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Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma.

ABSTRACT: Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically because of its anatomical location and its frequent association with primary sclerosing cholangitis. Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node-negative patients has been advanced by select liver transplant centers for the treatment of patients with unresectable disease. This approach has most commonly used external-beam radiotherapy in combination with biliary brachytherapy and 5-fluorouracil-based chemotherapy. Our center recently embarked on a protocol using stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node-negative patients until liver transplantation. We, therefore, retrospectively determined the tolerability and pathological response in this pilot study. During a 3-year period, 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50-60 Gy in 3-5 fractions over the course of 2 weeks). After 1 week of rest, capecitabine was initiated at 1330 mg/m(2) /day, and it was continued until liver transplantation. During neoadjuvant therapy, there were 35 adverse events in all, with cholangitis and palmar-plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplantation, and 6 patients received a liver transplant. The explant pathology of hilar tumors showed at least a partial treatment response in 5 patients, with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic indices and low proliferative indices were measured during histological examinations. Eleven transplant-related complications occurred, and the 1-year survival rate after transplantation was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.

SUBMITTER: Welling TH

PROVIDER: S-EPMC4185427 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma.

Welling Theodore H TH Feng Mary M Wan Shanshan S Hwang Sin Ye SY Volk Michael L ML Lawrence Theodore S TS Zalupski Mark M MM Sonnenday Christopher J CJ

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 20131121 1

Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically because of its anatomical location and its frequent association with primary sclerosing cholangitis. Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node-negative patients has been advanced by select liver transplant centers for the treatment of patients with unresectable disease. This approach has most commonly used external-beam radiotherapy in combination with biliary brachytherapy and 5-fluo ...[more]

PMID: 24115315

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Project description:PurposeRadiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC).Methods and materialsSerial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival.ResultsThirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm(3) vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002).ConclusionsSBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

Project description:BACKGROUND: Hilar cholangiocarcinoma is a rare tumour which is best managed by an aggressive surgical approach. The role of adjuvant or neoadjuvant radiation therapy, chemotherapy or chemoradiation remains controversial, as no prospective randomized studies have been performed. METHODS: This review summarizes the recent literature regarding the role of radiation, chemotherapy and chemoradiation in hilar cholangiocarcinoma. The results of a biliary cancer questionnaire regarding current treatment strategies are also reported. RESULTS: A number of retrospective studies have shown that patients treated with adjuvant radiation therapy have prolonged survival compared with untreated patients. However, most of these reports did not control for tumour stage or performance status. A carefully controlled trial from the Johns Hopkins Hospital did not demonstrate any benefit for adjuvant radiation therapy. A number of phase II trials of chemotherapy have demonstrated modest response rates (20-40%). The best responses have been reported with 5-fluorouracil (5-FU) in combination with interferon-alpha or with leucovorin and mitomycin C. Recent non-randomized reports of chemoradiation with 5-FU with or without gemcitabine as the radiosensitizer suggest, but do not prove, improved survival. Adjuvant chemoradiation is currently being employed at specialized centres most often in the Americas (71%) and the Asia/Pacific region (55%) and to a lesser degree in Europe (29%). DISCUSSION: The only chance for long-term survival in patients with hilar cholangiocarcinoma is complete resection with negative margins. Neither radiation therapy nor chemotherapy alone has been proven to prolong survival in completely or partially resected patients or in unresected patients. Recent uncontrolled data suggest that chemoradiation may improve survival in resected and locally unresectable patients. However, prospective, randomized multicentre trials need to be performed to confirm efficacy.

Project description:IntroductionMediastinal or hilar lymph node metastases are a challenging condition in patients affected by solid tumors. Stereotactic body radiation therapy (SBRT) could play a crucial role in the therapeutic management and in the so-called "no-fly zone", delivering high doses of radiation in relatively few treatment fractions with excellent sparing of healthy surrounding tissues and low toxicity. The aim of this systematic review is to evaluate the feasibility and tolerability of SBRT in the treatment of mediastinal and hilar lesions with particular regard to the radiotherapy doses, dose constraints for organs at risk, and clinical outcomes.Materials and methodsTwo blinded investigators performed a critical review of the Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA), starting from a specific question: What is the clinical impact of SBRT for the treatment of oligorecurrent/oligoprogressive mediastinal and hilar metastasis? All retrospective and prospective clinical trials published in English up to February 2022 were analyzed.ResultsA total of 552 articles were identified and 12 of them were selected with a total number of 478 patients treated with SBRT for mediastinal or hilar node recurrence. All the studies are retrospective, published between 2015 and 2021 with a median follow-up ranging from 12 to 42.2 months. Studies following SBRT for lung lesions or retreatments after thorax radiotherapy for stage III lung cancer were also included. The studies showed extensive heterogeneity in terms of patient and treatment characteristics. Non-small cell lung cancer was the most frequently reported histology. Different dose schemes were used, with a higher prevalence of 4-8 Gy in 5 or 6 fractions, but dose escalation was also used up to 52 Gy in 4 fractions with dose constraints mainly derived from RTOG 0813 trial. The radiotherapy technique most frequently used was volumetric modulated arc therapy (VMAT) with a median PTV volume ranging from 7 to 25.7 cc. The clinical outcome seems to be very encouraging with 1-year local control (LC), overall survival (OS) and progression-free survival (PFS) rates ranging from 84 to 94%, 53 to 88% and 23 to 53.9%, respectively. Half of the studies did not report toxicity greater than G3 and only five cases of fatal toxicity were reported.ConclusionsFrom the present review, it is not possible to draw definitive conclusions because of the heterogeneity of the studies analyzed. However, SBRT appears to be a safe and effective option in the treatment of mediastinal and hilar lymph node recurrence, with a good toxicity profile. Its use in clinical practice is still limited, and there is extensive heterogeneity in patient selection and fractionation schedules. Good performance status, small PTV volume, absence of previous thoracic irradiation, and administration of a high biologically effective dose (BED) seem to be factors that correlate with greater local control and better survival rates. In the presence of symptoms related to the thoracic lymph nodes, SBRT determines a rapid control that lasts over time. We look forward to the prospective studies that are underway for definitive conclusions.

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Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma.

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Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma.

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