ABSTRACT: Inoperable pancreatic adenocarcinoma is a dilemma that oncologists frequently encounter. Only 15% to 20% of patients are diagnosed when cancer of the pancreas is still surgically resectable. However, pancreaticoduodenectomy is the only curative option for this disease and should be offered to all patients who meet resection criteria and do not have significant comorbidities. For inoperable pancreatic cancer, the goals of treatment are to palliate symptoms and prolong life. Improved survival in locally advanced disease has been demonstrated with chemoradiation plus fluorouracil(Drug information on fluorouracil) or with gemcitabine(Drug information on gemcitabine) (Gemzar) alone. In metastatic disease, single-agent gemcitabine has been associated with improvement in symptoms and survival. Trials combining various chemotherapeutic agents with gemcitabine have not had a significant impact on overall survival, although meta-analyses suggest a small benefit. The targeted agent erlotinib (Tarceva) has shown a modest improvement in overall survival in combination with gemcitabine. This combination is another option for first-line therapy in patients with locally advanced or metastatic disease. Despite these recent advances, survival for patients with inoperable pancreatic cancer continues to be poor. Future investigations need to focus on understanding the molecular nature of this malignancy, with the goal of developing interventions based on this knowledge.
Cancer of the pancreas is the fourth leading cause of cancer death in the United States. It is one of the most challenging malignancies, since the majority of patients will have advanced disease on presentation. Only 15% to 20% of all patients with newly diagnosed pancreatic cancer will meet the criteria for resection.[2,3] Unless a reliable screening test is found, these statistics are unlikely to improve. Currently, the overall 1-year survival rate for all stages is 20%, with a 5-year survival of < 5%. The median survival times for patients with locally advanced and metastatic disease are 9 to 12 months and 3 to 6 months, respectively (Table 1).[1,2,4,5] Despite extensive investigations aimed at improving surgery, radiation, and systemic therapy for this disease, little progress has been made to improve overall mortality in recent years. This article discusses the current standards of care for treatment of inoperable pancreatic cancer.
The American Cancer Society estimates that more than 37,000 people will be diagnosed with pancreatic cancer in the United States in 2007. Reflecting the high mortality, it is predicted that over 33,000 people will die from the disease in the same year. Males and females are equally at risk. The peak incidence is in the 7th decade, with only 10% of pancreatic cancer cases occurring before age 50.
Risk factors for pancreatic cancer include advanced age (> 60) and cigarette smoking. In addition, diabetes mellitus and chronic pancreatitis have been associated with this disease. It is estimated that 5% to 10% of pancreatic cancers result from an inherited genetic factor. BRCA2 is the most common gene linked to pancreatic adenocarcinoma. Other hereditary syndromes such as hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, Peutz-Jeghers syndrome and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have also been associated with cancer of the pancreas.
Signs and Symptoms
Since the majority (> 70%) of pancreatic cancers occur in the head of the pancreas, symptoms are generally caused by compression of surrounding structures. Painless jaundice, caused by impingement of the bile duct, is the classic sign of pancreatic cancer. However, most patients describe an antecedent period of abdominal or back pain, followed by darkening of the urine and jaundice. Weight loss and depression are also common symptoms. On physical examination, the classic Courvoisier's sign of a palpable gallbladder is present in < 50% of patients. Lesions in the pancreatic tail are more likely to present with pain in the abdomen or signs of metastatic disease.
Contrast-enhanced computerized tomography (CT) is the preferred imaging modality for evaluation of the biliary tree and pancreas. Magnetic resonance imaging (MRI) is an alternative for patients who cannot undergo contrast-enhanced CT. In patients presenting with an inoperable pancreatic head mass causing biliary obstruction, endoscopic retrograde cholangiopancreatography (ERCP) with stent placement should be performed to relieve the obstruction.
Tissue for pathologic evaluation should be obtained from the pancreatic lesion under CT or endoscopic ultrasound (EUS) guidance. EUS is preferred, since it is another modality for visualization of the mass and the surrounding vascular structures.[10,11] If a patient presents with metastatic lesions in addition to a pancreatic mass, biopsy of a metastatic lesion is usually preferred to obtain the diagnosis.
Adequate imaging with dynamic-phase spiral CT of the pancreas is critical to evaluate the relationship of the tumor to the important structures surrounding the pancreas. EUS is also helpful in this assessment. In addition, imaging of the remaining abdomen and the lungs should be performed to evaluate for metastatic disease. Per the National Comprehensive Cancer Network (NCCN) guidelines, head of the pancreas tumors are classified into three categories:
• Resectable tumors have no evidence of metastatic disease and the primary tumor is associated with patent superior mesenteric (SMV) and portal veins as well as a clear fat plane around the superior mesenteric artery (SMA) and celiac axis.
• Unresectable tumors encase the SMA or celiac axis, invade or encase the aorta or inferior vena cava (IVC), have metastatic lesions including para-aortic or celiac lymph nodes, are associated with SMV or portal vein occlusion, or invade the SMV below the transverse mesocolon.
• Borderline resectable tumors have severe unilateral SMV/portal vein impingement, gastroduodenal artery encasement up to the origin at the hepatic artery, or tumor abutment on SMA, or are tumors with limited involvement of the IVC, partial SMV occlusion, or invasion into the colon or mesocolon.
Management of borderline resectable cancer of the pancreas remains under debate, as these patients are at high risk for having margin-positive surgery. The remainder of this article focuses on the management of inoperable pancreas cancer.
The primary goals of therapy for inoperable pancreatic cancer are to palliate symptoms and prolong survival. However, treatment of metastatic cancer of the pancreas is challenging since patients are often symptomatic from their disease. Symptom control should always be a priority and may be the primary focus in patients with a poor performance status. Pain is a frequent complaint in pancreatic cancer and can be alleviated with a celiac plexus block or narcotic analgesics. Palliative radiotherapy may also be considered to improve pain control. Duodenal obstruction is a less common problem, which can be alleviated with stenting.
For locally advanced pancreatic cancer, combination therapy with chemotherapy and radiation is often a mainstay of treatment in the United States. Fluorouracil (5-FU) is the classic chemotherapeutic agent that has been combined with radiation therapy (RT). A randomized trial by the Mayo Clinic in the 1960s showed improved outcomes with the combination of 5-FU and RT vs RT alone in patients with locally advanced pancreatic cancer.
The Gastrointestinal Tumor Study Group (GITSG) then completed a three-arm, randomized trial of 106 patients, comparing 60 Gy of split-course RT alone vs 5-FU with 40 Gy of split-course RT or 5-FU with 60 Gy of split-course RT. In the two arms receiving concurrent chemoradiation, maintenance 5-FU was given following completion of radiotherapy. Median survival was improved from 22.9 weeks in the arm receiving RT alone to 44.2 weeks in the two arms receiving concurrent chemoradiation. Since the publication of these trials, concurrent 5-FU and RT has been considered a standard of care for locally advanced pancreatic cancer.
Given the beneficial effects seen with mitomycin(Drug information on mitomycin) in other gastrointestinal diseases,[17,18] the Eastern Cooperative Oncology Group (ECOG) tested mitomycin at 10 mg/m2 with 1,000 mg/m2/d of continuous-infusion 5-FU concurrently with RT (59.4 Gy) compared to RT alone (59.4 Gy). Mitomycin with 5-FU during radiation did not improve overall survival compared to those who received RT alone (8.4 vs 7.1 months; P = .16). However, it has been suggested that the trial may have been underpowered. Also, in contrast to the GITSG trial, chemotherapy was not given after RT, and laparotomy was required prior to study entry to exclude metastatic disease.
In vitro, gemcitabine has exhibited significant radiosensitizing properties, even at non-cytotoxic doses. This prompted several clinical studies of concurrent gemcitabine and radiation, which was found to be unexpectedly toxic.[21,22] The ECOG sought to determine the maximum tolerated dose of gemcitabine administered with a protracted venous infusion of 5-FU (200 mg/m2/d) and 59.4 Gy of RT. Dose-limiting toxicity was seen in two of three patients at the 100-mg/m2/wk dose level and three of four patients at the 50-mg/m2/wk dose level. In a Cancer and Leukemia Group B (CALGB) trial, twice-weekly gemcitabine (40 mg/m2) with concurrent RT to 50.4 Gy resulted in 60% grade 3/4 hematologic toxicity and 42% grade 3/4 gastrointestinal toxicity.
Given the unacceptable toxicity rates seen in these trials and the hypothesis that a more effective regimen for pancreatic cancer would be one that addresses both the local and distant sites of failure, attempts were made to give standard-dose gemcitabine with modified RT fields. A phase I trial from the University of Michigan delivered gemcitabine at 1,000 mg/m2 while testing the dose of RT to the gross tumor without elective nodal treatment. The dose level of 36 Gy in 2.4-Gy fractions was selected for further testing.
The subsequent multi-institutional phase II trial of full-dose gemcitabine with small-field RT (gross tumor volume plus a 1-cm margin to 36 Gy in 2.4-Gy fractions) was completed in patients with nonmetastatic cancer of the pancreas. Of the 20 patients thought to have resectable disease before treatment, 85% underwent pancreatic resection and 94% had negative margins. Of the patients who had surgery, 41% were alive with no recurrence at a median follow-up of 18 months.[25,26] A follow-up phase II trial of the same gemcitabine/RT regimen with the addition of bevacizumab(Drug information on bevacizumab) (Avastin) is near completion.
Another phase II study tested induction gemcitabine at 1,000 mg/m2 for 7 weeks followed by gemcitabine at 400 mg/m2 weekly for 3 of 4 weeks in two cycles given concurrently with 50.4 Gy of RT in 28 fractions. After combined chemoradiation, gemcitabine maintenance therapy was given. Although this was a small study of 20 patients, the regimen was well-tolerated and disease stabilization was noted.