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Illustrative Case Series
Metastatic Pancreatic Cancer
By Jerome Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.
A 58-year-old auto salesman was referred for initial management of metastatic pancreatic cancer. He had been well until approximately 3 months prior when he began to experience epigastric and mid-back pain. During this time he lost approximately 10 pounds (5% of his body weight). Blood work, including a CBC and liver and renal function tests, were normal. Both amylase and lipase were in the normal range, but the CA19-9 was elevated at 359 U/mL (normal range up to 37 U/mL). He was referred to a gastroenterologist who reported normal lower and upper endoscopy. An abdominal CT scan revealed a 3.5 x 4.2 cm mass in the body of the pancreas with apparent partial occlusion of the portal vein and nodal involvement near the porta hepatis and retroperitoneally. A CT-guided lymph node biopsy revealed a high-grade adenocarcinoma consistent with a presumed pancreatic primary. The patient's past medical history was remarkable for a 10-year history of hypertension and a 2-year history of type II diabetes mellitus controlled on oral hypoglycemics. Although diabetes has been common in his family, there was no history of cancer among his parents, siblings, or children. Cigarette and alcohol history were negative.
On physical examination he appeared a robust middle-aged man, 5'11" tall, 193 pounds. BP was 140/74, P-78 regular, and O2 sat was 97% on room air. There was no scleral icterus nor palpable lymphadenopathy. His chest was clear to percussion and auscultation. The abdomen was soft with some epigastric and right upper quadrant tenderness, but without discretely palpable mass. Extremities and neurological exams were normal.
In considering therapy, the first question of paramount importance is whether the disease is resectable, which would provide the best chance for long-term survival. However, the involvement of both retroperitoneal and porta hepatis lymph nodes as well as the proximity and partial occlusion of the portal vein might preclude surgery. A careful inspection by MRI and/or laparoscopy would be warranted as well as consultation from an experienced surgical oncologist. If the portal vein is abutted but not invaded or the segment of involvement is small enough that suitable vessel both proximal and distal would be available for reconstruction, it might be possible that an aggressive surgical approach could be undertaken.
However, the likelihood is that this patient initially would be treated with chemotherapy. Although the data are not convincing at this time, initial chemotherapy might be considered "neoadjuvant" and surgery offered upon completion of one or two cycles. If this were to be planned, it would be best coordinated with radiation oncology, as combined modality might offer the greatest chance for later surgical resection.
If it is determined that resection is not feasible, my recommended initial approach would be with chemotherapy alone. Until recently, the standard treatment would be either gemcitabine alone or in combination with the tyrosine kinase inhibitor erlotinib (Tarceva®). This is based primarily on studies comparing gemcitabine to 5-FU/leucovorin in randomized trials conducted in the 1990s, including a pivotal Phase 3 trial that demonstrated improvement in median overall survival and 1-year survival compared to 5-FU (5.7 months vs 4.4 months and 18% vs 2%, respectively).1 Although there was only a modest response rate (5%) and improvement in overall survival, gemcitabine rapidly became the standard first-line therapy for advanced pancreatic cancer. In 2007, Moore et al demonstrated improvement in survival (6.24 months vs 5.91 months) in a trial that compared gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor that targets and blocks EGFR, vs gemcitabine alone.2 Although the improvement was small, this was the first gemcitabine combination to show any benefit in a Phase 3 trial when compared to gemcitabine alone and it has engendered interest in targeting the EGFR pathway in metastatic pancreatic cancer.
At the American Society of Clinical Oncologists (ASCO) Annual Meeting in June 2010, preliminary data from the PRODIGE 4/ACCORD 11 trial that compared gemcitabine to oxaliplatin and irinotecan plus fluorouracil and leucovorin (FOLFIRINOX) were presented.3 This randomized, Phase 3 trial enrolled 250 patients with metastatic pancreatic cancer and was halted when the interim analysis demonstrated significant improvements in progression-free survival and median overall survival with FOLFIRINOX (6.4 months vs 3.3 months, and 11.1 months vs 6.8 months, respectively). Furthermore, the objective response rate was 31% for the FOLFIRINOX arm compared to 9% in the gemcitabine arm. Approximately 48% of patients on FOLFIRINOX were alive at 1 year compared with 30% of patients who received gemcitabine. The median progression-free survival was 6.4 months for those on FOLFIRINOX and 3.3 months for those treated with gemcitabine. Clearly there were more adverse effects observed in those treated with FOLFIRINOX, although these were not severe enough that treatment had to be stopped. Treated patients experienced longer preservation of quality of life, but still it is not clear that this aggressive approach should be considered standard for patients with less than good performance status and for those with impaired hepatic function.
In the current case, and based upon the ASCO presentation of the PRODIGE 4/ACCORD 11 trial (which I believe has yet to be published as a manuscript) and the patient's seemingly excellent performance status, my inclination would be to treat first line with the FOLFIRINOX regimen and reserve gemcitabine for treatment at the time of disease progression.
Two other points merit mention. This patient has a 2-year history of diabetes and one wonders whether the onset of glucose intolerance was an early clue of evolving pancreatic cancer. Although the mechanism explaining the association between diabetes and pancreatic cancer has not been worked out satisfactorily, it is clear that such an association exists.4,5 In fact, some have suggested that middle-aged or older patients with new onset diabetes be examined either by ultrasound or CT scan to determine if there is an early (resectable) pancreatic cancer. The costs of such screening may preclude its widespread application in today's economy, but certainly this is a question that should be addressed.
The second point refers back to this patient. In addition to the chemotherapy provided, aggressive supportive management would be in order, particularly in this patient who had been well and is now facing a life-threatening illness. Significant clinical depression and even suicide is more common in patients with this diagnosis than in the general population or in patients with other forms of life-threatening cancers (as reported by Turaga et al6 and reviewed in this issue of Clinical Oncology Alert). Accordingly, those attending his care should be alert to signs and symptoms of depression and appropriate referral and/or treatment with antidepressant medicines should be initiated early.
1. Burris HA 3rd, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403-2413.
2. Moore MJ, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-1966.
3. Conroy T, et al. Randomized phase III trial comparing FLOFIRINOX (F: 5FU/leucovorin (LV), irinotecan (I), and oxaliplatin (O)) versus gemcitabine (G) as first line treatment for metastatic pancreatic adenocarcinoma (MPA). Preplanned interim analysis results of the PRODIGE. J Clin Oncol 2010;28(15 Suppl):4010a.
4. Chari ST, et al. Pancreatic cancer-associated diabetes mellitus: Prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134:95-101.
5. Pannala R, et al. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 2008;134:981-987.
6. Turaga KK, et al. Suicide in patients with pancreatic cancer. Cancer 2011;117:642-647.