Challenges on the Road to Treatment Advances for Pancreatic Cancer

Localized pancreatic cancer, whether resectable or unresectable, is a separate entity from metastatic pancreatic cancer. Multiple studies have demonstrated that even in the setting of unresectable disease, the progression-free and overall survival of patients with localized pancreatic cancer exceeds that associated with metastatic pancreatic cancer.[1,2] Regardless of tumor size and vascular involvement, the presence or absence of metastases is the greatest prognostic indicator. The article by Duffy and O’Reilly addresses the unique entity of localized pancreatic cancer.

Clinical Trials and Preclinical Models

The clinical trials that have led to the current treatment of pancreatic cancer are largely based on concepts extrapolated from other diseases. The molecular heterogeneity of pancreatic cancer, including the abundant genetic and epigenetic changes, and the contribution of the stromal elements require a distinct approach.

In 2007, the National Institutes of Health sponsored a pancreatic cancer State of the Science meeting to address these important issues in an attempt to understand human pancreatic cancer biology and develop new paradigms of translational clinical research. The issues addressed included the need to (1) identify critical questions and prioritize key strategies and concepts to test; (2) identity cell and stromal-associated signaling pathways that are targets for new drug development; (3) determine how best to utilize preclinical models to identify and test targeted therapy and predictable biomarkers; (4) identify appropriate endpoints and statistical designs for pilot studies; (5) facilitate innovation and collaboration among physician/scientists.

Preclinical models mimicking pancreatic cancer have been challenging. In vitro cell systems may identify drug mechanism of action, but are insufficient to identify the multifarious interactions with the cell stroma and stem cell signaling. The use of orthotopically implanted or genetically engineered tumor models offer a better predictor of clinical activity but still may not be representative of the complex microenvironment of human pancreatic cancer.

Using all of these model systems, as well as high-throughput screens, knockout models, and phosphoproteomics, candidate genes that are mutated or overexpressed in high frequency can establish a genetic signature for human pancreatic cancer. It is feasible that the genetic signature of a localized pancreatic cancer may differ from one that is either clinically localized with subclinical metastases or frankly metastatic. This distinction would clearly identify a population that may benefit from intensive local therapy.

Role of Radiation Therapy

The authors accurately summarize the controversy regarding radiation therapy for localized pancreatic cancer, both in the adjuvant setting and as definitive therapy. To better define the role of radiation as adjuvant therapy, special attention needs to be applied to standardization of the surgical margin status and the radiation fields.

The evaluation of radiation as a component of definitive therapy for locally advanced disease is hampered by the lack of surrogate response markers. Radiographic measures of response are not easily reproducible and offer a poor surrogate for survival. Functional imaging or changes in biomarkers have not been validated as surrogate endpoints for early-phase studies. Despite these deficiencies and challenges, determining the benefit of radiation therapy for localized pancreatic cancer was not considered a high priority while systemic control of disease is so inadequate.

Biologic Diversity

As noted by the authors, localized pancreatic cancer can potentially be a great source of knowledge in understanding tumor cell biology. Maintaining tumor biorepositories of resected pancreatic cancer, stromal tissue, and germline DNA for patients on adjuvant therapy protocols may aid in identifying important prognostic and predictive markers. Using a neoadjuvant treatment approach for resectable pancreatic cancer, important signaling relationships between the stromal tissue and tumor tissue may be uncovered as well as the interaction with pancreatic stem cell signaling. The creation of an ideal reference set for tissue sampling based on high-quality tissue and improved access and sharing of existing biorepositories are critical to the advancement of the field, especially in regard to biomarker validation and drug development.

While it is important to recognize localized pancreatic cancer as a separate entity, the biologic diversity of pancreatic cancer presents challenges for all stages of disease. Surgical resection of resectable pancreatic cancer has evolved to a level that is safe with acceptable morbidity and mortality when preformed at high-volume centers. The recently completed portfolio of trials in the adjuvant (Radiation Therapy Oncology Group [RTOG] 9704 and Charit Onkologie [CONKO] 001),[3,4] locally advanced (Eastern Cooperative Oncology Group [ECOG] 4201),[5] and advanced (Cancer and Leukemia Group B [CALGB], Southwest Oncology Group [SWOG] 0205, Eastern Cooperative Oncology Group [ECOG] 6201, National Cancer Institute of Canada [NCIC])[1,2,6,7] disease settings have failed to advance the field beyond the suboptimal benefits of gemcitabine (Gemzar). Further benefits will only be gained through improved systemic therapies; however, traditional phase II paradigms have proven inadequate to justify moving forward to phase III trials.

In the end, unless we can understand the biology of the stroma-tumor interaction, it will be difficult to identify targeted therapeutic strategies. That said, the roadmap created by the investigators at the State of the Science meeting will provide a structure with which to achieve advances in the treatment and cure of pancreatic cancer.

-Mary F. Mulcahy, MD
-Al B. Benson III, MD

This commentary refers to the following article: What Is the Optimal Treatment of Localized Pancreatic Adenocarcinoma?

References:

References

1. Kindler HL, Niedzwiecki D, Hollis D, et al, for the Cancer and Leukemia Group B: 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(18S):199s, 2007.
2. Moore MJ, Goldstein D, Hamm J, et al, for the National Cancer Institute of Canada Clinical Trials Group: 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.
3. Regine WF, Winter KA, Abrams RA, et al: Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial. JAMA 299:1019-1026, 2008.
4. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled triall. JAMA 297:267-277, 2007.
5. Loehrer PJ, Powell ME, Cardenes HR, et al, for the Eastern Cooperative Oncology Group: A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201 (abstract 4506). J Clin Oncol 26(15S):214s, 2008.
6. Philip PA, Benedetti J, Fenoglio-Preiser J, 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(18S):199s, 2007.
7. Poplin E, Levy DE, Berlin J, et al: Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion[FDR]) versus gemcitabine + oxaliplatin(GEMOX) in patients with advanced pancreatic cancer (E6201) (abstract LBA4004). J Clin Oncol 24(18S):180s, 2006.