Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma

Hospital records of 485 patients who were pathologically diagnosed, by ultrasonography-guided percutaneous liver biopsy, with IHCC at the National Cancer Center, Korea, from June 2001 to March 2012 were retrospectively reviewed. IHCC resectability was determined by clinical and radiographic findings, with extensive bilobular invasion, major vessel involvement, and extrahepatic metastases considered markers of unresectable disease. Of the 132 patients with advanced-stage unresectable IHCC who received palliative systemic chemotherapy, 92 (69.7%) were treated with capecitabine plus cisplatin (XP) and were retrospectively analyzed. All patients were found to have stage IVa (46.7%) or IVb (53.3%) disease according to the seventh edition of the American Joint Committee on Cancer-TNM staging system[19]. Of the 92 included patients, 25 (27.2%) received XP chemotherapy with concurrent radiotherapy (XP-CCRT group) and 67 (72.8%) received XP chemotherapy alone (XP group). Patients who underwent surgical resection, those who were treated with other chemotherapy regimens, and those who received supportive care alone were excluded (Figure 1). The present study was approved by the Institutional Review Board of the National Cancer Center, Korea (NCCNCS-12-686), and was conducted in accordance with the guidelines of the International Conference on Harmonization/Good Clinical Practice and the principles of the Declaration of Helsinki.

Each patient received 1000 mg/m² oral capecitabine twice daily for the first 14 days of each 21-day cycle, followed by a 7-day rest period, together with 30 mg/m² intravenous cisplatin for 1 hour with standard hydration on days 1 and 8 of each cycle[20]. Patients were continued on XP chemotherapy until progressive disease or the development of severe toxicity.

Among included patients, 25 patients underwent concurrent RT. Eligible criteria for RT included: 1) radiographically assessable disease, 2) adequate laboratory findings including common blood cell counts (white blood cell ≥ 2,000/mm³, hemoglobin ≥ 7.5 g/dL, platelet ≥ 100,000/mm³), total bilirubin ≤ 3.0 mg/dL, serum creatinine ≤ 1.5 mg/dL), 3) adequate oral intake of 1,500 calories/day. Meanwhile, exclusion criteria for RT were as follows: 1) previous history of RT adjacent to the planned RT field, 2) multifocal intrahepatic lesions which did not covered by planned RT field.

Planning of external beam radiotherapy (RT) was based on radiographic findings from abdominal computed tomography (CT) and/or magnetic resonance imaging. The gross tumor volume was defined by these planning imaging studies. Then, the clinical target volume included the gross tumor volume and the volumes of adjacent lymph nodes (LNs) in the porta hepatis, celiac axis, and pancreaticoduodenal ligament, regardless of the presence of extrahepatic metastases. The clinical target volume and gross tumor volume plus a 5–10 mm margin were included in the initial and boot planning target volume. Of the 25 patients in this group, 18 (72.0%) were treated with 3-dimensional conformal RT using 2–4 ports, 5 (20.0%) received intensity-modulated RT using 2–5 ports, and 2 (8.0%) received proton beam RT using 2 ports. All these patients underwent a CT simulation in the treatment position. In this treatment planning, the planning target volume would be encompassed by a 90% iso-dose volume of the prescribed dose.

Concurrent RT was applied in single fractions of 2.0–3.0 Gy once a day and 5 times a week, with a mean total RT dose of 44.7 Gy (range 25.0–60.0 Gy). Although usual target doses were between 37.5 Gy and 50.0 Gy, several fractions of booster RT were performed in some well-tolerate patients with limit dose of 60.0 Gy.

Patients were evaluated by physical examination and assessments of complete blood counts and blood chemistry after each cycle. Abdominal CT was performed after every 2 cycles of chemotherapy to measure tumor response, which was classified according to the Response Evaluation Criteria in Solid Tumor (RECIST) guidelines[21]. PFS was defined as the time from diagnosis to the development of progressive disease (PD) or death whichever came first. Toxicity was monitored according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0.

Table 1 shows the baseline clinical characteristics of the 92 enrolled patients. Of these patients, 72 (78.3%) were male and 20 (21.7%) were female; their median age was 58 years (range 26–78 years). Eighty-seven patients (94.6%) had good performance status (Eastern Cooperative Oncology Group [ECOG] scale 0 or 1). The mean maximum tumor size was 7.3 cm, and the mean serum concentrations of carbohydrate antigen (CA) 19–9 and carcinoembryonic antigen (CEA) were 2675.4 U/mL and 107.7 ng/mL, respectively. Evaluation using the morphologic classification system proposed by the Liver Cancer Study Group of Japan[22] indicated that 79 (85.9%) patients had mass-forming type and 13 (14.1%) had periductal infiltrative type IHCC. In addition, 76 patients (82.6%) had LN metastasis and 49 (53.3%) had extrahepatic metastasis. Patients in XP-CCRT group had significantly higher rate of single intrahepatic lesion than those in XP group (72.0% vs. 41.3%, p = 0.007), however, other baseline clinical characteristics of the XP-CCRT and XP groups did not differ significantly.

Patients in the XP-CCRT group received more cycles of chemotherapy than those in the XP group (5.6 vs. 4.0 cycles, p = 0.082). Of the 92 patients, tumor response could not be assessed in 2 patients because of a lack of follow-up CT data. Of the 90 patients evaluable for tumor response, 4 (4.4%) had a partial response (PR) and 37 (41.1%) had stable disease (SD). Disease control rate (DCR), which accounted for patients with complete response (CR), PR, and SD, was higher in the XP-CCRT than in the XP group, although the difference was not statistically significant (56.0% vs. 41.5%, p = 0.217) (Table 2).

The median follow-up duration of the 92 patients was 5.3 months (interquartile range [IQR], 3.0–9.5 months). The median PFS for all patients was 2.6 months (95% confidential interval [CI] 2.0–3.2 months), and the median OS was 7.9 months (95% CI 5.8–10.0 months). Median PFS (4.3 vs. 1.9 months, p = 0.001) and OS (9.3 vs. 6.2 months, p = 0.048) were significantly longer in the XP-CCRT than in the XP group (Figure 2, Table 2), but the 1-year survival rates did not differ significantly (30.4% vs. 22.4%, p = 0.438).

The rates of hematologic and non-hematologic toxicities are listed in Table 3. Neutropenia and hand-foot syndrome were more frequent in the XP-CCRT than in the XP group. However, the frequency of grade 3 and 4 toxicities did not differ between the groups. In the XP-CCRT group, 3 patients (12.0%) had grade 3 neutropenia without fever, 5 (20.0%) had grade 3 thrombocytopenia, and 1 (4.0%) had grade 4 hand-foot syndrome. Treatment was well tolerated in both treatment groups and there were no treatment-related deaths.