The article entitled "Neoadjuvant Strategies for Pancreatic Cancer," by Drs. Evans, Wolff, and Crane, is an excellent review of past and current developments in adjuvant therapy for pancreatic cancer. In addition to a thorough literature review, the authors draw on their own extensive experience in neoadjuvant therapy for pancreatic cancer at M. D. Anderson Cancer Center.
Adjuvant Therapy Dilemmas
The authors point out the pitfalls and unproven value of postoperative chemoradiation therapy, especially given that recurrence patterns in this setting usually reflect early disease dissemination. Until recently, systemic chemotherapy has not been a major emphasis of either pre- or postoperative adjuvant therapy. This trend is changing. The current Radiation Therapy Oncology Group (RTOG) trial is randomizing resected patients to systemic chemotherapy first (fluorouracil [5-FU] or gemcitabine(Drug information on gemcitabine) [Gemzar]) followed by 5-FU-based chemoradiation. The European Study Group for Pancreatic Cancer (ESPAC) trial (referred to by Dr. Evans and coauthors) has not yet demonstrated a benefit for chemoradiation, but a trend favoring chemotherapy is emerging. Finally, the authors emphasize the importance of systemic therapy in describing their future plans for neoadjuvant treatment (their Figure 4).
Although it is clear that chemoradiation cannot be delivered to about 25% of patients undergoing resection, no randomized trial has provided evidence that the two approaches, neo vs postoperative adjuvant therapy, are therapeutically equivalent. As the authors acknowledge, 25% of patients "progress through" neoadjuvant therapy and are no longer surgical candidates at the time of planned resection. As the authors also point out, this phenomenon is important and averts the potential morbidity of surgery. However, it also underscores the need for "intent to treat" reporting of data with inclusion of all patients (resected or not), so that comparisons with existing data on postoperative adjuvant therapy can be made.
Preoperative Therapy and Staging
The latter point is extremely important in assessing the benefit of neoadjuvant therapy that is administered with the intent of making unresectable tumors resectable. Although this may be technically feasible, it may not be wise. Even small (1 cm) pancreatic adenocarcinomas are associated with a high incidence of lymph node metastases. Furthermore, as the authors note, the majority of treatment failures occur outside of the pancreatic bed (primarily in the peritoneum, liver, and lung). Thus, it may be wiser to concentrate on more effective systemic therapy until we understand the true value of preoperative chemoradiation in patients with resectable disease.
Finally, the authors’ discussion of preoperative staging and management is useful, thorough, and evidence based. However, one small point for discussion is the authors’ assertion that endoscopically guided fine-needle aspiration is now the procedure of choice for obtaining a tissue diagnosis prior to initiating therapy. While this is certainly a reliable approach, there are no comparative data favoring this approach over a similar biopsy procedure performed percutaneously under computed tomography (CT) guidance; CT-guided biopsies are both accurate and sensitive in this setting.
In summary, this is an excellent review of the early management of patients with potentially resectable pancreatic cancer, outlining the strengths and weaknesses of our current strategies. Future clinical investigation in this setting must focus on optimizing effective systemic therapy, understanding the true value of local radiation, and identifying appropriate candidates for surgical resection.