Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma

Background A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA. Methods We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center. Results In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p < 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0–13.6%) in the gem-cis group versus 34.3% (95% CI 28.1–41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19–0.39). Conclusions This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.

manifestation. 4,5Therefore, most patients are only eligible for palliative systemic treatment. 6The median overall survival (OS) of patients with unresectable iCCA is about 5 months when no systemic treatment is administered. 7,8alliative systemic treatment for iCCA is typically investigated in studies including all patients with biliary cancers: cholangiocarcinoma (intrahepatic, perihilar, and distal) and gallbladder cancer.The most common regimen for advanced biliary cancers is the combination of gemcitabine and cisplatin (gem-cis), which offers a small OS benefit over gemcitabine monotherapy (11.7 versus 8.1 months, respectively, HR 0.64, p < 0.001). 2 Patients with advanced iCCA mostly have locally advanced rather than distant metastatic disease. 5,9A post-hoc analysis of 34 patients with liver-confined unresectable iCCA, treated with gem-cis in the ABC trials, found a median OS of 16.7 months (95% CI 8.2-20.0)and 3-year OS of 2.8%. 10 These results are a benchmark for any additional locoregional treatment.
Regional treatments are increasingly used to improve OS in liver-confined unresectable iCCA.The main rationale for locoregional treatment of locally advanced iCCA is that most patients die from progressive disease in the liver with biliary obstruction and liver failure. 11Liver-directed therapy via a hepatic arterial infusion pump (HAIP) enables the delivery of high-dose chemotherapy (floxuridine) directly into the liver.A continuous flow of intra-arterial chemotherapy is delivered in the hepatic artery via a surgically implantable subcutaneous pump with a catheter in the gastroduodenal artery (GDA), which is a side branch of the hepatic artery.Floxuridine has a 95% first-pass effect, which allows for a 400-fold intra-tumoral concentration compared with systemic administration, without systemic side effects.][14] The aim of this study was to compare OS after gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy with or without systemic chemotherapy in patients with liver-confined unresectable iCCA.

Cohort Selection
The study protocol of this multicenter retrospective study was approved by the Institutional Review Board (IRB) of Erasmus MC Cancer Institute Rotterdam (MEC-2021-0501) prior to data collection and processing.Informed consent was waived by the IRB.Data were retrieved from existing medical records.
All consecutive patients diagnosed with liver-confined unresectable iCCA, confirmed by a biopsy, or determined at a multidisciplinary team meeting, were identified.The patients that were treated with systemic gem-cis in Erasmus MC Cancer Institute (Rotterdam, the Netherlands) and Amsterdam UMC (Amsterdam, the Netherlands), were identified between January 2014 and December 2019.The patients that were treated with HAIP floxuridine in Memorial Sloan Kettering Cancer Center (New York, United States), were identified between January 2000 and December 2019.Patients in both groups were excluded if they had undergone prior liver surgery or had distant metastases at time of diagnosis.Patients with locoregional lymph node metastasis (pathologically proven or based on imaging) were not excluded.In the gem-cis group, patients were excluded if they had received first-line chemotherapeutic regimens other than gem-cis.Patients were followed until death or the date they were lost to follow-up.
The following data were extracted for each patient: demographics, baseline hepatobiliary disease, Eastern Cooperative Oncology Group (ECOG) performance status, prior treatment, drainage, date of diagnosis, tumor distribution, cancer antigen (CA) 19-9 serum level at start of treatment, concurrent systemic treatment administration, and date of death or last follow-up.Second-line systemic treatment data were not collected.Tumor distribution included the presence of locoregional lymph node metastasis (pathologically proven or based on imaging), diameter of the largest tumor, and number of tumors.Subsequent locoregional treatments after gem-cis administration or HAIP chemotherapy were also collected.

Variable Definitions
Liver-confined unresectable iCCA was defined as disease confined to the liver that is unresectable owing to tumor location and/or multifocal involvement and/or locoregional lymph node metastasis.The primary endpoint OS was defined as the time between date of diagnosis and date of death or last follow-up.Resection rate was defined as the percentage of patients who underwent surgery after initial treatment.
Patients' performance status and CA 19-9 serum level were those measured at the closest time before the start of initial treatment.Multifocal disease was defined as more than one lesion in the liver on imaging, whether it concerned intrahepatic metastases or satellites surrounding the largest lesion.Locoregional lymph nodes were positive or negative for cancer based on pathology results of excisions and biopsies.Locoregional lymph nodes were considered suspicious for cancer on imaging, as defined by a short axis larger than 10 mm and/or a necrotic center of the lymph node assessed by an expert radiologist.Gemcitabine with Cisplatin Versus Hepatic …

Statistical Analysis
Continuous variables are presented as mean with standard deviation (SD) or medians with interquartile range (IQR) or range.Differences were tested with the help of Student's t-test or the Mann-Whitney test, depending on the variable's distribution.Categorical variables are presented as proportions with corresponding frequencies, and differences were tested with the chi-square (χ 2 ) or Fisher exact test, whichever was appropriate.Missing values were excluded from analysis.
OS was estimated using the Kaplan-Meier method.Patients lost to follow-up were censored.Cox proportionalhazards (CPH) models were used to assess associations between the primary endpoint OS and several variables, including patient demographics and tumor characteristics.The multivariate analysis used the backward selection regression method.Variables that were statistically significant on univariate analysis (p < 0.20) were included in the multivariate model along with known relevant variables.Outcomes are presented as hazard ratio (HR) with 95% confidence intervals (CI).Pre-specified sensitivity analyses were performed for first-line (i.e., without previous systemic chemotherapy) and second-line (i.e., with previous first-line systemic chemotherapy) HAIP chemotherapy.Within the subgroup of patients receiving first-line HAIP chemotherapy, patients with and without concurrent systemic chemotherapy were compared.A sensitivity analysis was also performed by adding prognostic factors from the literature (i.e., tumor diameter, serum level CA 19-9) to the multivariate model.
Analyses were performed with the statistical software program R (R Core team, 2021: version 4.1.0,Vienna, Austria) using the package 'survival' and the statistical software program IBM SPSS (IBM Corp. Released 2020.IBM SPSS Statistics for Windows, Version 27.0.Armonk, NY: IBM Corp).All tests were two-tailed and statistical significance was defined as p < 0.05.

RESULTS
In total, 268 patients with liver-confined unresectable iCCA were included: 76 in the gem-cis group and 192 in the HAIP chemotherapy group.Of the 76 patients who received gem-cis, 50 were treated in Erasmus MC Cancer Institute and 26 in Amsterdam UMC (Fig. 1).Baseline characteristics are presented in Table 1.In the gem-cis group, 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023).The diameter of the largest tumor was similar in both groups (8.5 vs 8.4 cm, p = 0.833).ECOG performance status did not differ between the groups (ECOG 0 or 1, 95.6% vs 97.1%, p = 0.214).Baseline hepatobiliary disease was more common in the gem-cis group (18.4% vs 5.2%, p = 0.001).Most patients (n = 134, 69.8%) received HAIP chemotherapy as first-line treatment; 58 patients (30.2%) in the HAIP group received prior firstline systemic chemotherapy.HAIP chemotherapy was combined with systemic chemotherapy in 138 patients (71.9%), with regimes including gemcitabine with cisplatin or oxaliplatin, gemcitabine monotherapy, and irinotecan (Table 2).Forty-two patients (21.9%) received HAIP as first-line treatment without concurrent systemic treatment.

DISCUSSION
In this study of patients with liver-confined unresectable iCCA, we found that patients had a median OS of 11.8 months when treated with gem-cis alone versus months A SEER population-based cohort study of 5616 patients with advanced intrahepatic cholangiocarcinoma reported a median OS of about 5 months and a 3-year OS of about 3%. 8Patients who received gem-cis for liver-confined unresectable iCCA in the ABC trials had a median OS of 16.7 months, with no survivors beyond 3 years. 2The median OS after gem-cis in the present study was 11.8 months with a 3-year OS of 3.5%.This median OS was lower compared with the ABC trials, a difference that likely reflects the strict inclusion criteria.In a previous study, we found that about 40% of patients who received gem-cis for advanced iCCA in the "real world" did not fulfill inclusion criteria of the ABC trials. 15Regardless of baseline patient characteristics, however, the 3-year OS in any advanced iCCA cohort receiving palliative systemic chemotherapy has been close to zero.
The main rationale for locoregional treatment for advanced iCCA is that most patients die from progressive disease in the liver with biliary obstruction and liver failure.In a large cohort study of 362 patients with iCCA at MD Anderson, the authors found that in patients who were treated with palliative systemic chemotherapy (n = 99), 71 (72%) died from liver failure secondary to local tumor progression. 11The impact of local (rather than distant) tumor progression may also explain why the survival curves of patients with liver-confined unresectable iCCA and patients with extrahepatic metastases were overlapping in the subgroup of patients with iCCA who received gem-cis in the ABC trials. 103][14] These trials consistently reported a partial response rate of about 50%, a median OS of about 25 months, and a 3-year OS rate of about 35%.A recent systematic review and meta-analysis of HAIP chemotherapy with floxuridine for unresectable iCCA included 154 patients from four studies and found a median OS of 29.0 months (range 25.0-39), a 3-year OS of 39.5% (95% CI 31.5-47.4),and a 5-year OS of 9.7% (95% CI 0.0-23.4). 16In particular, the 3-year OS of 35% is an enormous improvement compared with negligible 3-year OS with systemic chemotherapy alone.In our study, most patients (152/192, 79%) who received HAIP chemotherapy also received systemic chemotherapy before or during HAIP chemotherapy.It is unlikely that systemic chemotherapy alone was responsible for the favorable survival outcomes in the HAIP group, considering that 3-year OS was not observed with systemic chemotherapy alone in the ABC trials. 10We could not demonstrate a difference in OS between patients who received first-line HAIP with or without systemic treatment.The sample size, however, was low and we believe that HAIP chemotherapy should be given in addition to systemic treatment.HAIP chemotherapy has no systemic toxicity and the complication rates (e.g., biliary sclerosis and pump pocket infection) are low in experienced hands. 179][20][21] iCCA lesions are often too large for percutaneous ablation.Several percutaneous intra-arterial approaches have been investigated, including transarterial chemoembolization and selective internal radiotherapy (SIRT).A phase II trial investigated a combination of first-line SIRT and systemic gem-cis in locally advanced iCCA patients (n = 41) with a median OS of 22 months (95% CI 14-52 months). 22These results are promising, but appear to be inferior to HAIP chemotherapy.A phase III trial investigating first-line SIRT in patients with liver-confined iCCA was prematurely closed due to lack of accrual (NCT02807181).The main advantage of HAIP chemotherapy compared with SIRT is that lesions are treated across the entire liver, regardless of the number of lesions and whether they are visible on imaging.
This study has several limitations.First, the comparison between the two treatment groups was not randomized and patients were included over a long period of time.We adjusted for known poor prognostic factors, but unknown confounders may have biased the results.For example, about 5% of patients with liver-confined iCCA on imaging have occult peritoneal metastases.These patients would not be eligible for HAIP chemotherapy when metastatic disease is detected at surgical exploration for pump implantation.In the gem-cis cohort these metastases would remain undetected.However, any residual selection bias cannot explain a 3-year OS after HAIP chemotherapy of 1 in 3 patients versus no 3-year OS in the gem-cis group of the ABC trials.][25][26][27][28][29] In a phase II study, 108 patients with previously treated advanced CCA with FGFR2 fusions or rearrangements received infigratinib.The median OS was only 12 months, but the 3-year OS was about 25%. 25 In the FOENIX-CCA2
a Before start therapy.b ECOG performance score missing in 30 patients.c Number of lesions missing in 1 patient.d Based on imaging or pathologic confirmation.HAIP hepatic arterial infusion pump, Y90 yttrium-90, RFA radiofrequency ablation, MWA microwave ablation, IRE irreversible electroporation, TACE transarterial chemoembolization.a Locoregional treatment after gem-cis or HAIP.b One patient was treated with both ablation and TACE.c One patient was treated with both ablation and resection.

TABLE 3
Univariate and multivariate analysis for overall survival (OS) HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative oncology group, PSC primary sclerosing cholangitis, HAIP hepatic arterial infusion therapy, NA not assessed.According to the American Joint Committee on Cancer (AJCC) staging.Based on imaging or pathologic confirmation.
a Before start of therapy.b c