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Radiation therapy, chemotherapy and chemoradiation in hilar cholangiocarcinoma.

ABSTRACT: 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.

SUBMITTER: Nakeeb A

PROVIDER: S-EPMC2043100 | biostudies-other | 2005

REPOSITORIES: biostudies-other

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Project description: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.

Project description:Photodynamic therapy (PDT) of solid cancers comprises the administration of a photosensitizer followed by illumination of the photosensitizerreplete tumor with laser light. This induces a state of local oxidative stress, culminating in the destruction of tumor tissue and microvasculature and induction of an anti-tumor immune response. However, some tumor types, including perihilar cholangiocarcinoma, are relatively refractory to PDT, which may be attributable to the activation of survival pathways in tumor cells following PDT (i.e., activator protein 1 (AP-1)-, nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-ÎºB)-, hypoxia-inducible factor 1-alpha (HIF-1Î±)-, nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), and unfolded protein response-mediated pathways). To assess the activation of survival pathways after PDT, human perihilar cholangiocarcinoma (SK-ChA-1) cells were subjected to PDT with zinc phthalocyanine (ZnPC)-encapsulating liposomes. Following a 30-minute incubation with liposomes, the cells were either left untreated or treated at low (50 mW) or high (500 mW) laser power (cumulative light dose of 15 J/cm2). Cells were harvested 90 minutes post-PDT and whole genome expression analysis was performed using Illumina HumanHT-12 v4 expression beadchips. Hilar cholangiocarcinoma (SK-ChA-1) cells were incubated with PBS (control group) or 500 Î¼M zinc phthalocyanine (ZnPC)-encapsulating liposomes (ZnPC-ITLs, final lipid concentration). After 30 minutes, cells that were incubated with ZnPC-ITLs were either kept in the dark (ITL group) or were treated with 500-mW (ITL 500) or 50-mW (ITL 50) laser light (n = 3 per group, cumulative light dose of 15 J/cm2). Ninety minutes after photodynamic therapy, total cellular RNA was isolated and gene expression levels were analyzed by using the Illumina HumanHT-12 v4 platform. The data was analyzed in the context of survival signalling and comparisons were made with the control group.

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Radiation therapy, chemotherapy and chemoradiation in hilar cholangiocarcinoma.

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