The case of recurrent pancreatic cancer presented in this issue of ONCOLOGY by Dr. Dasari and colleagues illustrates the significant challenges faced by both medical and surgical oncologists in the management of pancreatic adenocarcinoma. This case describes an all-too-common clinical scenario: A thorough preoperative assessment indicating resectable disease, but with the initial medical oncology assessment revealing overt metastatic disease. The development of distant metastases in the short interval between pre-operative and post-operative staging reflects the aggressive underlying biology associated with a subset of patients with this malignancy. New insight into the genetic evolution of pancreas adenocarcinoma from Yachida and colleagues suggests that the latent period between initial development of pancreas adenocarcinoma and development of metastases is measured in years, however detection of the diagnosis at an early stage remains an ongoing challenge for clinicians.
Pre-operatively, it is difficult to distinguish the patients with potential for long-term survival from those who are destined to relapse early with distant metastases and who are thus unlikely to benefit from surgical intervention. Furthermore, the morbidity associated with pancreaticoduodenectomy may delay or prevent the use of post-operative adjuvant systemic therapy, leaving micrometastatic disease untreated. These observations provide a compelling rationale for the use of neoadjuvant therapy, which is particularly relevant for patients with borderline resectable disease. For this group, the use of neoadjuvant therapy is supported by the current National Comprehensive Cancer Network (NCCN) practice guidelines and by the consensus statement of the American Hepato-Pancreato Biliary Association (AHPBA).[2,3] There are currently no randomized data evaluating the use of neoadjuvant therapy compared to postoperative adjuvant therapy for pancreatic adenocarcinoma, although the feasibility and safety of neoadjuvant chemotherapy and chemoradiation has been confirmed in phase II trials from several academic centers.[4,5] A recent systematic review of 111 studies of neoadjuvant therapy in pancreatic cancer found that one-third of patients initially considered unresectable were able to undergo surgical resection following neoadjuvant therapy, and the survival of this group was similar to patients who underwent surgical resection at diagnosis. The interpretation of this data is limited by a lack of standard definition of resectable disease, however it offers support for the inclusion of both resectable and borderline unresectable patients in trials of neoadjuvant therapy.
In the case discussed by Dasari et al, the patient’s post operative CA 19.9 level was significantly elevated at 483U/ml four weeks post-operatively, prompting further radiologic evaluation and the identification of extensive metastatic disease. The post-operative CA 19.9 level has been shown to have a prognostic implication in patients who undergo surgical resection of pancreatic adenocarcinoma. In the RTOG 9704 clinical trial, Berger et al reported on 385 patients treated with adjuvant chemoradiation , where prospective evaluation of the impact of CA 19.9 on survival was included as a secondary endpoint. The median overall survival of patients with CA 19.9 > 180 post operatively was 9 months, compared to 21 months for patients with CA 19.9 < 180 (P < .0001). Levels were assessed a median of 45 days post surgical resection. It remains unclear if this prognostic implication arises simply due to the presence of radiographically occult disease or extensive micrometastases, or if increased secretion of CA 19.9 indicates a more aggressive underlying tumor biology.
Dasari and colleagues provide a comprehensive review of the published data regarding gemcitabine/capecitabine and gemcitabine/platinum combination chemotherapy regimens for advanced pancreatic cancer. In patients with ECOG performance status 0-1, several meta-analyses have indicated a survival benefit to the addition of either agent to a gemcitabine backbone,[8,9] while a consistently increased response rate is seen with combination chemotherapy, compared to single-agent gemcitabine in individual trials. More recent data, however, has provided the strongest evidence to date for the use of combination chemotherapy regimens in pancreatic adenocarcinoma. The PRODIGE4/ACCORD II phase III trial, presented at the American Society of Clinical Oncology in 2010, randomized 342 patients with metastatic pancreatic adenocarcinoma to six months of chemotherapy with FOLFIRINOX (5-fluorouracil/leucovorin/oxaliplatin/irinotecan) or gemcitabine alone. Enrollment was limited to patients with ECOG performance status 0-1 and age less than 75 years. No prior therapy was allowed. A significant overall survival benefit was seen in the FOLFIRINOX arm, with a median survival of 11.1 months vs 6.8 months in the gemcitabine arm (P < .0001, HR 0.57). The 18-month survival rate in the combination arm was 18.6%, compared to 6% in the gemcitabine arm. The response rate to FOLFIRINOX was 31.6%, compared to 9.4% with single-agent therapy. There was also a notable prolongation in progression-free survival. However, these benefits came at the cost of a significant increase in febrile neutropenia rates, with a grade 3 or 4 febrile neutropenia rate of 5.4% vs 0.6% (P = .009); there was also significantly more grade 3 / 4 diarrhea (12.7% vs 1.2%), fatigue (23.2% vs 14.2%) and peripheral neuropathy (9% vs 0) with the combination regimen. The rates of toxic death, however, were equal in both arms (one patient in each). Based on these data, FOLFIRINOX is a reasonable choice of first-line chemotherapy in selected patients who retain an excellent performance status. The high response rate makes this a promising regimen for future evaluation in trials of neoadjuvant therapy, and evaluation in the adjuvant setting is planned.
Looking to the future, several promising novel agents are undergoing prospective evaluation in advanced pancreatic adenocarcinoma. Novel formations of taxanes, including nab-paclitaxel, an albumin-bound nanoparticle form of paclitaxel, and Endo-Tag-1, a novel paclitaxel formulation with both anti-vascular and cytotoxic effects, have also recently shown encouraging data in treatment of advanced pancreatic cancer. These agents offer the theoretic advantage of targeting the stromal and vascular environment as well as neoplastic cells, and are currently either undergoing or are planned for prospective evaluation in phase III randomized trials. Other pathways of interest in the development of targeted therapy include the RAS, hedgehog, and tyrosine kinase signaling pathways. Recently published pre-clinical data by Olive et al demonstrated increased tumor delivery and enhanced efficacy of gemcitabine in the presence of the hedgehog pathway inhibitor IPI-926 in mouse models of pancreatic cancer. This indicates a potential role for this class of drugs in combination with cytotoxic agents, in which the effect on increasing tumor vascular density and disruption of desmoplastic stroma facilitates drug delivery to tumor cells. A multicenter phase II trial of the hedgehog pathway inhibitor GDC-0449 with nab-paclitaxel and gemcitabine is currently underway.
In conclusion, pancreatic adenocarcinoma remains a challenging malignancy, as evidenced by the case presented in this issue of ONCOLOGY by Dasari and colleagues. This case highlights several current issues, in particular the observation that neoadjuvant therapy may allow better selection of patients for surgical intervention. The encouraging overall survival benefit reported by the PRODIGE 4 / ACCORD II trial would make FOLFIRINOX a reasonable consideration for first line treatment of metastatic disease in this asymptomatic patient, following careful discussion of potential toxicities. Over the coming decade, the ongoing development of novel therapeutic strategies directed at key signaling pathways, and the optimal combination of these agents with cytotoxic chemotherapy will afford us the potential to achieve a meaningful improvement in survival for patients with both localized and metastatic disease.
Financial Disclosure: Dr. O’Reilly receives research funding from Sanofi-Aventis.
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