The Washington Manual of Oncology, 3 Ed.

Pancreatic Cancer

Andrea Wang-Gillam

CANCER OF THE PANCREAS

 I. PRESENTATION

1. Subjective. Typical presenting symptoms include painless jaundice, weight loss, abdominal pain, back pain, nausea, vomiting, and pruritus. Infrequently, new-onset diabetes develops prior to the diagnosis of pancreatic cancer.
2. Objective. Physical examination findings may include sclerotic icterus, jaundice, ascites, left supraclavicular adenopathy (Virchow’s node), periumbilical adenopathy (Sister Mary Joseph’s node), or perirectal drop metastases (Blumer’s shelf).
3. WORKUP AND STAGING. Pancreatic ductal adenocarcinoma is the most common histology of pancreatic cancer. Neuroendocrine tumors in the pancreas are uncommon (less than 5%) and carry a much better prognosis than ductal adenocarcinoma. The treatment for pancreatic neuroendocrine tumors is completely different from that for adenocarcinoma, so it is crucial to distinguish between the two histologies at the time of diagnosis. Metastatic disease to the pancreas is rare.

 The golden standard diagnostic procedure for pancreatic cancer is to perform an upper endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of the primary pancreatic cancer, especially in patients without frank metastasis. Although the brushing is commonly collected in patients undergoing endoscopic retrograde cholangiopancreatography for obstructive jaundice, the sample yield for a positive cytology varies. In patients with metastatic disease, it is reasonable to obtain a biopsy from the easily accessible metastatic sites. Tumor marker CA 19-9 is not used for diagnosis because it can be positively elevated in patients with benign conditions such as biliary obstruction. Additionally, about 10% of patients with pancreatic cancer have normal CA 19-9 because of being Lewis-negative phenotypes.

 Given the vague symptoms and lack of an effective screening method, only 10% to 20% of patients with pancreatic cancer have resectable disease at the time of diagnosis; therefore, the classic pathological staging of tumor, node, metastasis (TNM) system is not practical for the majority of pancreatic cancer patients. Clinical staging based on the radiographic findings is the preferred staging method, and it classifies patients into four categories: resectable, borderline resectable, locally advanced, and metastatic disease. To optimally delineate the vasculature involvement of the tumor, which is the main determinate for surgical resection in localized cancer, the preferred imaging tool is a computed tomography (CT) scan (a triple-phase, high-speed helical scanning) with contrast enhancement, which is commonly referred to as “pancreatic protocol” CT. Staging with laparoscopy may be needed to evaluate peritoneal metastasis. In fact, up to 37% of cases with apparent locally advanced disease have peritoneal metastases seen upon laparoscopy (Gastrointest Surg 2004;8:1068).

 III. MANAGEMENT

1. Resectable disease. Surgery remains the only modality clearly established to cure pancreatic cancer. Unfortunately, only 10% to 20% of patients present with apparently resectable disease. The Whipple procedure is indicated for tumors in the head of pancreas, while distal pancreatectomy is reserved for tumors in the body and tail of the pancreas. The clinical outcome is superior if surgery is performed in a high-volume surgery center. Among all pathological features of the resected tumor, the positive malignant lymph node appears to be the strongest predictor for outcome.

In light of a distal recurrence rate of 70%, adjuvant therapy is recommended to patients with adequate recovery from curative resection. Adjuvant therapies have evolved over the years; however, a controversy remains regarding radiation therapy (RT), and RT is not part of adjuvant care for these patients in Europe. At present, four large randomized phase III adjuvant trials in pancreatic cancer have demonstrated the benefit of adjuvant therapy (see Table 18-1). The CONKO-001 study was the first randomized phase III trial to demonstrate the survival benefit from a course of 6 months of gemcitabine as adjuvant therapy (JAMA2013;310:1473). The 5-year and 10-year overall survival rates were superior in the gemcitabine arm compared with surgery alone (20.7% vs. 10.4% and 12.2% vs. 7.7%, respectively). The disease-free survival was also favorable in the gemcitabine arm (13.4 months vs. 6.7 months; hazard ratio, 0.55; P<0.001). The ESPAC-3 trial was initially designed to randomly assign pancreatic cancer patients post surgical resection to receive 5-FU plus folinic acid or gemcitabine or surgery alone. The surgery arm was discontinued because of the benefit of adjuvant gemcitabine therapy reported in the CONKO-001 study. In the ESPAC-3 study, the median survival was 23 months for patients receiving the 5-FU plus folinic acid compared with 23.6 months for those receiving gemcitabine (JAMA 2010;304:1073). Both the CONKO-001 and the ESPAC-3 studies were conducted in Europe where RT was not part of adjuvant regimen.

In North America, the Radiation Therapy Oncology Group (RTOG) conducted a study (RTOG-9704) of pancreatic cancer patients postresection who were randomly assigned to receive either gemcitabine followed by 5-FU and radiation followed by gemcitabine or 5-FU followed by 5-FU and radiation followed by 5-FU. The two treatment arms differed on the systemic therapy components. The study reported superior survival in patients with pancreatic head tumors treated with the gemcitabine-based regimen (20.5 months vs. 16.9 months, hazard ratio, 0.82; P=0.09) (JAMA 2008;299:1019). More recently, Japanese researchers reported the preliminary results of their trial using S1 or gemcitabine as adjuvant therapy in the pancreatic cancer at the 2013 American Society of Clinical Oncology (ASCO) meeting, and so far, the survival benefit in this trial has surpassed all previous adjuvant studies with a 2-year survival rate of 70% in the S1 arm and 53% in the gemcitabine arm. Currently, S1 is available only in Asia.

1. Borderline resectable and locally advanced pancreatic cancer. Borderline resectable disease is an emerging entity. It is distinguished from locally advanced disease by having less involvement of the tumor vasculature. For example, if the tumor abuts the superior mesentery artery (SMA), it is considered borderline resectable because there is still a chance for resection, despite the fact that the risk for a positive margin is high. If the tumor encases the SMA, then it is considered locally advanced because the chance of resection with a clean margin is zero; so by definition, patients with locally advanced disease are not candidates for curative resection. The detailed radiographic differences of vascular involvement between borderline resectable and locally advanced pancreatic cancer can be found on the National Comprehensive Cancer Network (www.nccn.org).

Because of the 70% distant recurrent rate in patients who undergo curative resection, it is logical to consider systemic therapy prior to surgery. The rationales for exploring this approach include identifying patients with rapidly progressive disease so that they may avoid an unnecessary operation, eliminating micrometastases, improving the effectiveness of RT (because surgery may interfere with the effectiveness of postoperative RT as a result of vascular damage from surgery), and downstaging tumors to decrease the risk of positive surgical margins. This upfront systemic therapy approach to managing borderline resectable pancreatic cancer is gaining acceptance in the oncology community. Although the optimal upfront therapy remains undefined, aggressive chemotherapy regimens with proven survival benefits in the metastatic setting, such as 5FU, oxaliplatin, irinotecan (FOLFIRINOX), or gemcitabine and nab-paclitaxel, have been extrapolated to this setting. Concurrent chemotherapy and RT has also been used in this setting.

The standard treatment for patients with locally advanced pancreatic cancer is systemic chemotherapy. The benefit of concurrent chemotherapy and RT in this setting was initially reported in the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) study (J Clin Oncol 2007;25:326). The study reviewed the outcome of patients with locally advanced pancreatic cancer who were enrolled in phase II or III GERCOR studies and had achieved stable disease after 2 to 3 months of systemic therapy. It compared the survival of those who received chemotherapy with that of those who received chemotherapy and RT after being treated with systemic therapy for a period of 3 months. The addition of RT to the chemotherapy regimen increased survival by more than 3 months (15.0 months vs. 11.7 months; P=0.0009); however, this study was criticized because of its retrospective nature. More recently, a large randomized prospective phase III study for patients with locally advanced pancreatic cancer disease was completed. The study has a 2 × 2 factorial design for which patients were first randomized to receive gemcitabine or gemcitabine plus erlotinib for 4 months; then they were randomized again to continue on chemotherapy alone or receive chemotherapy and RT. The preliminary results of this study were presented at the 2013 ASCO Annual Meeting, and no survival difference between the chemotherapy alone and chemotherapy and RT arms was observed. Additionally, patients who received gemcitabine plus erlotinib did not have any additional survival benefit but experienced slightly more toxicity. This large prospective study provides level I evidence that concurrent chemotherapy and RT does not provide any additional benefit in locally advanced disease.

5. Metastatic pancreatic cancer. Patients with metastatic pancreatic cancer have a poor prognosis, with survival of less than 1 year. Gemcitabine has been the cornerstone of frontline therapy for the past decade. It was compared with 5-FU in patients with advanced pancreatic cancer, and the median survival favored gemcitabine (5.65 months vs. 4.41 months, P=0.0022). Clinical benefit was defined as improvement for ≥4 weeks in pain, analgesic use, weight loss, or performance status without worsening of another one of these symptoms. The likelihood of clinical benefit favored gemcitabine (24% vs. 5%). As a consequence of this study, gemcitabine was soon established as standard therapy (J Clin Oncol 1997;21:3402).

While targeted agents have flourished in multiple cancer types, the success of this approach in pancreatic cancer has been more elusive. Erlotinib (an epidermal growth factor receptor inhibitor) combined with gemcitabine was tested in patients with advanced pancreatic cancer. A small but statistically significant survival benefit was observed in patients receiving gemcitabine plus erlotinib compared with those receiving gemcitabine alone (6.24 months vs. 5.91 months, hazard ratio, 0.82; P=0.038). Interestingly, the development of a rash appeared to be a positive prognostic factor for patients receiving erlotinib; patients who developed grade 0, 1, and 2+ rash had median survivals of 5.3, 5.8, and 10.5 months, respectively (J Clin Oncol 2007;25:1960).

More recently, two regimens have become standard of care in the frontline setting for metastatic pancreatic cancer (Table 18-2). A phase III study of FOLFIRNIOX or gemcitabine in patients with metastatic pancreatic cancer with good performance status demonstrated the survival benefit of FOLFIRINOX (11.1 months vs. 6.8 months; P<0.001). Median progression-free survival was also favorable in patients who received FOLFIRINOX (6.4 months vs. 3.3 months; P<0.001). The response rate was also significantly higher in the FOLFIRINOX arm (31.6% vs. 9.4%; P<0.001); however, the aggressive FOLFIRINOX regimen results in moderate toxicities including neutropenia, fatigue, and diarrhea (N Engl J Med 2011;364:1817).

The combination of nab-paclitaxel plus gemcitabine as the frontline therapy has gained popularity after nab-paclitaxel was approved in pancreatic cancer by the Food and Drug Administration. A randomized phase III study (MPAC) of nab-paclitaxel plus gemcitabine versus gemcitabine as the frontline therapy in patients with metastatic pancreatic cancer yielded a median overall survival of 8.5 months in the combination arm compared with 6.7 months in the gemcitabine alone arm. The 1-year survival rate was higher in those who received the combination therapy compared with those who received gemcitabine alone (35% vs. 22%; P<0.001). The severe side effects of the combination regimen include neutropenia and neuropathy (N Engl J Med 2013;369:1691). At present, multiple novel agents are being combined with nab-paclitaxel plus gemcitabine in clinical trials.

Despite the poor prognosis associated with pancreatic cancer, about 40% of patients who progress on frontline therapy are able to receive second-line therapy. So far, in patients progressed on gemcitabine-based therapy, 5-FU and oxaliplatin (OFF regimen) have shown to provide a survival benefit compared with those who received best supportive care (4.82 months vs. 2.30 months; P=0.008) (Eur J Cancer 2011;47:1678). The OFF regimen was further tested against FF (5FU-folinic acid) in a randomized phase III trial in patients with metastatic disease, and the survival was superior in patients who received OFF (5.89 months vs. 3.09 months; P=0.01). The study was reported in the abstract form. For patients who progressed on frontline FOLFIRINOX or a FOLFIRINOX-like regimen, a gemcitabine-based regimen has been the natural choice for second-line therapy, but there are no studies yet to support this approach given the fairly recent adoption of FOLFIRINOX. Beyond two lines of therapy, there is no standard of care available. These patients, in general, should be referred for clinical studies.

 IV. EPIDEMIOLOGY. Pancreatic cancer is the fourth most common cause of cancer death in the United States. It is projected to be the second most common cancer-related death by 2030. Approximately 46,000 patients were diagnosed with pancreatic cancer in 2013, and about 40,000 died the same year, underscoring the extremely poor prognosis associated with this disease. While the majority of pancreatic cancers are sporadic, 10% of cases are hereditary. An increased risk for pancreatic cancer is seen in populations that have hereditary pancreatitis, hereditary breast cancer (BRCA and PALB2 mutations), Peutz–Jeghers syndrome, familial atypical multiple mole melanoma (FAMMM) syndrome, and Lynch syndrome.

1. FUTURE DIRECTIONS. New strategic approaches in targeting pancreatic cancer are under investigation. Strategies that disrupt dense stroma are a current center of focus. Additionally, clinical trials that use immunotherapy have gained recent momentum. Because more than 90% of pancreatic tumors harbor a KRAS mutation and direct targeting of KRAS has not been successful, targeted agents that inhibit KRAS downstream mediators are currently being evaluated in clinical studies.

SUGGESTED READINGS

Callery MP, Chang KJ, Fishman EK, et al. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 2009;250(1):96–102.

Lim KH, Chung E, Khan A, et al. Neoadjuvant therapy of pancreatic cancer: the emerging paradigm? Oncologist 2012;17(2):192–200.

Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013;310(14):1473–1481.

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

Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized trial. JAMA2008;299(9):1019–1026.

Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364(19):1817–1825.

Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369(18):1691–1703.