CHARM II: Chemotherapy for Ablation and Resolution of Mucinous Pancreatic Cysts
CHARM II: Chemotherapy for Ablation and Resolution of Mucinous Pancreatic Cysts
The purpose of this study is to evaluate the efficacy and safety of chemotherapeutic
 pancreatic cyst ablation using ethanol lavage followed by the infusion of a dual-agent
 chemotherapeutic cocktail (paclitaxel + gemcitabine) compared with alcohol-free saline lavage
 followed by infusion of the same dual-agent chemotherapeutic cocktail (paclitaxel +
 gemcitabine) for the ablation of pancreatic cystic neoplasms using endoscopic ultrasound
 guided fine needle infusion (EUS-FNI) for agent delivery.
Pancreatic cystic lesions are increasingly encountered and typically discovered incidentally
 on cross-sectional imaging, occurring in approximately 2% of all American adults with a 37%
 prevalence in individuals over 80. Most of these cysts are mucinous (neoplastic) in origin
 and represent precursor lesions for pancreatic adenocarcinoma.

 Discovering a pancreatic cyst typically presents a treatment dilemma, with options including
 either indefinite radiographic surveillance with MR (magnetic resonance) or CT imaging or
 surgical resection, both of which have significant limitations. Surveillance carries
 significant economic and possible psychological burdens while waiting for signs of malignancy
 to develop, as well as radiation exposure with computed tomography. On the other hand,
 surgical resection possesses a significant risk of serious adverse events (20%-40%) and
 mortality (1-2%). This clinical dilemma delineates the pressing need to develop effective,
 but more minimally invasive approaches for the elimination of these premalignant pancreatic
 cysts, and among these, endoscopic ultrasound guided fine needle infusion (EUS-FNI) has
 emerged as an innovative and promising approach. Between November 2011 and December 30, 2015,
 investigators from interventional endoscopy, surgical oncology, hematology oncology, and
 pathology of the Penn State Hershey Medical Center conducted the CHARM I clinical trial. This
 was a prospective, randomized, double-blind, single-center study with an N of 46 patients
 required for 80% power to prove non-inferiority. Final results from CHARM I were as follows:
 Patients treated included 23 females and 16 males with the majority of lesions located in the
 body and head of the pancreas. Both the alcohol and alcohol-free groups recorded a 47% rate
 of complete ablation at 6 months, which increased to 64% for both groups at the 1 year
 follow-up. One subject experienced a complication in the alcohol arm (6%), and no subjects
 experienced complications in the alcohol-free arm.

 The overall objectives of CHARM II are to verify the significant findings of CHARM I in a
 multi-center clinical trial as requested by national investigators in this field. We expect
 that administering a specifically designed chemotherapeutic cocktail without prior ethanol
 lavage will result in an equivalent rate of cyst resolution with fewer complications when
 compared with lavage using alcohol. The results of this study will provide important
 information about the most efficient and safest method for treating premalignant pancreatic
 cysts, an important step for treating these lesions with a minimally invasive technique and
 preventing their progression to pancreatic cancer. Standard alternative treatment options for
 this patient group (if not taking part in this study) would be ongoing periodic radiographic
 surveillance with MR or CT imaging waiting for signs of malignancy to develop or to consider
 surgical resection (an option with significant rates of morbidity and mortality).

 This is an investigator-initiated, prospective, randomized, double-blinded, multi-center
 study evaluating ethanol lavage and chemotherapy for the ablation of mucinous and
 indeterminate type pancreatic cysts with malignant potential. Participants will be screened
 for the study according to inclusion and exclusion criteria. After confirming their
 eligibility, patients will be randomized to one of the following EUS-FNI treatment arms in a
 1:1 ratio:

 Control arm: After removal of cyst fluid, cysts will be lavaged for 3 to 5 minutes with 98%
 ethanol and then infused with an admixture of 3 mg/ml paclitaxel and 19 mg/ml gemcitabine.

 Experimental arm: After removal of cyst fluid, cysts will be lavaged for 3 to 5 minutes with
 normal saline and then infused with an admixture of 3 mg/ml paclitaxel and 19 mg/ml
 gemcitabine.

 Patients will be contacted by the study team via phone call at both 72 hours and 30 days
 after their EUS procedure to assess any adverse events that may have occurred. Within 2-3
 weeks of the having the EUS procedure, patients will receive the cyst fluid pathology
 results. At 3 months after the initial procedure, patients will undergo a follow-up EUS
 examination in the same manner as the initial EUS exam. During this exam, a complete
 pancreaticobiliary evaluation will be conducted, and the diameter of the previously treated
 cyst will be measured in the x and y dimensions to assess the 3 month response. Any cyst
 still >15mm and amenable to repeat ablation will undergo a second EUS-guided chemoablation
 treatment using the same lavage that the patient was randomized to initially. At both 12
 months and 24 months after the initial procedure, the patient will be seen in the GI clinic
 and undergo either an MRI-MRCP (magnetic resonance cholangiopancreatography) or enhanced CT
 scan for a full pancreaticobiliary evaluation to assess the end-point treatment response.
Inclusion Criteria:

 -  Adult subjects over the age of 18.

 -  Patients with a previously-detected pancreatic cyst(s) 2-5 cm in diameter which is
 consistent with a mucinous type cyst as per ASGE guidelines, including indeterminate
 type cysts.

 -  Able to give written informed consent.

 -  Capable of safely undergoing endoscopy with deep sedation or general anesthesia.

 Exclusion Criteria:

 -  Lesions which are consistent with a benign cyst by clinical, cytological, chemical,
 and radiographic evaluation as per ASGE guidelines (i.e., consistent with a pseudocyst
 or serous cystadenoma).

 -  Known or suspected pancreatic cancer or pathologic lymphadenopathy.

 -  Cysts with the following high-risk features: main pancreatic duct dilation of > 5mm,
 epithelial type mural nodules (> 2mm)33, pathologically thick wall/septation (> 2mm),
 cytology showing high grade dysplasia or "suspicious for malignancy", signs of common
 bile duct or pancreatic duct obstruction, solid mass component within or associated
 with the cyst (> 2mm), pancreatic duct stricture associated with tail atrophy, or
 previous fine needle aspiration failure due to excessive cyst fluid viscosity. (Of
 note, the following higher-risk features ARE eligible: recent growth in size, atypical
 cells on cytology, and symptoms referable to the pancreas.)

 -  Septated cysts with > 4 compartments.

 -  Confirmed pancreatitis within the last 3 months.

 -  Baseline lab values (must be within 6 months of consent date) in the following ranges:
 white blood cells > 14 or < 2 K/uL, hematocrit <30%, platelets <30 K/uL,
 non-pharmacologic INR >1.7, CA19-9 >2x ULN, lipase >2x ULN, creatinine >3.0 mg/dl
 (unless stable on renal replacement therapy), ALT >500 U/L, total bilirubin >2.5
 mg/dl.

 -  Any pre-existing or discovered medical condition that would, at the discretion of the
 investigator, interfere with the completion of and/or participation in the existing
 protocol. This includes severe pre-existing medical conditions which would preclude a
 reasonable 5 year life expectancy (and thus neutralize the patient's benefit from
 ablating a premalignant type pancreatic cyst).

 -  Pregnancy, breastfeeding, or incarcerated individual.