Neoadjuvant Strategies for Pancreatic Cancer

This report by Drs. Evans, Wolff, and Crane is a well-written and concise description of their extensive experience with the treatment of pancreatic cancer. They and others at the M. D. Anderson Cancer Center should be congratulated for their innovative, methodical, and thoughtful approach to the treatment of this lethal disease.

Only 4% of patients with adenocarcinoma of the pancreas survive 5 years; the majority die of their disease within the first year. This dismal survival rate is due, in part, to the fact that most patients initially present with advanced disease. However, even for the 15% to 20% diagnosed with "localized disease" who undergo potentially curative resection, survival is poor, with 5-year rates ranging from 10% to 20%.

The Argument for a Neoadjuvant Approach

Various neoadjuvant or adjuvant strategies have been developed recently in an attempt to improve the survival of patients with resectable disease. These are based mostly on either pre- or postoperative administration of combined-modality chemoradiation. To date, no approach has been found to be superior in terms of survival.

The authors and their colleagues have adopted a neoadjuvant approach based on the following premises:

1. Neoadjuvant therapy can be safely administered to most patients, thereby avoiding the effect of delayed postoperative recovery that may preclude postoperative therapy in 20% of patients.

2. The surgical procedure is improved by reducing the incidence of positive margins and thus the local recurrence rate. In addition, Dr. Evans et al have presented data suggesting that the incidence of pancreaticojejunal anastomotic fistulization is also reduced.

3. Patients who are found to have disseminated disease at restaging following neoadjuvant chemoradiation are spared the morbidity of an unnecessary laparotomy.

Staging Disease Accurately

The ability to accurately stage the extent of disease is critical to the success of a neoadjuvant approach. In diseases for which neoadjuvant therapies have been established (such as esophageal or rectal cancer), pretreatment radiologic staging has been shown to be accurate. However, that is not the case for adenocarcinoma of the pancreas despite recent advances in radiologic imaging. Subradiologic, small-volume metastatic disease is not uncommon. In my experience, liver metastases are present in approximately 25% of patients at the time of restaging following administration of neoadjuvant therapy. These data are similar to what is seen with laparoscopic staging of patients who present with potentially resectable disease following radiologic work-up.

In a recent study of 577 patients with peripancreatic malignancy who were considered to have resectable disease, 150 were found to have evidence of unresectability at laparoscopic staging. Of these, 137 patients had liver or extrapancreatic peritoneal disease that was not appreciated despite adequate radiologic imaging. Other researchers have published similar results. The majority of patients with metastatic disease were not treated surgically and were offered systemic therapies. None received radiation—a modality that would have had minimal or no impact on either their quality of life or ultimate survival.

The Question of Resectability

Taking the authors’ data, it could be argued that their approach overtreats a considerable number of patients. The benefit of neoadjuvant therapy in patients with progressive disease at restaging or subsequent laparotomy is questionable. In addition, combined-modality therapy is not without risk in this population of patients, many of whom are elderly and have significant comorbid conditions. Clearly, the area of patient selection needs further study before this approach can be applied more widely.

The definition of resectability is also somewhat variable from institution to institution depending on the philosophy or aggressiveness of the unit, making the interpretation of data somewhat difficult. Nonetheless, there is no convincing evidence that neoadjuvant therapy improves resectability rates. In their article, the authors cite a resectability rate of 74% following rapid-fractionation chemoradiation. At Memorial Sloan-Kettering, the combination of a contrast-enhanced, thin-cut, dynamic computed tomography scan and laparoscopic staging has resulted in a resectability rate of more than 90%. In addition, despite other reported results, we have been unable to demonstrate "downstaging" of surgically staged, locally advanced disease with the use of combined-modality therapy.

In a recent report from our institution, only 3 of 87 patients who were restaged following therapy were considered to have been converted from unresectable to resectable disease.[1] Of these patients, only one was ultimately resected.

Future Therapies Awaited

These disappointing results highlight our current lack of effective therapies. The authors have concisely summarized the results of recent randomized trials, none of which have demonstrated that any therapy has superior efficacy. It may be that the current approach at M. D. Anderson of combining novel radiosensitizing agents with biological modifiers and chemotherapeutic agents holds promise. Some preliminary evidence that this may indeed be the case has been reported recently from the Virginia Mason Medical Center in Seattle.[2] These investigators reported the results of a phase II trial of an interferon/cisplatin (Platinol)/fluorouracil (5-FU)-based chemoradiation protocol that resulted in significant improvement in actuarial survival, compared to concurrent treatment with standard 5-FU-based chemoradiation. This trial, it is hoped, will form the basis of a future American College of Surgeons Oncology Group trial.

The M. D. Anderson group should be applauded for their honest and innovative approaches to this disease. We also believe that future progress will be made, not by adopting a nihilistic attitude, but rather, through novel therapies based on our increasing understanding of the biological basis of this disease. We await their future results with interest.