The incidence of pancreatic ductal adenocarcinoma approximates its mortality rate. Surgical removal of locally confined disease is the only realistic curative option. Even with this approach, however, the relapse rate is so high that surgical resection (with adjuvant chemotherapy) is viewed by many as deferring rather than eliminating recurrence. As pointed out by Wisinski and colleagues in their comprehensive review, in terms of increasing the range and efficacy of therapeutic options in the advanced disease setting, progress has been modest and incremental.
Approximately 10% of pancreas cancer is familial, and the risk of pancreatic ductal adenocarcinoma developing in a first-degree relative of a patient with this diagnosis is 2.5- to 5-fold higher than normal.[1,2] The bulk of this increased risk lies in a minority of families for whom no screening test (for pancreatic cancer) currently exists. The prospective maintenance of family history registries at institutions that see large numbers of patients with this disease is crucial to understanding familial predisposition and will help focus screening studies, which in time may have a wider applicability.
For the vast majority of patients who either present with de novo advanced disease or develop a recurrence postsurgically, the goals of therapy are to maintain or improve quality of life while prolonging survival.
Role of Radiotherapy
In the locally advanced/inoperable setting, the role of radiation therapy (RT) has grown increasingly controversial, mirroring the discussion surrounding the use of radiation in the adjuvant setting. The tendency of pancreatic cancer for early systemic progression diminishes the importance of local control measures in patients presenting with inoperable disease that has not clinically metastasized. The exception to this is the patient with pain related to locoregional disease who may derive palliative benefit from early radiation.
Admittedly, prospective randomized data are lacking. The Groupe Cooprateur Multidisciplinaire en Oncologie (GERCOR) investigators performed a retrospective analysis of 181 patients with locally advanced pancreatic ductal adenocarcinoma who had been entered on prior prospective GERCOR studies and who had been offered chemoradiation (at the discretion of the investigator), but only if they had remained metastasis-free after a 3-month period. Patients who were metastasis-free after initial chemotherapy showed a survival advantage if they proceeded to chemoradiation, compared to those who continued with chemotherapy alone (median overall survival = 15.0 vs 11.7 months, respectively; P = .0009). These data suggest that radiation may offer a survival benefit in selected patients with localized disease only after a test of time.
The importance of surgical staging for patients with locally advanced disease is also reflected by the fact that approximately 20% have subclinical peritoneal metastases and would not benefit from RT. In trials of radiation in the locally advanced setting, in the absence of surgical staging one might observe a relative dilution of the RT effect due to the presence of patients with unappreciated metastatic disease. Fluorouracil-based therapy is still the standard of care when chemoradiation is employed.
Gemcitabine (Gemzar) has been explored in phase I and II studies, but the optimal dose and scheduling remain unclear. We performed a phase I study of gemcitabine-based chemoradiation in the locally advanced setting in association with erlotinib (Tarceva), which demonstrated the feasibility of this combination. While recognizing the limitiations of survival endpoints in phase I studies, the impressive survival of 18.4 months reflects both the potential efficacy of this therapy in the first-line setting and the fact that all the patients were surgically staged. As our systemic therapies improve, issues of locoregional tumor control will become increasingly important.
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2. Ghadirian P, Liu G, Gallinger S, et al: Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer 97:807-810, 2002.
3. Del Chiaro M, Zerbi A, Falconi M, et al: Cancer risk among the relatives of patients with pancreatic ductal adenocarcinoma. Pancreatology 7:459-469, 2007.
4. Huguet F, Andre T, Hammel P, et al: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25:326-331, 2007.
5. Duffy A, Kortmansky J, Schwartz GK, et al: A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol Sept 17, 2007 [epub ahead of print].
6. Kindler HL, Niedzwiecki D, Hollis D, et al: A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB) (abstract 4508). J Clin Oncol 25:199s, 2007.
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