Key Challenges in Managing Advanced Pancreatic Cancer

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.[3] 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.[4] 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.

Other Agents

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.[5] 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.

As pointed out by the authors, progress in the metastatic setting has been mixed. The negative phase III data for bevacizumab (Avastin)- and cetuximab (Erbitux)-containing regimens is particularly disappointing given their demonstrated efficacy in other gastrointestinal cancers and the strong rationale for their use in pancreatic ductal adenocarcinoma.[6,7] As outlined by the authors, cytotoxic combinations of gemcitabine with capecitabine (Xeloda) and platinum agents do appear to offer a small benefit, particularly in patients with good performance status.

Survival Benefit

What is one to make of the recently published study by Moore et al? In this study, 569 patients with untreated locally advanced or metastatic pancreatic cancer were randomized to receive gemcitabine with either erlotinib or placebo. The investigators observed a very modest but statistically significant improvement in progression-free survival (hazard ratio [HR] = 0.77, 95% confidence interval [CI] = 0.64–0.92; P = .004), 1-year survival (23% vs 17%; P = .023), and median overall survival (6.24 vs 5.91 months, HR = 0.82, 95% CI = 0.69–0.99; P = .038) favoring the erlotinib arm.[8] This was the first trial to show a survival benefit for any combination therapy in pancreatic cancer and led to US Food and Drug Administration approval of this combination in front-line therapy for pancreatic cancer in 2005.

As has been the experience with epidermal growth factor receptor (EGFR) inhibitors in colorectal cancer and lung cancer, the occurrence of a rash in the study by Moore et al was associated with improved survival after controlling for other prognostic factors (P = .037; HR = 0.74; 95% CI = 0.56–0.98). The median survival rates for patients with grade 0, 1, and 2+ rash were 5.3, 5.8, and 10.5 months, respectively; and the 1-year survival rates were 16%, 9%, and 43% (P < .001). These data suggest that although the benefit for the entire cohort is small, a specific subpopulation of patients do benefit significantly from the addition of erlotinib.

The molecular basis for sensitivity/resistance to erlotinib in pancreatic cancer is unclear. Unlike the case in non–small-cell lung cancer, no predictive EGFR mutations have been discovered.[9] Likewise, the relationship between K-ras mutations and response to tyrosine kinase inhibition (a well established inverse relationship in lung cancer and probably colon cancer) has not been elucidated for pancreatic cancer.[10,11]

Looking Ahead

Future priorities in pancreatic cancer include the following: (1) Given the negative phase III data involving regimens that had appeared promising at the phase II level, an increased consideration should be given to the incorporation of a randomized phase II trial design in order to strengthen the signal prior to committing to phase III development. (2) We need a renewed focus on conducting clinical trials in the significant population of patients who proceed to second-line therapy.

In parallel with these efforts, a major emphasis on tissue procurement may assist in furthering an understanding of the fundamentals of pancreatic cancer tumor biology when new strategies work, and perhaps even more importantly, when and why they do not. Although concrete progress in this field has been limited, we believe the future holds promise-not the least of which is a reflection of the interest of clinical investigators, society at large, and major and minor pharma in this disease.

-Austin Duffy, MD
-Eileen M. O'Reilly, MD

References:

1. Schenk M, Schwartz AG, O'Neal E, et al: Familial risk of pancreatic cancer. J Natl Cancer Inst 93:640-644, 2001.

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.

7. Philip PA, Benedetti J, Fenoglio-Preiser C, et al: Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study (abstract LBA4509). J Clin Oncol 25:199s, 2007.

8. Moore MJ, Goldstein D, Hamm J, 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 25:1960-1966, 2007.

9. Kwak EL, Jankowski J, Thayer SP, et al: Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 12:4283-4287, 2006.

10. Moore MJ, da Cunha Santos G, Kamel-Reid S, et al: The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3 (abstract 4521). J Clin Oncol 25(18S):202s, 2007.

11. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Medicine 2:e17, 2005.