Accepted Manuscript Stereotactic Body Radiotherapy (SBRT) for Locally Advanced Extrahepatic and Intrahepatic Cholangiocarcinoma Kiri A. Sandler, M.D., Darlene Veruttipong, M.P.H., Vatche G. Agopian, M.D., Richard S. Finn, M.D., Johnny C. Hong, M.D., Fady M. Kaldas, M.D., Saeed Sadeghi, M.D., Ronald W. Busuttil, M.D., Ph.D., Percy Lee, M.D. PII:
S2452-1094(16)30062-8
DOI:
10.1016/j.adro.2016.10.008
Reference:
ADRO 51
To appear in:
Advances in Radiation Oncology
Received Date: 2 August 2016 Revised Date:
30 September 2016
Accepted Date: 24 October 2016
Please cite this article as: Sandler KA, Veruttipong D, Agopian VG, Finn RS, Hong JC, Kaldas FM, Sadeghi S, Busuttil RW, Lee P, Stereotactic Body Radiotherapy (SBRT) for Locally Advanced Extrahepatic and Intrahepatic Cholangiocarcinoma, Advances in Radiation Oncology (2016), doi: 10.1016/j.adro.2016.10.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Stereotactic Body Radiotherapy (SBRT) for Locally Advanced Extrahepatic and Intrahepatic Cholangiocarcinoma Kiri A. Sandler, M.D.1, Darlene Veruttipong, M.P.H.1, Vatche G. Agopian, M.D.2, Richard S.
RI PT
Finn, M.D.3, Johnny C. Hong, M.D.2, Fady M. Kaldas, M.D.2, Saeed Sadeghi, M.D.3, Ronald W. Busuttil, M.D., Ph.D.2, Percy Lee, M.D.1
Department of 1Radiation Oncology, 2Surgery, 3Department of Medicine, Division of
Conflicts of interest: None
AC C
EP
TE D
Corresponding author: Percy Lee, M.D. 200 UCLA Medical Plaza, B265 Los Angeles, CA 90095 Office: 310-825-9771 Fax: 310-794-9795 Email:
[email protected]
M AN U
Short Title: SBRT for unresectable cholangiocarcinoma
SC
Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
This is one of the largest reported studies composed primarily of patients with extrahepatic unresectable cholangiocarcinoma treated with stereotactic body radiation therapy and chemotherapy with or without orthotopic liver transplantation (OLT). Compared to historical controls, we demonstrated a favorable local control (1-year actuarial rate of 78%) and overall survival (59% at one year) in the entire cohort, especially in the subset of patients who received OLT (median overall survival 31.3 months).
ACCEPTED MANUSCRIPT
ABSTRACT Objectives: We report single-institution clinical efficacy and safety outcomes for patients with unresectable
RI PT
locally advanced cholangiocarcinoma treated with stereotactic body radiotherapy (SBRT), a subset of whom received neoadjuvant SBRT and chemotherapy as part of an orthotopic liver transplantation (OLT) protocol.
SC
Methods:
From October 2008 to June 2015, 31 consecutive patients with unresectable extrahepatic (n = 25)
M AN U
or intrahepatic (n = 6) cholangiocarcinoma were treated with SBRT and retrospectively analyzed. Four patients underwent liver transplantation and 1 underwent resection. SBRT was delivered in 5 fractions, with a median dose of 40 Gy. Toxicity was scored using CTCAE v4.0. Overall survival, time to progression, and local control were estimated using the Kaplan-Meier
Results:
TE D
method.
The median follow up time was 11.5 months. The 1-year and 2-year overall survival rates were
EP
59% and 33% with a median survival of 15.7 months. The 1-year and 2-year freedom from progression was 67% and 34%. Median time to progression was 16.8 months. Nine patients had
AC C
local failure. The actuarial 1-year and 2-year local control rates were 78% and 47%. Among patients who went on to have OLT, the median overall survival was 31.3 months. Twenty-four patients (77%) experienced some form of acute Grade 1-2 toxicity, most commonly fatigue or pain. Five patients (16%) experienced Grade ≥ 3 toxicity. Conclusions:
ACCEPTED MANUSCRIPT
SBRT is a promising option for patients with unresectable or recurrent cholangiocarcinoma, either as a component of neoadjuvant therapy prior to OLT, or as part of definitive therapy for
AC C
EP
TE D
M AN U
SC
RI PT
unresectable patients not eligible for transplantation.
ACCEPTED MANUSCRIPT
INTRODUCTION Cholangiocarcinoma is a malignancy of the biliary duct epithelium and is typically classified as either intrahepatic or extrahepatic. Klatskin tumors arise at the bifurcation of the
RI PT
common bile duct and represent about 50 percent of cases.1 Cholangiocarcinoma is uncommon, but there is some evidence that its incidence is increasing over the past few decades.2 Prognosis is generally poor, however it is improved in patients able to undergo surgical resection.
SC
Unfortunately, few patients are candidates for resection at the time of presentation.3 Treatment for unresectable or recurrent disease typically focuses on palliation with overall survival in single
M AN U
digits at 5 years and median survival of approximately 7 months.4 Definitive radiation therapy, with or without chemotherapy, improves median survival in unresectable cases from 2-4 months to 9-12 months.5, 6 Even with locoregional radiation therapy, local recurrence is commonly the first site of progression and mortality is often associated with consequences of local tumor
TE D
growth. This has led to an interest in improving local control by escalating radiotherapy dose both with brachytherapy7 and SBRT, both with encouraging results. A retrospective series from Mayo Clinic reported 10 patients with unresectable primary or recurrent cholangiocarcinoma
EP
who underwent SBRT using a median dose of 55 Gy.8 This study demonstrated 100% local control at a median follow up of 14 months, but the toxicity was unfortunately high. Recent
AC C
retrospective data from MD Anderson demonstrated a dose-dependent improvement in local control and overall survival9 when radiation therapy with a biologic effective dose (BED) of greater than 80.5 was delivered, which compared favorably with surgical resection. The toxicity profile in this study was favorable, however the majority of the patients had intrahepatic disease. Very little data is available reporting the use of SBRT in the treatment of unresectable extrahepatic cholangiocarcinoma. We thus sought to understand our institutional clinical
ACCEPTED MANUSCRIPT
outcomes utilizing SBRT and chemotherapy; both neoadjuvantly prior to orthotopic liver transplant (OLT), and definitively in patients who were not eligible for OLT.
RI PT
METHODS AND MATERIALS Patients and follow up:
Thirty-one patients with cholangiocarcinoma who underwent SBRT between October
SC
2008 and June 2015 were included in the study. Our institutional review board approved the study, and retrospectively acquired data were de-identified according to the Health Insurance
M AN U
Portability and Accountability Act guideline. A subset of patients were part of a single institution prospective study evaluating the use of neoadjuvant SBRT with chemotherapy followed by orthotopic liver transplant (OLT) for unresectable or recurrent cholangiocarcinoma. Of the 31 patients, 18 were on the study and evaluated for transplant, 14 patients were listed, and 4
TE D
ultimately underwent OLT. Inclusion and exclusion criteria:
Consecutive patients who were treated with SBRT for either intrahepatic or hilar
EP
cholangiocarcinoma were included. Patients were diagnosed by malignant stricture on cholangiography or biopsy/cytology results demonstrating malignancy, CA 19-9 >100 U/mL, or
AC C
aneuploidy. Patients were excluded if they had uncontrolled infection, a lesion >8 cm on imaging, medical conditions or other malignancies which preclude liver transplantation, or extrahepatic malignancy. All of the patients underwent a complete staging workup that typically consisted of positron emission tomography (PET) with computed tomography (CT) and magnetic resonance imaging (MRI). Patients with locoregional nodal involvement were included if the location was adjacent to the primary tumor and thus amenable for inclusion in the
ACCEPTED MANUSCRIPT
high-dose SBRT volume. All of the patients were treated and seen in follow up by the same radiation oncologist (PL). All patients underwent a surgical staging operation prior to OLT. SBRT Treatment Planning:
RI PT
All planning CT scans were obtained on a Siemens SOMATOM Definition AS scanner (Siemens Healthcare Diagnostics, Los Angeles, CA) with IV contrast and a 4-dimensional CT scan (4D CT) was performed under free-breathing conditions. Images were acquired during the
SC
portal venous phase. Data from PET-CT and/or MRI scan with Eovist were incorporated in the target definition when available and helpful. For each case, the gross tumor volume (GTV),
M AN U
normal liver, right and left kidneys, spinal cord, esophagus, stomach, duodenum near GTV, and bowel bag were segmented. An internal target volume (ITV) was generated using the maximumintensity projection derived from the 4D CT in order to derive the tumor’s motion envelope. The ITV was then expanded to 5 to 8 mm in order to generate a planning target volume (PTV).
TE D
The volume of normal liver (i.e., total liver minus PTV) receiving 15 Gy was kept
