J Gastrointest Canc DOI 10.1007/s12029-014-9662-3
CASE REPORT
Response to Nab-Paclitaxel plus Gemcitabine in a Patient with Primary Resistance to FOLFIRINOX Zachary Reese & Shiven Patel & David D. Stenehjem & Ignacio Garrido-Laguna
# Springer Science+Business Media New York 2014
Introduction Survival rates for patients with most gastrointestinal malignancies have consistently increased in the last 20 years. Unfortunately, this has not been paralleled in patients with pancreatic cancer which continues to be a devastating disease with a 5-year survival rate of less than 5 % [1]. In fact, pancreatic cancer is projected to become the deadliest cancer by 2020 [2]. Single agent gemcitabine, a nucleoside analog, became the standard of care nearly two decades ago when it was shown to have a modest improvement in survival compared to 5-fluorouracil (5FU) in patients with advanced disease [3]. However, multiple randomized phase 3 trials failed to show any improvement in survival with gemcitabine in combination with cytotoxic or targeted therapies [4–8]. The addition of erlotinib to gemcitabine led to a modest 10-day improvement in survival in a large randomized phase 3 trial [9]. While it is possible that a small subset of patients with advanced disease will benefit from adding erlotinib, it is also possible that erlotinib could be detrimental for other patients. Indeed, it is well known that antiEGFR therapies, such as erlotinib, are detrimental in Z. Reese : S. Patel : I. Garrido-Laguna (*) Department of Internal Medicine (Division of Oncology) and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Suite 2100, Salt Lake City, UT 84112, USA e-mail: [email protected] D. D. Stenehjem Pharmacotherapy Outcomes Research Center (PORC), College of Pharmacy, University of Utah, Salt Lake City, UT, USA D. D. Stenehjem Department of Pharmacy, Huntsman Cancer Institute, Salt Lake City, UT, USA
patients with KRAS-positive non-small cell lung cancer or colorectal cancer [10]. A closer review of the PA.3 study shows that KRAS wild-type patients treated with gemcitabine and erlotinib demonstrated a trend toward improved survival, while the opposite was true for patients with KRAS mutations. Though this difference was not statistically significant, a true detrimental effect from adding erlotinib to patients with KRAS mutations may have gone undetected given that only 20 % of patients had tissue available for biomarker analysis [11]. A retrospective review of Korean patients with advanced pancreatic cancer showed that gemcitabine and erlotinib led to improved overall survival in KRAS wild-type patients compared with those harboring KRAS mutations (9.7 vs. 5.2 months, hazard ratio (HR)=0.45, p=0.002). Additionally, patients with KRAS mutations treated with erlotinib had a trend toward poorer survival compared to other regimens (5.2 vs. 7.0 months, HR 0.64, p=0.067) [12]. These patients were evaluated for KRAS mutations at only three codons using traditional Sanger sequencing, leading to a likely underestimate of the true incidence of KRAS mutations. It is possible that newer deep sequencing techniques could identify additional patients with RAS mutations, thus helping to further delineate potential benefits and harms of erlotinib treatment. More recently, two large randomized phase 3 trials have shown improvements in survival using FOLFIRINOX (a combination of 5FU, irinotecan, and oxaliplatin; PRODIGE trial) or nab-paclitaxel plus gemcitabine (Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT)) in patients with metastatic disease. The Partenariat De Recherche En Oncologie Digestive (PRODIGE) trial recruited previously untreated patients less than 75 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. FOLFIRINOX led to an approximate 4-month improvement in median overall survival compared to single
J Gastrointest Canc Fig. 1 Partial response to therapy in liver metastases
agent gemcitabine (11.2 vs. 6.8 months, HR=0.57, p
CASE REPORT
Response to Nab-Paclitaxel plus Gemcitabine in a Patient with Primary Resistance to FOLFIRINOX Zachary Reese & Shiven Patel & David D. Stenehjem & Ignacio Garrido-Laguna
# Springer Science+Business Media New York 2014
Introduction Survival rates for patients with most gastrointestinal malignancies have consistently increased in the last 20 years. Unfortunately, this has not been paralleled in patients with pancreatic cancer which continues to be a devastating disease with a 5-year survival rate of less than 5 % [1]. In fact, pancreatic cancer is projected to become the deadliest cancer by 2020 [2]. Single agent gemcitabine, a nucleoside analog, became the standard of care nearly two decades ago when it was shown to have a modest improvement in survival compared to 5-fluorouracil (5FU) in patients with advanced disease [3]. However, multiple randomized phase 3 trials failed to show any improvement in survival with gemcitabine in combination with cytotoxic or targeted therapies [4–8]. The addition of erlotinib to gemcitabine led to a modest 10-day improvement in survival in a large randomized phase 3 trial [9]. While it is possible that a small subset of patients with advanced disease will benefit from adding erlotinib, it is also possible that erlotinib could be detrimental for other patients. Indeed, it is well known that antiEGFR therapies, such as erlotinib, are detrimental in Z. Reese : S. Patel : I. Garrido-Laguna (*) Department of Internal Medicine (Division of Oncology) and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Suite 2100, Salt Lake City, UT 84112, USA e-mail: [email protected] D. D. Stenehjem Pharmacotherapy Outcomes Research Center (PORC), College of Pharmacy, University of Utah, Salt Lake City, UT, USA D. D. Stenehjem Department of Pharmacy, Huntsman Cancer Institute, Salt Lake City, UT, USA
patients with KRAS-positive non-small cell lung cancer or colorectal cancer [10]. A closer review of the PA.3 study shows that KRAS wild-type patients treated with gemcitabine and erlotinib demonstrated a trend toward improved survival, while the opposite was true for patients with KRAS mutations. Though this difference was not statistically significant, a true detrimental effect from adding erlotinib to patients with KRAS mutations may have gone undetected given that only 20 % of patients had tissue available for biomarker analysis [11]. A retrospective review of Korean patients with advanced pancreatic cancer showed that gemcitabine and erlotinib led to improved overall survival in KRAS wild-type patients compared with those harboring KRAS mutations (9.7 vs. 5.2 months, hazard ratio (HR)=0.45, p=0.002). Additionally, patients with KRAS mutations treated with erlotinib had a trend toward poorer survival compared to other regimens (5.2 vs. 7.0 months, HR 0.64, p=0.067) [12]. These patients were evaluated for KRAS mutations at only three codons using traditional Sanger sequencing, leading to a likely underestimate of the true incidence of KRAS mutations. It is possible that newer deep sequencing techniques could identify additional patients with RAS mutations, thus helping to further delineate potential benefits and harms of erlotinib treatment. More recently, two large randomized phase 3 trials have shown improvements in survival using FOLFIRINOX (a combination of 5FU, irinotecan, and oxaliplatin; PRODIGE trial) or nab-paclitaxel plus gemcitabine (Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT)) in patients with metastatic disease. The Partenariat De Recherche En Oncologie Digestive (PRODIGE) trial recruited previously untreated patients less than 75 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. FOLFIRINOX led to an approximate 4-month improvement in median overall survival compared to single
J Gastrointest Canc Fig. 1 Partial response to therapy in liver metastases
agent gemcitabine (11.2 vs. 6.8 months, HR=0.57, p
