Background

The treatment of cancer patients has become complex as a result of the introduction of new therapies and insights into how to use these therapies. Quite often the true benefit of new therapies is unknown in relation to the current standard of care. Moreover, the one-size-fits-all approach is being replaced by personalized treatments based on not only molecular markers but also performance status. In addition to these factors, the treatment of most gastrointestinal cancers involves fighting battles on two fronts—the systemic battle and the local battle. The integration of systemic treatments with localized treatments such as surgery and radiotherapy requires an integrated team approach. As a result of these factors, we feel the optimal management of cancer in the modern era is through a multidisciplinary team (MDT) approach that involves at the very least medical oncology, radiation oncology, surgery, pathology/cytopathology, diagnostic imaging, pain management, and social services. This chapter is a presentation of the benefit of a multidisciplinary approach as it applies to the focus of our group—pancreatic cancer. It should be noted, however, that the concepts of this chapter apply to all gastrointestinal cancers.

Pancreatic cancer is the third leading cause of cancer-related deaths despite having the eleventh most common incidence of all malignancies in the United States. It is estimated that in the year 2016 approximately 53,070 patients in the United States were diagnosed with pancreatic cancer and that 41,780 were died from the disease.¹ The median age of diagnosis in the United States is 72 years, and over 66% of patients are diagnosed after the age of 65.² There is a slight predominance in African Americans and Caucasians as opposed to Hispanics and Asians.³

Presentation

Most patients with pancreatic adenocarcinoma present late in the course of disease, as early pancreatic cancer is often silent.⁴ Patients commonly present with signs and symptoms of biliary obstruction including jaundice, pruritus, light- or clay-colored stools, dark urine, and scleral icterus. Occasionally, pancreatitis and cholangitis may be the presenting symptoms of this malignancy.⁵ It should be recognized that these signs and symptoms are common for cancer of the head of the pancreas and that pancreatic body/tail lesions are often more advanced at presentation. Involvement of the celiac nerve plexus may result in epigastric abdominal pain, classically presenting as a dull pain that radiates to the mid-back. Early bowel or stomach obstruction may result in early satiety, nausea, vomiting, and/or dyspepsia. Some patients with pancreatic cancer present with diabetes mellitus, and diabetes can be present for several years before a diagnosis is established. Migratory thrombophlebitis is an uncommon, but well-recognized, presenting sign in this malignancy.⁶

Cross-sectional imaging can be used to characterize pancreatic masses and a tissue diagnosis can often be obtained through endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). In general, pancreatic adenocarcinomas tend to be hypoattenuating on venous-phase CT, while the next most common pancreatic neoplasm, the neuroendocrine tumor, tends to enhance on arterial phase. However, it should be noted that variations of the common features also exist and benign conditions such as autoimmune pancreatic and chronic pancreatic may mimic pancreatic adenocarcinoma. It should also be noted that pancreatic adenocarcinoma can arise in association with cystic neoplasms such as intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplams (MCN). While a full discussion of these variations is beyond the scope of this chapter, it should be known that many of these lesions can present in a similar fashion to classic pancreatic adenocarcinoma. Pancreatic neuroendocrine tumor may have systemic symptoms based on whether or not the tumor is hormone producing, as in the case of an insulinoma.⁷ The discussion of appropriate treatment options in the multidisciplinary setting of a newly diagnosed pancreatic mass should recognize these alternative diagnoses.

Natural History

Analysis of the patterns of failure following the treatment of pancreatic cancer suggests that control of both local and distant diseases is necessary, even for patients considered to have early-stage surgically resectable disease. Owing to the retroperitoneal location of the pancreas, the proximity of the pancreas to the stomach, small bowel (particularly the adjacent duodenum), spleen, and abdominal vasculature, pancreatic cancers often invade these tissues and produce pain, bleeding, nausea, vomiting, and gastrointestinal obstruction.⁸ Regional lymph node metastases are also common, most often to the pancreaticoduodenal, porta hepatis, celiac axis, superior mesenteric, and paraaortic nodes. At diagnosis, more than 80% of patients will have disease that extends into adjacent organs, regional lymph nodes, or other soft tissue.⁸

Approximately 50% of patients will have metastatic disease at the time of diagnosis.^9,10 The most common recognized site of distant metastatic disease is the liver, followed by the lung, peritoneal cavity, and other distant sites.⁵ The majority of patients who present with localized disease and undergo surgery also eventually recur both locally and at distant sites.¹¹ The subsequent discussion will introduce the modalities of treatment and their implementation at different stages of the disease.

Several risk factors have been established for the development of pancreatic cancer. They include age, cigarette smoking, chronic pancreatitis, diabetes mellitus, and genetic predisposition. Of these, cigarette smoking remains the only modifiable risk factor.⁵

The median survival for early-stage disease is 20 to 24 months, with a 5-year survival of only 15% to 20%.^9,10 Patients with locally advanced disease have a median survival of 9 to 15 months, while patients with metastatic disease live a median survival of 4 to 6 months.^9,10

Molecular Biology

The exomes of pancreatic cancer and of all of the most common types of tumors of the pancreas have been completely sequenced, providing unprecedented insight into the somatic mutations in these neoplasms.¹² The sequencing of infiltrating ductal adenocarcinomas of the pancreas revealed that four genes, KRAS, p16/CDKN2A, TP53, and SMAD4, are each somatically altered in >50% of the cancers. KRAS, an oncogene on chromosome 12, is activated by point mutation in 95% of ductal adenocarcinomas. The protein coded for by the KRAS gene is a small GTPase that plays an important role in cell signaling through the mitogen-activated protein kinase (MAPK) and other pathways. The point mutations in KRAS occur early in pancreatic neoplasia, and almost exclusively target three codons (codons 12, 13, and 61), making KRAS mutations relatively easy to identify and suggesting that KRAS mutations could form the basis for gene-based tests to detect early curable pancreatic neoplasia.¹³

The p16/CDKN2A gene, a tumor suppressor gene on chromosome 9p, is inactivated in approximately 95% of pancreatic cancers.¹⁴ The protein product of the p16/CDKN2A gene, p16, plays an important role in the regulation of the cell cycle and loss of p16 function in pancreatic cancer is believed to promote unrestricted cell growth. The TP53 tumor suppressor gene on chromosome 17p is inactivated in 75% of pancreatic cancers.¹⁴ TP53 codes for the p53 protein, and p53 plays an important role in cellular stress responses, particularly by activating DNA repair, inducing growth arrest, and triggering cell death (apoptosis). Loss of p53 function, through mutation of the TP53 gene, therefore promotes pancreatic neoplasia through the loss of a number of critical cell functions. The fourth major gene that is somatically targeted in pancreatic cancer is the SMAD4 (previously designated DPC4) tumor suppressor gene on chromosome 18q.¹⁵ The protein product of the SMAD4 gene, Smad4, functions in the transforming growth factor beta (TGFβ) cell signaling pathway. SMAD4 gene mutations in pancreatic cancer are associated with poor prognosis and with more widely metastatic disease.¹⁶

Pathology

The most common solid neoplasm of the pancreas is the invasive ductal adenocarcinoma, more commonly called “pancreatic cancer.” The neoplastic cells of invasive ductal adenocarcinoma form glands and infiltrate into tissues.¹⁷ Grossly, these cancers are usually solid and firm, and send tongues of neoplastic cells far beyond the main tumor. Microscopically, most invasive ductal adenocarcinomas invade nerves and spread along perineural spaces. These cancers also have a proclivity to invade lymphatic spaces and small veins, and in so doing spread to regional lymph nodes and metastasize to the liver. As a result, by the time most invasive ductal adenocarcinomas are diagnosed, they have spread beyond the gland and are not amenable to surgical resection.

Another important histologic feature of invasive ductal adenocarcinomas of the pancreas is that these cancers elicit an intense desmoplastic reaction.^17–19 This desmoplastic reaction is composed of fibroblasts, inflammatory cells, small blood vessels, and a complex extracellular matrix, and is associated with significantly increased interstitial fluid pressure within the tumor. This elevated interstitial fluid pressure has been hypothesized to be an impediment to perfusion of the tumor, explaining the low attenuation seen on contrast-enhanced imaging, and the elevated pressure may serve as an obstacle to the diffusion of therapeutic agents.¹⁸

Staging

The American Joint Committee on Cancer (AJCC) has been the historical standard for staging of pancreatic cancer. The seventh edition of the TNM (Tumor-Node-Metastasis) staging from the AJCC is provided in Table 140-1.²⁰

Although the AJCC system is useful in stratifying patients by outcome, the management of patients revolves around classifying them as localized and resectable, localized and unresectable, and metastatic. This is best determined with a high-quality contrast-enhanced CT scan. A number of institutional panels including the MD Anderson Cancer Center (MDACC) and National Comprehensive Cancer Network (NCCN) have proposed a staging system to stratify patients based on whether they are surgically resectable, borderline resectable, unresectable, or metastatic.²¹ More recently, a consensus guideline modified on the basis of the MD Anderson staging criteria was recommended by a joint committee of American Hepato-Pancreato-Biliary Association (AHPBA), Society of Surgical Oncology (SSO), and the Society for the Surgery of the Alimentary Tract (SSAT) (Table 140-2).²² This AHPBA/SSO/SSAT staging system is routinely used in the Johns Hopkins Pancreas Multidisciplinary Cancer Clinic (PMDC).

The resectability of a pancreatic tumor depends on the presence or absence of metastatic disease, and on the degree of involvement of major vessels. The assessment of vascular involvement is made separately for the arterial axes and the portovenous system. With regards to the latter, any degree of involvement of the portal vein or superior mesenteric vein is considered resectable as long as the vessel can technically be reconstructed following en bloc resection. In contrast, involvement of the major arteries is most often made based on the degree of encasement identified on the axial plane of cross-sectional imaging. The arteries of importance include the superior mesenteric, celiac, and hepatic arteries.^9,21,23–25 Greater than 180-degree encasement of any of these vessels is considered locally advanced and unresectable.²¹ Rare exceptions are made in which short-segment encasement of the hepatic artery is resected en bloc and reconstructed. Less than 180 degree of involvement is considered borderline resectable and is associated with an increased likelihood of a margin-positive resection, higher local recurrence, and decreased survival.²¹ These patients are most often offered preoperative chemoradiotherapy prior to resection.

The discussion of treatment options in this chapter will utilize the AHPBA/SSO/SSAT staging system as opposed to the AJCC TNM system.

Diagnosis and Evaluation

A patient with suspected pancreatic adenocarcinoma should undergo a pancreas protocol CT scan (intravenous contrast, 2-mm cuts through the pancreas) and a chest CT.²¹ A pancreas protocol MRI is acceptable if patients are unable to take intravenous contrast necessary for CT. A pancreas protocol CT is a multiphase contrast-enhanced set of images including a noncontrast CT scan along with arterial, pancreatic parenchymal, and portal-venous phase contrast enhancement. The contrast enhancement between the pancreatic parenchyma and the tumor is greatest during the late arterial phase. As surgical decisions regarding resectability are a direct result of the tumor–vasculature relationship identified on imaging, three-dimensional (3D) rendering postprocess may help make this assessment. An MRI may be particularly helpful in identifying extrapancreatic disease, particularly in helping to identify small hepatic and/or peritoneal metastases.²¹ The use of positron emission tomography (PET) scans is an area of ongoing research, but retrospective data demonstrate increased sensitivity of identifying metastatic disease than with CT alone.²⁶ Further, recent data support the use of PET scan to help better characterize the extent of soft tissue extension of a pancreatic tumor prior to radiation treatment planning.²⁷

While a biopsy is not required prior to surgical resection, pathologic confirmation of malignancy is necessary prior to the initiation of neoadjuvant or definitive chemotherapy or radiation therapy.²¹ The best option to establish a tissue diagnosis of the primary lesion is FNAs obtained by an EUS. Alternatively, FNA can be performed under CT guidance and this is the preferred route for obtaining tissue of possible hepatic metastases.

If a patient has biliary obstruction in which surgery is either delayed or not favored, biliary decompression may be performed during an endoscopic retrograde cholangiopancreatography (ERCP).²¹ This procedure combines endoscopic and fluoroscopic imaging and allows for palliation with stent placement. The choice of metal versus plastic stents also remains a relatively controversial issue. Many NCCN member institutions prefer plastic stents in the purely palliative setting, that is, patients with a life span less than 3 months, while a metal stent is preferred if patients are receiving neoadjuvant or definitive chemoradiation.²¹ An ongoing prospective clinical trial seeks to better compare the choice of stent in the setting of preoperative pancreatic cancer (ClinicalTrials.gov, NCT01191814).

While many tumor-associated antigens have been studied for their diagnostic value in pancreatic cancer, none has shown as strong of a correlation with this disease as has carbohydrate antigen19-9 (CA 19-9).²¹ This is a sialylated Lewis A blood group antigen commonly associated with pancreatic and hepatobiliary disease and tumors. However, it must be noted that CA 19-9 is neither a sensitive nor a specific marker for pancreatic cancer. Elevation of CA 19-9 may occur in cases of biliary obstruction (either benign or malignant). Therefore, the best assessment of this antigen should be made following biliary decompression and bilirubin normalization.²¹ While CA 19-9 has not been shown to be a definitive predictor of tumor response to chemotherapy, levels of this antigen following surgical resection correlate with survival. Data from a prospective clinical trial, RTOG 9704, indicated that a CA 19-9 level of >180 U/mL postoperatively is associated with a significantly worse survival than levels below this value (HR = 3.53, p < 0.0001).²⁸ The NCCN panel recommends the use of CA 19-9 in the preoperative setting with a normalized bilirubin, postoperative setting to address patient prognosis, and during follow-up for surveillance monitoring.²¹

Surgically resected pancreatic tumors are best evaluated by pathologists with extensive experience with tumors of the pancreas.²¹ This evaluation includes establishing the tumor type, histologic grade, primary tumor size (in centimeters), regional nodal involvement, and metastatic disease. Further, the extent of tumor extension into vessels, the margin status, and perineural invasion within the tumor should all be documented. Of note, the presence of pancreatic intraepithelial neoplasia, a precursor lesion to invasive pancreatic cancer, at a margin does not portend a worse prognosis in patients with an invasive pancreatic cancer.²⁹

A multidisciplinary evaluation is the preferred method to properly stage a patient prior to initiation of therapy.²¹ This ensures an objective patient assessment and improves communication among disciplines. In up to 30% of cases, a single-day multidisciplinary clinic involving multiple treatment providers and ancillary staff at a high volume institution can result in a change in diagnosis and/or management.³⁰ Ideally, patients with nonmetastatic pancreatic cancer should undergo a multidisciplinary assessment with specialists in radiation oncology, medical oncology, surgical oncology, pain, and pathology. Given the huge burden this diagnosis presents to the entire family, social work can be helpful. When indicated, nutrition should also be consulted.

Resectable Pancreatic Cancer

Surgery is the mainstay of treatment for resectable pancreatic cancer. At the Johns Hopkins PMDC, up-front surgery is routinely recommended to all resectable patients unless the patient is interested in participating in neoadjuvant therapy clinical trials or is not medically fit for surgery. The role of the MDT approach in the management of resectable pancreatic cancer is particularly important. More accurate radiographic diagnosis is one strategy to identify patients who have locally advanced or micrometastatic disease, as these patients would not benefit from aggressive up-front surgery. Resectable disease with a very high CA 19-9 level without biliary obstruction can be suggestive of systemic micrometastases, thus these patients may benefit from up-front systemic therapy prior to local therapy (radiation or surgery).

It is still controversial whether initially resectable patients would benefit from neoadjuvant (preoperative) therapy. Theoretical advantages of neoadjuvant therapies include reduction in toxicity, increase in efficacy, addressing systemic disease recurrence risk initially, and optimal patient selection for pancreatectomy through exclusion of patients with rapidly progressive metastatic disease. Currently, prospective and retrospective studies suggest that both up-front surgery and neoadjuvant therapy are associated with similar overall long-term survival (Table 140-3). Nonetheless, the subset of patients who underwent curative surgery after neoadjuvant therapy had a much longer survival (if they did not progress prior to surgery) compared with those who had up-front surgical resection. However, it is not known if this subpopulation of patients truly benefits from neoadjuvant therapy or if neoadjuvant chemotherapy merely selects those patients with more favorable tumor biology. A randomized study comparing immediate surgery versus neoadjuvant therapy is needed to validate the role of neoadjuvant therapy in patients with resectable tumors. Neoadjuvant therapy for resectable patients should be administrated in the setting of clinical trials. An ongoing multicenter phase III study comparing resectable pancreatic cancer randomized to adjuvant gemcitabine or neoadjuvant gemcitabine/oxaliplatin followed by adjuvant gemcitabine (NEOPAC) may for the first time help determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer.

Postoperative (adjuvant) therapy is considered to be the standard of care for resected pancreatic cancer. The role and timing of radiation, as well as the ideal chemotherapy regimen, continue to be topics of debate in the literature.^36,37 At the Johns Hopkins PMDC, a combination of chemotherapy and radiation is favored in the adjuvant setting. However, the sequence of chemotherapy and radiation therapy is individualized. Patients with a close or positive resection margin (R1 resection) are treated with chemoradiation therapy (CRT) first, followed by further adjuvant chemotherapy. Patients with node-positive disease (regional lymph node metastasis) are treated with 4 to 6 months of systemic chemotherapy first, followed by CRT if there is no evidence of disease at the completion of chemotherapy. Individuals with T1/T2 tumors and N0 resections are usually given 6 months of chemotherapy alone, though some patients also elect to receive adjuvant radiation therapy. At Johns Hopkins PMDC, these patients are often treated with two cycles of gemcitabine-based chemotherapy, followed by chemoradiation, and concluded by another two cycles of gemcitabine-based chemotherapy. If patients chose not to have radiation therapy, we recommend 6 months of systemic chemotherapy. While a large amount of data exists regarding adjuvant therapy, a consensus has not yet been reached regarding exact treatment recommendations. A multidisciplinary assessment with radiation and medical oncologists following surgery allows patients and families to discuss the benefits and drawbacks of including radiation therapy in this context.

SURGICAL PRINCIPLES

Approximately 20% of patients with pancreas cancer are candidates for a potentially curative resection. The majority of resectable tumors are located in the head, neck, and uncinate process of the pancreas and are resected by a pancreaticoduodenectomy (Whipple operation). Patients with resectable tumors in the body or tail of the pancreas will undergo distal pancreatectomy and splenectomy.³⁸

The goal of a potentially curative operation is to achieve a margin free of cancer (R0) in the least physiologically disruptive manner allowing for the delivery of adjuvant therapy. A margin-negative resection is achieved in 60% to 80% of operations.^8,39–41 However, while these patients are considered cleared of all known disease, their long-term survival remains poor, suggesting that microscopic disease is almost always left behind. Even in the setting of margin-negative resections the 5-year survival rate is 25%, and the 10-year survival rate is less than 10%.⁴⁰ Studies correlating lymph node status with survival reveal that survival is improved for lymph node–negative patients.^17,18,42 Wagner et al⁴¹ report a median survival time of 26 months in lymph node–negative patients as compared to 16 months in lymph node–positive patients.