International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Prognostic Factors and Patterns of Locoregional Failure After Surgical Resection in Patients With Cholangiocarcinoma Without Adjuvant Radiation Therapy: Optimal Field Design for Adjuvant Radiation Therapy Zahra Ghiassi-Nejad, MD, PhD,* Paola Tarchi, MD,y Erin Moshier, MS,z Meng Ru, MS,z Parissa Tabrizian, MD,x Myron Schwartz, MD,x and Michael Buckstein, MD, PhD* Departments of *Radiation Oncology, zPopulation Health Science and Policy, and xSurgery, Icahn School of Medicine at Mount Sinai, New York, New York; and yDepartment of General Surgery, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy Received Mar 20, 2017, and in revised form Jun 13, 2017. Accepted for publication Jun 27, 2017.
Summary Locoregional recurrences after surgical resection for cholangiocarcinoma cause significant morbidity and mortality. This retrospective analysis explores risk factors for local failures and maps locoregional recurrences in patients who underwent surgery without adjuvant radiation. The recurrence map provides valuable information for delineating optimal
Purpose: To identify prognostic factors and patterns of local failure in patients with cholangiocarcinoma (CCA), after surgical resection in the absence of adjuvant radiation, for optimal definition of target volumes encompassing the majority of local recurrences. Methods and Materials: A chart review was performed in patients who underwent resection for primary CCA (intrahepatic, hilar, and distal) between 1999 and 2014. Local failure was defined as recurrence in a theoretical reasonable postoperative radiation volume. This includes the cut surface of liver, biliary anastomosis, hilum, portal nodes, celiac nodes, peri-pancreatic nodes, gastro-hepatic nodes, and retroperitoneal nodes. Patients who received adjuvant radiation were excluded. Results: A total of 189 patients underwent surgical resection for CCA, of whom 145 patients had sufficient follow-up. Median follow-up was 41.6 months (95% confidence interval 35.4-48.7 months). Of the 145 cases, 102 were intrahepatic and 43 were hilar/ distal CCA. Adjuvant chemotherapy was given in 38 cases (26%), of which 20 (54%)
Reprint requests to: Michael Buckstein, MD, PhD, Department of Radiation Oncology, Icahn School of Medicine at Mt. Sinai, 1184 5th Ave, First Floor, New York, NY 10029. Tel: (212) 241-7502; E-mail: Michael
[email protected] Supported by National Cancer Institute Cancer Center Support Grant P30 CA196521-01. Int J Radiation Oncol Biol Phys, Vol. 99, No. 4, pp. 805e811, 2017 0360-3016/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2017.06.2467
Conflict of interest: none. AcknowledgmentsdThe authors thank the Tisch Cancer Institute Biostatistics Shared Resource Facility, Icahn School of Medicine at Mount Sinai, for analysis, interpretation of data, and preparation of the manuscript.
806
International Journal of Radiation Oncology Biology Physics
Ghiassi-Nejad et al.
planning target volumes for adjuvant radiation.
were gemcitabine-based. Eighty-six patients (59%) had a documented recurrence, of whom 44 (51%) had a locoregional component. Among patients who had a recurrence, 23 (27%) had a recurrence at the biliary anastomosis and/or cut liver surface. Twentyeight patients (32.6%) had a recurrence in the regional lymph nodes, most prevalent in the portal (16.3%) and retroperitoneal (17.4%) lymph nodes. Univariable analysis identified tumor size, any vascular invasion, presence of satellites, stage/nodal status, and receipt of chemotherapy as significant prognostic factors of overall recurrence among intrahepatic patients. Presence of satellites, and stage 3/Nx status remained statistically significant in multivariable modeling. Conclusions: The areas at highest risk for locoregional recurrence after surgical resection for primary CCA are the biliary anastomosis/cut liver surface, portal lymph nodes, and retroperitoneal lymph nodes. Although these results need to be validated, adjuvant radiation should possibly cover these areas to maximize locoregional control. Ó 2017 Elsevier Inc. All rights reserved.
Introduction Cholangiocarcinoma (CCA) is a cancer originating from the epithelial lining of the biliary system and is the second most common primary liver tumor after hepatocellular carcinoma (1). The incidence of CCA in the United States is currently 2 in 100,000 and, according to some reports, is on the rise (2). Cholangiocarcinoma is anatomically classified according to tumor location as intrahepatic (IHC) or extrahepatic (EHC), which is further divided into hilar (Klatskin) and distal CCA, separated by the cystic duct insertion. Although prior studies estimated that IHC represented a minority of CCAs (3), more recent assessments show the incidence of IHC seems to be rising across the world. Although frequently grouped together, IHC and EHC have different embryologic origins that may reflect distinct diseases. Surgical resection remains the only known curative treatment; however, recurrence is common and significantly impacts survival. In the unresectable setting, the ABC-02 trial demonstrated a survival advantage in patients with biliary malignancies treated with gemcitabine and cisplatin (4), but the benefits of adjuvant therapy after surgery are less characterized. Factors such as lymph node positivity and positive margins (5) have previously been found to be associated with worse survival. A meta-analysis reviewing the benefit of adjuvant therapy for biliary malignancies found a nonsignificant improvement in overall survival with adjuvant therapy compared with surgery alone. The survival benefit was significant with any adjuvant therapy in lymph nodeepositive disease and R1 resections (6). Similarly, a recent observational study using the National Cancer Database revealed an overall survival benefit for adjuvant chemotherapy or chemoradiation treatment when these poor prognostic features were present (7). A large group Surveillance, Epidemiology, and End Results analysis of IHC suggests that radiation favorably impacts overall survival both postoperatively and definitively (8). More recently, results from a single-arm, phase 2
Southwest Oncology Group trial demonstrated promising results for the use of adjuvant concurrent capecitabine and radiation therapy in the setting of EHC or gallbladder carcinoma (9). Although there is growing agreement on the use of adjuvant chemoradiation for select patients, there is no consensus on the appropriate treatment target for adjuvant radiation. There are also limited data on which patients are at highest risk for local failure. Patterns of failure analyses have helped define adjuvant radiation targets in the gastrointestinal tract (10, 11). We sought out to map the pattern of locoregional failure after surgical resection, to establish a reasonable radiation treatment volume encompassing the majority of these failures.
Methods and Materials Patient selection The study was approved by our internal institutional review board. A chart review was performed in patients who underwent resection for primary CCA (intrahepatic, hilar, and distal) between 1999 and 2014. Overall 189 patients underwent surgical resection with curative intent for CCA, of whom 145 had at least 2 years of potential follow-up from time of resection to data abstraction (to limit censoring bias) and had at least 1 restaging CT scan of the abdomen available for review. Locoregional failure was defined as recurrence in a theoretically reasonable postoperative radiation target volume. These areas were defined as the cut surface of liver, biliary anastomosis, hilum, portal nodes, celiac nodes, peri-pancreatic nodes, gastro-hepatic nodes, and retroperitoneal nodes (down to L3).
Recurrence mapping Recurrences were plotted on a template patient CT scan using Eclipse software (Varian Medical Systems, Palo Alto,
Volume 99 Number 4 2017
CA), creating a 3-dimensional map of local/regional failures. Local failures were plotted in relation to the portal vein, celiac axis, and renal vessels.
Statistical analysis Continuous patient-, disease-, and tumor-related variables were summarized by the median and range, whereas categorical variables were summarized by number (percentage). Cumulative incidence functions were used to estimate time to overall and local recurrence in a competing risk setting. In the analysis of overall recurrence, first recurrence (regardless of location) was considered the defining event, whereas death without prior recurrence was the competing event. Site-specific recurrence was considered the defining event, whereas death without prior recurrence and other site recurrence were competing events. Univariable and multivariable hazard ratios (HRs) for overall recurrence and site-specific recurrence were estimated using Fine and Gray’s (1999) extension of Cox regression, which models the hazards of the cumulative incidence function. Univariable and multivariable hazard ratios are presented for each outcome, considering the following covariates: tumor size, positive margins, presence of satellites, vascular invasion, perineural invasion, stage/nodal status, and chemotherapy. All hypothesis testing was 2sided, with the type 1 error rate fixed at 5% for determination of factors associated with time-to-event outcomes. Statistical analyses were performed with the SAS version 9.4 (SAS Institute, Cary, NC) software package.
Results Clinical characteristics The baseline clinical and pathologic characteristics are demonstrated in Table 1. One hundred eighty-nine patients underwent surgical resection for CCA. Among them, 145 patients had sufficient follow-up with no radiation. Median age was 63.2 years (range, 24-89 years), and median follow-up was 41.6 months (95% confidence interval [CI] 35.4-48.7 months). One hundred two cases were intrahepatic, and 43 were hilar/distal CCA. Adjuvant chemotherapy was given in 38 cases (26%), of which 20 (54%) were gemcitabine-based.
Patterns of failure in resected cholangiocarcinoma
807
Table 1 Patient demographic and clinical characteristics (NZ145) Characteristic
n (%) or median (range)
Age at resection (y) Sex Male Female Race White Other Tumor size (cm) pT stage T1 T2 T3 T4 pN stage N0 N1 N2 Nx Histology Cholangiocarcinoma Cholangiocarcinoma arising from intraductal papillary neoplasm Adenosquamous carcinoma Margins Negative Positive Differentiation Well Moderately Poor Vascular invasion None Microvascular Macrovascular Perineural invasion No Yes Presence of satellites No Yes Stage 1/1b 2/2b 3/3a/3b 4/4a/4b
63.2 (24.1-89.3) 72 (50) 73 (50) 85 60 5.0 9 25 69 38 4 1 63 35 2 44
(61) (39) (1-18) Missing (18) (51) (28) (3) Missing (44) (24) (1) (31)
138 (95) 4 (3)
3 (2)
107 38 8 5 73 59
(74) (26) Missing (4) (53) (43)
61 (42) 75 (52) 9 (6) 80 (55) 65 (45) 115 30 8 24 53 33 27
(79) (21) Missing (17) (39) (24) (20)
Pathologic factors prognostic of recurrence We initially sought to determine pathologic factors prognostic of overall recurrence (locoregional or distant). Differentiation and histology were not considered as prognostic factors because there were too few patients (n
