Searching for Clinical and Economic Value in Pancreatic Cancer

Pancreatic cancer is an extremely aggressive tumor type that continues to carry a dismal prognosis. Research regarding the cause of the cancer has continued, but important breakthroughs have been slow in coming. Additionally, pancreatic tumors demonstrate a resistance to chemotherapy, which has contributed to clinicians’ frustration in obtaining remission, or even a firm foothold in managing it. This may also be related to the relatively late stage of the tumor at thetime of diagnosis. Therefore, early diagnosis and the future discovery of an effective screening method could change the clinical picture and alter the search for value in managing this deadly cancer.

Mortality Increasing Unlike for Other Cancers

Table

Death rates for most cancers have trended downward over the past 10 years; however, this has not been the case for pancreatic cancer. The incidence rate has increased by 0.9% per year in Caucasian men and women and African American men, while remaining stable in all others.¹ The illustrates the likelihood of developing pancreatic cancer over one’s lifetime.¹ The majority of patients (74%) diagnosed will die within 1 year of diagnosis, whereas only 6% will survive for 5 years—this is the lowest relative survival of any cancer tracked by the American Cancer Society and the National Cancer Institute. Patients’ average life expectancy after diagnosis of metastatic disease is only 5 to 7 months.² It is not one of the top 5 cancers in men or women in terms of incidence, yet it is the fourth leading cause of cancer death among men and women. More than 45,000 Americans will be diagnosed with pancreatic cancer in 2013, and over 38,000 will die this year.¹

The incidence of pancreatic cancer increases with age, with the median age at diagnosis being 71 years. More men than women are diagnosed with the disease.¹

Pancreatic cancer typically refers to a ductal adenocarcinoma (exocrine pancreatic cancer). A less common type is a neuroendocrine tumor (endocrine pancreatic cancer). The public profile of pancreatic cancer has been raised in recent years with the chronicled cases of Patrick Swayze (who had exocrine pancreatic cancer) and Steve Jobs (who had endocrine pancreatic cancer).³ In fact, the dire prognosis for patients with pancreatic cancer has driven people like Jobs to seek unorthodox treatment and unproven therapies.

Patients with pancreatic neuroendocrine tumors have a somewhat better median overall survival than those with ductal adenocarcinomas. Unfortunately, the incidence of these tumors appears to be increasing.⁴

The cause(s) of pancreatic cancer are unknown. Family history is a positive risk factor and is identified in 5% to 10% of those diagnosed; the risk increases as the number of family members diagnosed with the disease increases. Smoking is also a risk factor, with a 2.5% to 3.6% increase in risk compared with non-smokers. As the number of life-years of smoking increases, so does the risk for pancreatic cancer.⁵ Other potential risk factors include age; obesity; alcohol use; consumption of red and processed meat, and fructose sweeteners; chronic pancreatitis; diabetes; chronic infections (eg, hepatitis B virus, hepatitis C virus, and Helicobacter pylori); some surgeries (eg, partial gastrectomy, cholecystectomy); cystic fibrosis; and periodontal disease.¹

Pancreatic cancer is usually not detected or diagnosed in the early stages of the disease, as there are no specific symptoms. Symptoms that bring patients to the physician’s office include: nausea, vomiting, abdominal discomfort, abdominal pain that is localized to the tumor area, anorexia, weight loss, generalized weakness, and fatigue. The majority of the tumors develop in the head of the pancreas, which leads to obstructive cholestasis, rather than the tail of the pancreas. Overall, most tumorsare found when only about 15% to 20% of patients are still candidates for surgery.^1,5

Figure

As would be expected, costs for treating patients who undergo surgery are greater than costs for patients who have nonresectable tumors (either locoregional or metastatic). A Surveillance, Epidemiology, and End Results (SEER) Medicare database study that included patients diagnosed between 2000 and 2007 found the mean total costs for those 3 patient groups to be $134,000 (surgical candidates), $65,300 (patients with locoregional tumors), and $49,000 (patients with metastatic disease), with an average cost of $61,700. The largest portion of the costs was related to hospitalizations and cancer-related procedures ().⁶ Undoubtedly, improved treatment strategies may increase the cost of treating patients with pancreatic cancer by increasing their lifespans.

Genetics and Biomarkers

Pancreatic cancer is genetically heterogeneous. One study analyzing 24 tumors found 63 genetic abnormalities in each tumor that were believed to be likely relevant for the disease. It has been determined that there are always at least 1 or more genetic defects involving 4 genes in patients with pancreatic cancer.⁵ Recent research has determined that germline mutations in BRCA1 and BRCA2 predispose women to pancreatic cancer, doubling their risk for developing it. The 5-year survival for these individuals was no greater than 5%.⁷

Epidermal growth factor receptor (EGFR) overexpression has been identified in 40% to 65% of pancreatic tumors. This overexpression leads to tumors being resistant to chemotherapy and an even poorer prognosis.⁸ Since pancreatic tumors vary so much between patients, a highly individualized approach to treating the disease will probably be needed to improve patient outcomes.⁹

Currently, only 1 biomarker is approved by the US Food and Drug Administration for pancreatic cancer, serum Ca-19-9 (carbohydrate antigen 19-9, also known as cancer antigen-GI and CA-GI).¹⁰ This marker is useful for identifying the tumor location, stage, and resectability.¹¹ However, not all pancreatic tumors produce Ca-19-9; therefore, it is not sensitive or specific enough to be used as a screening test.^1,12 However, the test does have value for evaluating effectiveness of treatment and early detection of recurrent disease.⁵

Other frequently used tests include endoscopic ultrasound, helical computed tomography, magnetic resonance imaging, and endoscopic retrograde cholangiopancreatolography. To confirm the diagnosis, fine-needle aspiration biopsy is standard procedure.^1,13

Staging of Pancreatic Cancer

Staging of the disease guides the type of treatment that will be the most effective. The 4 stages associated with pancreatic cancer are differentiated by the location of the tumor and whether it has spread to lymph nodes and distant organs. Stage I indicates that the tumor is restricted to the pancreas, and stage IV describes cancer that has spread to a distant organ, such as the liver or lungs. Patients with stage III or IV tumors are generally not candidates for surgical resection, and this comprises about 80% of patients.^13,14 The lethality of this cancer in late stages cannot be overemphasized; survival is somewhat greater when diagnosed at an earlier stage. When a patient has surgery after being diagnosed with stage I or stage II cancer, the 5-year survival is 20% to 25%, whereas a patient diagnosed with stage IV cancer has a 5-year survival that is below 1%.^1,15

Treatment Options

Surgery is the only treatment option that can cure early-stage disease. However, a small percentage of patients present with stage I pancreatic cancer, because of the difficulty in diagnosing it. Surgical procedures most commonly performed include cephalic pancreatoduodenectomy (also known as the Whipple procedure), distal pancreatectomy, and total pancreatectomy. Predictors of improved survival include younger age and early-disease stage.5,16 After surgery, adjuvant chemotherapy either alone or in combination with radiation therapy has been shown to improve survival. Neoadjuvant therapy, both chemoradiation or chemotherapy in combination or alone, are also options, especially when the patient has locally advanced or borderline rescectable disease. In patients undergoing surgery, the chemotherapy regimens initiated after the surgery usually include gemcitabine, 5-fluorouracil (5-FU) with leucovorin, or capecitabine.¹⁴

Since surgery for pancreatic cancer can involve several organs in the digestive system in addition to an already diseased organ, several potential morbidities should be considered. Up to 80% of patients undergoing surgical procedures for pancreatic cancer will require oral pancreatic enzyme replacement therapy (PERT). The dose of lipase required usually ranges from 160,000 to 400,000 units daily. A proton pump inhibitor may be added to improve the efficacy of the PERT, if there is adequate gastric acid secretion.¹⁷ Since at least a portion of the pancreas is removed during surgery, the body’s ability to produce insulin is compromised. As a result, up to 50% of patients develop diabetes and require insulin therapy postsurgery.¹⁸ Other complications observed after surgery include gastroparesis, dumping syndrome, and vitamin and mineral deficiencies.¹⁹

For the majority of patients whose tumor is not resectable, the therapeutic options are chemoradiation and/or chemotherapy. Gemcitabine has been the mainstay of therapy since the late 1990s, when the drug was shown to increase median survival to 5.7 months compared with 4.4 months for those taking 5-FU (P = .0025), but the 1-year survival was worth noting (18% versus 2%, respectively).²⁰ Capecitabine is a pro-drug of 5-FU, and it has also demonstrated benefit in treating patients with pancreatic cancer.²¹ A combination therapy regimen, FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin), was compared with gemcitabine in patients with stage IV metastatic disease that involved up to 6 distal sites. The combination therapy group showed an improved median overall survival (11.1 vs 6.8 mo, respectively; P <.0001). Median progression-free survival was also longer in the combination therapy group (6.4 vs 3.3 mo, respectively; P <.001).²² Targeted EGFR therapy using erlotinib plus gemcitabine led to a marginally longer overall survival than gemcitabine alone (6.2 vs 5.9 mo, respectively; P = .038).²³

Cost Considerations

Since pancreatic cancer is such a devastating disease, strategies for screening individuals at high risk would be beneficial. Two cost-effectiveness studies of screening high-risk individuals led researchers to conclude that early cancer can be detected by screening; however, until new biomarkers with high specificity and sensitivity become available, this strategy may not be cost-effective.²⁴ Owing to the poor outcomes of patients with pancreatic cancer, the evaluation of cost-effective treatment strategies remains challenging. Alas, the survival of these patients is consistently short, and expressing incremental cost-effectiveness ratios (ICERs) in terms of years yields inadequate comparisons. For this reason, ICERs for pancreatic cancer interventions are often expressed in quality-adjusted life-months (QALMs), not life-years.

A recent review examined 6 treatment strategies: no treatment, radiotherapy only, chemotherapy only, chemotherapy plus radiotherapy, surgery alone, and surgery plus adjuvant therapy. The groups having surgery plus adjuvant therapy, chemotherapy alone, and no treatment were the only groups that were considered costeffective. An ICER of $7663 per QALM was seen in the surgery plus adjuvant therapy group compared with the notreatment group, which was primarily related to an increase in survival. Of note was that the ICER was most favorable in high-performing healthcare centers versus low-performing centers ($5991/QALM vs $9144/QALM, respectively). This indicates that decreasing costs will be related to improved therapies and utilizing high-performing care centers for providing the treatments.²⁵

Another study examined the cost-effectiveness of gemcitabine monotherapy, gemcitabine plus conventional radiotherapy, gemcitabine plus intensity modulated radiotherapy (IMRT), and gemcitabine with stereotactic body radio therapy (SBRT). The SBRT group had better results both clinically and economically than each of conventional radiotherapy and SBRT groups, respectively, but only produced an increase of 0.20 quality-adjusted life-years (QALYs), at an incremental cost of $13,700 compared with gemcitabine alone. Using a willingness to pay of $50,000 per QALY as the threshold for costeffectiveness, the probability of costeffectiveness was 78% for gemcitabine monotherapy and 21% for SBRT, while at a willingness-to-pay threshold of $200,000 per QALY, the probability of cost-effectiveness for SBRT was 73%.²⁶

Another type of cost strategy evaluation was undertaken that determined the budget impact of adding erlotinib to gemcitabine therapy in patients with nonresectable pancreatic cancer. The budget impact was $0.02 per member per month; this small amount was primarily the result of the low incidence of pancreatic cancer among the hypothetical managed care organization of 500,000 members. It would be difficult to deny patients the additional drug being added to a gemcitabine regimen even with limited survival benefits.²⁷

Both the National Cancer Institute (NCI) and pharmaceutical companies are investigating new modalities for treating pancreatic cancer. The NCI has increased its budget for this disease by more than 50% since 2000. Yet, the complexity and variability of each tumor continues to challenge clinical treatment. As we learn more about the genetic makeup of pancreatic cancer, it will undoubtedly lead to new therapies, new combination therapy regimens, and biomarkers that will aid in the detection and monitoring of therapy. These advances will hopefully translate into better patient outcomes and economically sound treatment strategies. EBO Payer Perspective Interview With Irwin W. Tischler, MD EBO: Why is pancreatic cancer such a difficult problem today? Do we have sufficient information on its risk factors to be of use in prevention?

Dr Tischler: Pancreatic cancer is the fourth-most common cause of cancerrelated deaths in the United States. There is little doubt that there are risk factors associated with pancreatic cancer. These include cigarette smoking, heavy alcohol intake, exposure to certain occupation-related chemicals, and obesity. Chronic pancreatitis has also been identified as a risk factor. A recent study demonstrated a 7-fold increase of pancreatic cancer for patients with a history of pancreatitis, and clinical studies are evaluating pancreatic cancer’s relationship with other risk factors. Truly familial pancreatic cancer is uncommon. However, there may be a genetic predisposition in up to 10% of patients with pancreatic cancer. There is also an increase of pancreatic cancer in families who have the BRCA2 gene mutation.

EBO: What do you see as the best value for our efforts to prevent, treat, or manage pancreatic cancer today?

Dr Tischler: I believe our best efforts lie in educating our customers about their risk factors and how those risks can be reduced by changing lifestyle behaviors.

EBO: Pancreatic cancer is usually detected or diagnosed in the latter stages of the disease. What can health plans do to help improve this situation or is this more of an issue requiring better provider education?

Dr Tischler: It is unclear whether screening high-risk individuals is beneficial. Studies are ongoing in an effort to answer this question.

EBO: With regard to the direct costs of treating the disease, surgical procedures and hospital stays are responsible for the lion’s share (22% and 33%, respectively). Chemotherapy and radiotherapy account for only 13% combined. Do you expect that the chemotherapy costs will increase as more effective treatments are introduced?

Dr Tischler: The overwhelming share of costs do relate to surgical procedures, including the cost of inpatient hospital stays. Mortality in the United States for pancreatic cancer has not changed much over the past 20 years, despite the introductionof more chemotherapy drug combination treatments. Overall, costs likely will continue to increase as newer chemotherapy agents become available, especially the targeted agents that are being used to treat many other malignancies.

EBO: Do you think that other treatment-associated costs will become major contributors to this scenario in the future (eg, pancreatic enzyme replacement or biomarker testing)? Dr Tischler: Biomarker, molecular profiling, and gene array studies are currently in progress, and I believe this is the future—not only for pancreatic cancer, but for managing other malignancies as well. The results of these studies may enable us to take a novel and personalized approach to treat specific molecular targets that can be identified, and that will be predictive of chemotherapy sensitivity to treat pancreatic and other malignancies.

EBO: In terms of pancreatic cancer (or perhaps all cancers), what, if any, clinical guidelines do you encourage oncologists to follow? Dr Tischler: Cigna encourages doctors who are treating our customers to follow evidence-based guidelines published by the NCCN and ASCO (American Society of Clinical Oncology). Cigna uses these guidelines to develop our coverage policies for pancreatic cancer and other malignancies.

EBO: Because of the limited success with current treatments of patients with pancreatic cancer, are you perhaps more lenient in your approval of investigational treatments? Dr Tischler: Cigna covers experimental treatments for pancreatic cancer if the treatment is being done in conjunction with a listed clinical trial.

EBO: Where do you expect the next big leap in pancreatic cancer management? Dr Tischler: I believe the next big leap, not only for pancreatic cancer but for all malignancies in general, will occur once we further unravel genetic and tumorspecific markers. Hopefully, this will enable oncologists to deliver personalized, effective therapy for all cancers.

Dr Tischler is national medical director for oncology at Cigna in Philadelphia, PA.Funding Source: None.Author Disclosures: Mr Mehr reports receiving payment for involvement in the preparation of this article. Ms Zimmerman reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.Authorship Information: Concept and design (SRM); acquisition of data (MPZ, SRM); analysis and interpretation of data (MPZ, SRM); drafting of the manuscript (MPZ, SRM); critical revision of the manuscript for important intellectual content (MPZ, SRM); and supervision (SRM). 1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013. 2. Pancreatic Cancer Facts 0212. Pancreatic Cancer Action Network. www.pancan.org/section_get_involved/advocate/downloads/Pancreatic%20Cancer%20Facts%20June%202012.pdf.Accessed February 5, 2013. 3. Begley S. Jobs’s unorthodox treatment. TheDaily Beast. 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