Stereotactic body radiotherapy (SBRT) for locally advanced extrahepatic and intrahepatic cholangiocarcinoma
TL;DR: 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 patients who are unresectables and not eligible for transplantation.
Abstract: Objectives We report single-institution clinical efficacy and safety outcomes for patients with unresectable locally advanced cholangiocarcinoma who were treated with stereotactic body radiation therapy (SBRT) and a subset of patients who received neoadjuvant SBRT and chemotherapy as part of an orthotopic liver transplantation (OLT) protocol Methods and materials From October 2008 to June 2015, 31 consecutive patients with unresectable extrahepatic (n = 25) 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 the Common Terminology Criteria for Adverse Events Version 40 Overall survival (OS), time to progression, and local control were estimated using the Kaplan-Meier method Results The median follow-up time was 115 months The 1- and 2-year OS rates were 59% and 33%, respectively, with a median survival of 157 months The 1- and 2-year freedom from progression was 67% and 34%, respectively Median time to progression was 168 months Nine patients had local failure The actuarial 1- and 2-year local control rates were 78% and 47%, respectively Among patients who also had OLT, the median OS was 313 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 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 patients who are unresectable and not eligible for transplantation
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TL;DR: A suggestion of improved local control was found with the use of higher RT doses and future prospective investigation using high-dose conformal RT with novel cytotoxic and/or biologic agents with radiosensitizing properties is warranted.
Abstract: Purpose: The purpose of this retrospective review is to determine the limitations of definitive chemoradiation in the treatment of patients with unresectable extrahepatic cholangiocarcinoma and to generate hypotheses to overcome them. Patients and Methods: Between 1957 and 2000, 52 patients with localized unresectable cholangiocarcinoma were treated with radiotherapy with or without concurrent chemotherapy. Twenty-seven patients received 30 Gy (GP1), 14 patients received 36–50.4 Gy (GP2), and 11 patients received 54–85Gy (GP3). Ir-192 intracavitary boost(median 20 Gy) was delivered in 3 patients and an intraoperative boost (20 Gy) was used in one patient. Thirty-eight of the 52 patients (73%) received concomitant protracted venous infusion 5-FU (200–300 mg/m2/day/M-F). The actuarial 1-year and median overall survival (OS), radiographic local progression (LP), symptomatic progression (SP) and distant failure (DM) were evaluated. Results: The first site of disease progression was local in 72% of cases. The actuarial local progression rate at 12 months for all patients was 59%. The median time to LP was 9, 11, and 15 months in GP1, GP2, and GP3, respectively (p = 0.48). Fifteen percent of all of patients developed metastatic disease (1-yr OS 18%). The median survival rate for all patients was 10 months (1-yr. OS 44%). Neither the radiotherapy dose, the use of concurrent chemotherapy, histologic grade, the initial extent of liver involvement, or the extent of vascular involvement influenced LP or OS. Grade 3 or greater toxicity was similar in all dose groups (22% vs. 14% vs. 27%, p = 0.718). Conclusion: The primary limitation of definitive chemoradiation was local progression. Although small numbers limited the statistical power of this study, there was a suggestion of improved local control with the use of higher doses of radiotherapy. To address this pattern of failure, future prospective investigation using high dose conformal radiotherapy with novel cytotoxic and/or biologic agents with radiosensitizing properties is warranted.
37 citations
TL;DR: There is evidence that locoregional therapies can provide local tumor control resulting in increased survival while avoiding some of the side effects of systemic treatments, increasing potential treatment options for patients who may be unsuitable for systemic palliative treatments.
Abstract: Cholangiocarcinoma is a rare and aggressive malignancy of the biliary tract. Complete surgical resection can be curative, but the majority of patients are diagnosed with advanced disease and usually die within a year of diagnosis. Most deaths are attributable to local disease progression rather than distant metastases, supporting the use of locoregional therapies. There is evidence that locoregional therapies can provide local tumor control resulting in increased survival while avoiding some of the side effects of systemic treatments, increasing potential treatment options for patients who may be unsuitable for systemic palliative treatments. This review considers the evidence for locoregional therapies in cholangiocarcinoma, which can be classified into endoscopic, vascular, percutaneous and radiation oncological therapies. Current guidelines do not recommend the routine use of locoregional therapies due to a lack of prospective data, but the results of ongoing trials are likely to increase the evidence base and impact on clinical practice.
34 citations
TL;DR: In patients with locally advanced cholangiocarcinoma, SBRT is a local treatment option with an acceptable toxicity profile which warrants further investigation in prospective trials.
Abstract: To evaluate the role of ablative radiotherapy doses in the treatment of hilar or intrahepatic cholangiocarcinoma (CCC) using stereotactic body radiotherapy (SBRT). Consecutive patients treated from 2007 to 2016 with CCC were evaluated. Local control and toxicities were assessed every 3 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) and the Common Terminology Criteria for Adverse Events v4.0, respectively. Overall survival (OS), local control (LC) and progression free survival were calculated from SBRT. Thirty seven patients with 43 lesions were retrospectively evaluated. The median dose delivered was 45 Gy (range 25-66 Gy) in 3-12 fractions, corresponding to a median equivalent dose in 2 Gy fractions (EQD210) of 56 (range 25-85) Gy. The median follow up was 24 months. The OS at 1 year was 56% with a median OS of 14 (95% CI: 7.8-20.2) months from start of SBRT and 22 (95% CI: 17.5-26.5) months from diagnosis. Eight lesions progressed locally. The local control rate (LC) at 1 year was 78%. The median progression free survival was 9 months (95% CI 2.8-15.2) 21 patients progressed in the liver but out of field and 15 progressed distantly. SBRT was well tolerated. Three patients (9%) developed a Grade III bleeding. Seven patients developed a cholangitis, one due to progression and the other because of a stent dysfunction 2-21(median 8) months from SBRT. In patients with locally advanced cholangiocarcinoma, SBRT is a local treatment option with an acceptable toxicity profile which warrants further investigation in prospective trials.
32 citations
Cites methods or result from "Stereotactic body radiotherapy (SBR..."
...[26] reported 16% grade ≥ 3 toxicities in a retrospective analysis with 31 patients (IHCCC = 6, EHCCC = 25) treated with SBRT....
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...These results could not be confirmed in subsequent analyses which included a higher number of patients [25, 26, 30]....
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...Sandler [26] R IHCC EHCC 6 25 5 40 78% 15....
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TL;DR: This is the second part of the Italian CCA guidelines, dealing with CCA treatment, that have been formulated in accordance with Italian National Institute of Health indications and developed according to the GRADE method and related advancements.
32 citations
TL;DR: In this paper, the authors present the existing evidence about MRgRT applications for liver malignancies, discussing the potential clinical advantages and the current pitfalls of this new technology, and discuss the potential benefits and potential pitfalls of using this technology.
Abstract: MR guided radiotherapy represents one of the most promising recent technological innovations in the field The possibility to better visualize therapy volumes, coupled with the innovative online adaptive radiotherapy and motion management approaches, paves the way to more efficient treatment delivery and may be translated in better clinical outcomes both in terms of response and reduced toxicity The aim of this review is to present the existing evidence about MRgRT applications for liver malignancies, discussing the potential clinical advantages and the current pitfalls of this new technology
31 citations
References
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TL;DR: R0 resection remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R1 resection, according to a large series of patients with bile duct cancer.
Abstract: Objective:To assess long-term survival and prognostic factors in a large series of patients with bile duct cancer.Summary Background Data:The incidence of bile duct cancer is low but increasing. Determinants of survival vary in the literature, due to a lack of sufficient numbers of patients in most
1,092 citations
"Stereotactic body radiotherapy (SBR..." refers background in this paper
...Klatskin tumors arise at the bifurcation of the common bile duct and represent approximately 50% of cases.(1) Cholangiocarcinoma is uncommon, but there is some evidence that its incidence has been increasing over the past few decades....
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Mayo Clinic1, University of Colorado Denver2, Northwestern University3, University of Nebraska Medical Center4, University of Wisconsin-Madison5, Washington University in St. Louis6, University of Utah7, University of California, Los Angeles8, Columbia University Medical Center9, University of Illinois at Chicago10
TL;DR: Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective.
442 citations
TL;DR: This phase 2 multi‐institutional study was designed to determine whether gemcitabine with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single‐fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).
Abstract: BACKGROUND
This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).
METHODS
A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m2) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT.
RESULTS
The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.
CONCLUSIONS
Fractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy. Cancer 2015;121:1128–1137. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
405 citations
"Stereotactic body radiotherapy (SBR..." refers background in this paper
...Herman et al conducted a phase 2 multiinstitutional trial to evaluate SBRT (33 Gy in 5 fractions) after gemcitabine in patients with unresectable pancreas adenocarcinoma.(22) In that series, the researchers observed 6 cases of severe late toxicity (13%)....
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TL;DR: Biologically potent doses of SBRT are well tolerated in patients with limited liver metastases, and form the basis for an ongoing Phase II S BRT study of 60 Gy over three fractions for liver metastased patients.
Abstract: Purpose: To determine the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) for liver metastases. Methods and Materials: A multicenter Phase I clinical trial was conducted. Eligible patients had one to three liver metastases, tumor diameter Results: Eighteen patients were enrolled (10 male, 8 female): median age, 55 years (range, 26–83 years); most common primary site, colorectal (6 patients); median aggregate gross tumor volume, 18 ml (range, 3–98 ml). Four patients had multiple tumors. No patient experienced a DLT, and dose was escalated to 60 Gy/3F without reaching MTD. Conclusions: Biologically potent doses of SBRT are well tolerated in patients with limited liver metastases. Results of this study form the basis for an ongoing Phase II SBRT study of 60 Gy over three fractions for liver metastases.
389 citations
"Stereotactic body radiotherapy (SBR..." refers methods in this paper
...The volume of duodenum receiving 20 Gy was kept at 9 mL, which was adapted from research by Murphy et al.10 Our liver constraint, which was more conservative than current guidelines, was adapted using the principles outlined by Schefter et al.11 The bowel and stomach constraints were used per Rwigema et al12 in which patients with abdominal and pelvic metastases were treated with SBRT using these constraints with minimal small bowel and stomach toxicity....
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...Our liver constraint, which was more conservative than current guidelines, was adapted using the principles outlined by Schefter et al.(11) The bowel and stomach constraints were used per Rwigema et al(12) in which patients with abdominal and pelvic metastases were treated with SBRT using these constraints with minimal small bowel and stomach toxicity....
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TL;DR: The impact of ICD-O-2 misclassification on site-specific cholangiocarcinoma incidence rates was investigated using data from the Surveillance, Epidemiology, and End Results (SEER) program using a Poisson regression model that was age-adjusted to the year 2000 U.S. population.
Abstract: Cholangiocarcinomas are topographically categorized as intrahepatic or extrahepatic by the International Classification of Diseases for Oncology (ICD-O). Although hilar cholangiocarcinomas (Klatskin tumors) are extrahepatic cholangiocarcinomas, the second edition of the ICD-O (ICD-O-2) assigned them a histology code 8162/3, Klatskin, which was cross-referenced to intrahepatic cholangiocarcinoma. Recent studies in the United States that included this code (8162/3, Klatskin) with intrahepatic cholangiocarcinoma reported an increasing incidence of intrahepatic cholangiocarcinoma and a decreasing incidence of extrahepatic cholangiocarcinoma. To investigate the impact of this misclassification on site-specific cholangiocarcinoma incidence rates, we calculated annual percent changes (APCs) with data from the Surveillance, Epidemiology, and End Results (SEER) program using a Poisson regression model that was age-adjusted to the year 2000 U.S. population. All statistical tests were two-sided. During 1992-2000, when SEER used ICD-O-2, 1710 intrahepatic cholangiocarcinomas, 1371 extrahepatic cholangiocarcinomas, and 269 hilar cholangiocarcinomas identified by code 8162/3, Klatskin were diagnosed. Ninety-one percent (246 of 269) of the hilar cholangiocarcinomas were incorrectly coded as intrahepatic cholangiocarcinomas, resulting in an overestimation of intrahepatic cholangiocarcinoma incidence by 13% and underestimation of extrahepatic cholangiocarcinomas incidence by 15%. However, even after the exclusion of tumors that were coded to the histology code 8162/3, Klatskin, age-adjusted annual intrahepatic cholangiocarcinoma incidence increased during this period (APC = 4%, 95% confidence interval = 2% to 6%, P<.001).
323 citations
"Stereotactic body radiotherapy (SBR..." refers background in this paper
...Cholangiocarcinoma is uncommon, but there is some evidence that its incidence has been increasing over the past few decades.(2) Prognosis is generally poor; however, it is improved in patients who can undergo surgical resection....
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