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60(5):277–300.

2. Saldinger PF, Reilly M, Reynolds K, et al. Is CT angiography sufficient for prediction of resectability of periampullary neoplasms. J Gastrointest Surg 2000;4(3):233–237.

3. Steiner E, Stark DD, Hahn PF, et al. Imaging of pancreatic neoplasms – comparison of MR and CT. Am J Roentgenol 1989;152(3):487–491.

4. Sendler A, Avril N, Helmberger H, et al. Preoperative evaluation of pancreatic masses with positron emission tomography using F-18-fluorodeoxyglucose: diagnostic limitations. World J Surg 2000;24(9):1121–1129.

5. Heinrich S, Goerres GW, Schafer M, et al. Positron emission tomography/computed tomography influences on the management of resectable pancreatic cancer and its cost-effectiveness. Ann Surg 2005;242(2):235–243.

6. Callery MP, Chang KJ, Fishman EK, Talamonti MS, Traverso LW, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 2009;16(7):1727–1733.

7. National Comprehensive Cancer Network. Guidelines. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 3/13/12.

8. Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res 1987;47(20):5501–5503.

9. Pleskow DK, Berger HJ, Gyves J, Allen E, McLean A, Podolsky DK. Evaluation of a serologic marker, CA19-9, in the diagnosis of pancreatic cancer. Ann Intern Med 1989;110(9):704–709.

10. Cwik G, Wallner G, Skoczylas T, Ciechanski A, Zinkiewicz K. Cancer antigens 19-9 and 125 in the differential diagnosis of pancreatic mass lesions. Arch Surg 2006;141(10): 968–973.

11. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006;24(33):5313–5327.

12. Berger AC, Garcia M, Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol 2008;26(36):5918–5922.

13. Koom WS, Seong J, Kim YB, Pyun HO, Song SY. CA 19-9 as a predictor for response and survival in advanced pancreatic cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys 2009;73(4):1148–1154.

14. Kinsella TJ, Seo Y, Willis J, et al. The impact of resection margin status and postoperative CA19-9 levels on survival and patterns of recurrence after postoperative high-dose radiotherapy with 5-FU-based concurrent chemotherapy for resectable pancreatic cancer. Am J Clin Oncol 2008;31(5):446–453.

15. Maithel SK, Maloney S, Winston C, et al. Preoperative CA 19-9 and the yield of staging laparoscopy in patients with radiographically resectable pancreatic adenocarcinoma. Ann Surg Oncol 2008;15(12):3512–3520.

16. Johnson DE, Pendurthi TK, Balshem AM, et al. Implications of fine-needle aspiration in patients with resectable pancreatic cancer. Am Surg 1997;63(8):675–679; discussion 679–680.

17. Mayo SC, Austin DF, Sheppard BC, Mori M, Shipley DK, Billingsley KG. Evolving preoperative evaluation of patients with pancreatic cancer: does laparoscopy have a role in the current era? J Am Coll Surg 2009;208(1):87–95.

18. Liu RC, Traverso LW. Diagnostic laparoscopy improves staging of pancreatic cancer deemed locally unresectable by computed tomography. Surg Endosc 2005;19(5):638–642.

19. Pisters PWT, Lee JE, Vauthey JN, Charnsangavej C, Evans DB. Laparoscopy in the staging of pancreatic cancer. Br J Surg 2001;88(3):325–337.

20. Yamada S, Takeda S, Fujii T, et al. Clinical implications of peritoneal cytology in potentially resectable pancreatic cancer – Positive peritoneal cytology may not confer an adverse prognosis. Ann Surg 2007;246(2):254–258.

21. Meszoely IM, Lee JS, Watson JC, Meyers M, Wang H, Hoffman JP. Peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreas. Am Surg 2004;70(3):208–213.

22. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual, 7th ed. New York, NY: Springer Verlag, 2010.

23. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC pancreatic cancer staging system – report from the National Cancer Database. Cancer 2007;110(4):738–744.

24. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas – 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4(6):567–579.

25. Chang DK, Johns AL, Merrett ND, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol 2009;27(17):2855–2862.

26. Ferrone CR, Kattan MW, Tomlinson JS, Thayer SP, Brennan MF, Warshaw AL. Validation of a postresection pancreatic adenocarcinoma nomogram for disease-specific survival. J Clin Oncol 2005;23(30):7529–7535.

27. Tomlinson JS, Jain S, Bentrem DJ, et al. Accuracy of staging node-negative pancreas cancer – a potential quality measure. Arch Surg 2007;142(8):767–773.

28. Helm J, Centeno BA, Coppola D, et al. Histologic characteristics enhance predictive value of American joint committee on cancer staging in resectable pancreas cancer. Cancer 2009;115(18):4080–4089.

29. van der Gaag NA, Rauws EAJ, van Eijck CHJ, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010;362(2):129–137.

30. Gooiker GA, van Gijn W, Wouters M, et al. Systematic review and meta-analysis of the volume-outcome relationship in pancreatic surgery. Br J Surg 2011;98(4):485–494.

31. Johnson CD, Schwall G, Flechtenmacher J, Trede M. Resection for adenocarcinoma of the body and tail of the pancreas. Br J Surg 1993;80(9):1177–1179.

32. Dalton RR, Sarr MG, Vanheerden JA, Colby TV. Carcinoma of the body and tail of the pancreas – is curative resection justified. Surgery 1992;111(5):489–494.

33. Kalser MH, Ellenberg SS. Pancreatic-cancer – adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120(8):899–903.

34. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region – phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999;230(6):776–782.

35. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350(12):1200–1210.

36. Hsu CC, Herman JM, Corsini MM, et al. Adjuvant chemoradiation for pancreatic adenocarcinoma: The Johns Hopkins Hospital-Mayo Clinic Collaborative Study. Ann Surg Oncol 2010;17(4):981–990.

37. Picozzi VJ, Kozarek RA, Traverso LW. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2003;185(5):476–480.

38. Picozzi VJ, Abrams RA, Decker PA, et al. Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031. Ann Oncol 2011; 22(2):348–354.

39. Regine WF, Winter KA, Abrams R, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US intergroup/RTOG 9704 phase III trial. Ann Surg Oncol 2011;18(5):1319–1326.

40. Riess H, Neuhaus P, Post S, et al. CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC). Ann Oncol 2008;19:45–46.

41. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection a randomized controlled trial. JAMA 2010;304(10):1073–1081.

42. Katz MHG, Pisters PWT, Evans DB, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg 2008;206(5):833–848.

43. Cohen SJ, Dobelbower R, Lipsitz S, et al. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: eastern cooperative oncology group study E8282. Int J Radiat Oncol Biol Phys 2005;62(5):1345–1350.

44. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic-carcinoma – a randomized comparison of high-dose (6000 Rads) radiation alone, moderate dose radiation (4000 Rads + 5-fluorouracil), and high-dose radiation +5-fluorouracil. Cancer1981;48(8):1705–1710.

45. Moertel CG, Childs DS, Reitemei.Rj, Colby MY, Holbrook MA. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1969;2(7626):865–867.

46. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Nat Cancer Inst 1988;80(10): 751–755.

47. Loehrer PJ Sr., Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29(31):4105–4112.

48. Klaassen DJ, Macintyre JM, Catton GE, Engstrom PF, Moertel CG. Treatment of locally unresectable cancer of the stomach and pancreas – a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil – An Eastern-Cooperative-Oncology-Group Study. J Clin Oncol 1985;3(3):373–378.

49. Hazel JJ, Thirlwell MP, Huggins M, Maksymiuk A, Macfarlane JK. Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas as a prospective randomized trial. J Can Assoc Radiol 1981;32(3):164–165.

50. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 2008;19(9): 1592–1599.

51. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2008;72(3):678–686.

52. Goodman KA, Regine WF, Dawson LA, et al. Radiation Therapy Oncology Group consensus panel guidelines for the delineation of the clinical target volume in the postoperative treatment of pancreatic head cancer. Int J Radiat Oncol Biol Phys 2012;83(3):901–908. The guidelines are also available for download at the RTOG website at: http://www.rtog.org/CoreLab/ContouringAtlases/PancreasAtlas.aspx

53. Crane CH, Antolak JA, Rosen II, et al. Phase I study of concomitant gemcitabine and IMRT for patients with unresectable adenocarcinoma of the pancreatic head. Int J Gastrointest Cancer 2001;30(3):123–132.

54. Ben-Josef E, Schipper M, Francis I, et al. Phase I/II radiation dose-escalation trial of intensity modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2011;81(2):S127–S128.

55. Brown MW, Ning H, Arora B, et al. A dosimetric analysis of dose escalation using two intensity-modulated radiation therapy techniques in locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys 2006;65(1):274–283.

56. Milano MT, Chmura SJ, Garofalo MC, et al. Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys 2004;59(2):445–453.

57. Spalding AC, Jee K-W, Vineberg K, et al. Potential for dose-escalation and reduction of risk in pancreatic cancer using IMRT optimization with lexicographic ordering and gEUD-based cost functions. Med Phys 2007;34(2):521–529.

58. Yovino S, Poppe M, Jabbour S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys 2011;79(1):158–162.

59. Yovino S, Maidment BW 3rd, Herman JM, et al. Analysis of local control in patients receiving IMRT for resected pancreatic cancers. Int J Radiat Oncol Biol Phys 2012;83(3):916–920.