In this issue of ONCOLOGY, the case and discussion provided by Dasari and colleagues highlight a significant problem for many patients with potentially resectable pancreatic cancer (PC)—the rapid emergence of preexisting metastatic disease. The authors describe the case of a 57-year-old woman with a resectable tumor after staging evaluation and management which included an endoscopic ultrasound (EUS), CT imaging, and endoscopic retrograde cholangiopancreatography (ERCP) with insertion of an endobiliary stent. Although the results from EUS are not detailed in the report, there were apparently no preoperative features to suggest more advanced disease, and she underwent surgery. Four weeks later, she presented with advanced disease manifested by an elevated CA 19-9, bilobar liver metastases, and possible local recurrence. This case illustrates some important considerations in the management of PC as we discuss here.
The Importance of Preoperative Imaging
The authors describe a CT scan that fits the resectability criteria (ie no involvement of the superior mesenteric artery and celiac axis and a patent superior mesenteric vein). Resectability can and should be determined with dynamic phase, multidetector CT or MR prior to surgery. Although EUS is often complimentary to cross-sectional imaging, in this case it did not appear to add useful information, and we believe the shift will be to three-dimensional reconstructions of acquired CT images to better define local tumor extent. It is imperative that jaundiced patients have their baseline CT scan optimized for pancreas imaging prior to ERCP and stent placement, given the clear risk of ERCP-related pancreatitis which may confound staging. Given our institutional interest in preoperative therapy, we prefer to use EUS with fine needle aspirate to acquire tissue to confirm the presence of malignancy.
Preoperative Management of Obstructive Jaundice
This patient underwent ERCP with plastic stent placement and experienced post stent cholangitis, which required a stent exchange. We agree with the authors that plastic stents in the preoperative setting are notorious for occlusion and probably unecessary for an asymptomatic, good-performance status patient undergoing up-front PD. We have experience using self-expanding metal stents in the setting of preoperative therapy, and these have not shown a negative impact on subsequent PD. In recent years, we have routinely inserted expandable metal stents in patients who will undergo > 8 weeks of preoperative therapy, and our experience suggests that this reduces the rate of stent failure.
Upfront Surgery and Adjuvant Therapy—Sobering Facts
This case reflects the current standard for a patient with potentially resectable PC, and the pitfalls associated with upfront resection. First, as Dr. McManus discussed, upfront surgery frequently leads to positive surgical margins, which even in high-volume centers, lead to median survivals of ~ 15 months.[2,3] Second, among patients undergoing resection for PC, only about 60% receive post-operative therapy, based on poor recovery, death, patient refusal, or evidence of metastatic disease,[4,5] as was observed in this woman. The frequency of early onset metastatic disease after surgery has not been rigorously studied. However, results from several studies demonstrate that approximately 15% of patients undergoing preoperative therapy will develop radiographically detectable metastatic disease within weeks of enrollment. Translating the preoperative experience into the adjuvant setting would suggest that at least 15% of patients who receive upfront surgery will have evidence of overt metastatic disease in the early recovery period. This is probably an underestimate since the physiologic response to surgery (immunosuppression, cytokine and growth factor surge, etc) may promote the growth of existing micrometastases in the postoperative period. Importantly, we believe that modern adjuvant trials have enrolled subsets of patients with overt metastatic disease, and this likely contributes to the third and most troubling challenge in using upfront surgery and adjuvant therapy: We have made virtually no progress with this approach since 1985.[7,8]
An Alterative Strategy for Resectable Disease: Pre-Operative Therapy
We believe that it is time for a broader exploration of preoperative therapy in PC centers of excellence. This exploration has sound rationale which includes the initiation of local and systemic therapy shortly after diagnosis rather than weeks after surgery; treatment of a relatively well-perfused tumor bed; and the provision of a time interval to assess underlying tumor biology, with restaging studies repeated prior to surgery to rule out the interval development of metastatic disease. Patients with rapid-onset metastases would thereby be spared the morbidity of surgery, a futile modality in this setting. Moreover, when high-quality staging is linked with preoperative chemoradiation, isolated local recurrence rates have been very low (less than 10%). In addition, emerging data suggests that R0 resection rates are somewhat higher using preoperative chemoradiation compared with upfront surgical resection, with survival at least as good as historical controls of the best adjvuant therapy.[10,11] Thus far, preoperative strategies for PC have not been widely adopted especially given the ineffective systemic therapies available. Nevertheless, in a cancer that is systemic in most patients at presentation, as better cytotoxic and molecular therapies are developed, a surgery-last strategy should become increasingly attractive.
Medical Management of Advanced Pancreatic Cancer
Dr. Messersmith provides a succinct yet comprehensive discussion of the management of metastatic PC. While past efforts to improve systemic therapy have been disappointing, newer therapies are showing some promise. Nano-particle albumin-bound paclitaxel (nab-paclitaxel) has recently been reported to be active in advanced PC when combined with gemcitabine, and results from an ongoing phase III trial comparing gemcitabine plus nab-paclitaxel with gemcitabine alone are anxiously awaited. This study is also designed to determine whether tumor-associated secreted protein, acidic, cysteine-rich (SPARC) levels are predictive of improved outcomes with nab-paclitaxel. More encouraging news has come from a report from Conroy and colleagues, who have presented results from a randomized phase III trial comparing a combination of fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) with gemcitabine as first-line treatment for metastatic PC. They reported a median OS of 10.5 months using FOLFIRINOX versus 6.9 months with gemcitabine, (HR = 0.61; 95% CI = 0.46-0.81; P < .001). Lastly, manipulation of the tumor microenvironment is a recent focus of preclinical research. Emerging data suggests that chemoresistance may be related to poor penetration of drugs into cancerous tissue, and using a hedgehog (Hh)-signaling pathway antagonist, IPI-926, Olive and colleagues have shown depletion of tumor-associated stroma, increased intratumoral vascular density, and improved delivery of gemcitabine in murine models of PC. All of these are important developments that may transform our local and systemic therapies. By combining our expanding weaponry with improved patient selection methods, we will hopefully begin to make more clinically meaningful advances in treatments for our patients.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Fishman EK, Ney DR, Heath DG, et al. Volume rendering versus maximum intensity projection in CT angiography: what works best, when, and why. Radiographics. 2006; 26(3):905-22.
2. Winter JM, Cameron JL, Campbell KA, , et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg. 2006;10(9):1199-210; discussion 210-1.
3. Fatima J, Schnelldorfer T, Barton J, , et al. Pancreatoduodenectomy for ductal adenocarcinoma: implications of positive margin on survival. Arch Surg. 2010; 145(2):167-72.
4. Herman JM, Swartz MJ, Hsu CC, et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol. 2008; 26(21):3503-10.
5. Corsini MM, Miller RC, Haddock MG, et al. Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975-2005). J Clin Oncol. 2008;26(21):3511-6.
6. Wolff RA, Varadhachary GR, Evans DB. Adjuvant therapy for adenocarcinoma of the pancreas: analysis of reported trials and recommendations for future progress. Ann Surg Oncol. 2008; (10):2773-86.
7. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120(8):899-903.
8. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073-81.
9. Greer SE, Pipas JM, Sutton JE, et al. Effect of neoadjuvant therapy on local recurrence after resection of pancreatic adenocarcinoma. Journal of the American College of Surgeons. 2008;206(3):451-7.
10. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3496-502.
11. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3487-95.
12. Von Hoff DD, Ramanathan R, Borad M, et al. SPARC correlation with response to gemcitabine plus nab-paclitaxel in patients with advanced pancreatic cancer: A phase I/II study. J Clin Oncol. 2009;27(15s; abstract 4525).
13. Conroy T, Desseigne F, Ychou M, et al. Randomized phase III trial comparing FOLFIRINOX (5FU/leucovorin, irinotecan, and oxaliplatin) versus gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma: Preplanned interim analysis of the PRODIGE4/ACCORD 11 trial. J Clin Oncol. 2010;28(7s; abstract 4010).
14.Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457-61.