Cholangiocarcinoma is a rare group of tumors that involve the hepatic biliary tree (1). Cholangiocarcinomas account for about 2% of all gastrointestinal malignancies and are the second most common hepatic tumor following hepatocellular carcinoma (2). The incidence of these tumors is thought to be increasing in recent decades, at least in Western countries, which is mostly related to an increase in intrahepatic cholangiocarcinoma (3, 4). Cholangiocarcinomas are classified according to their anatomical location as intrahepatic and extrahepatic, with tumors in the latter category further divided into perihilar or distal (1, 3). About half of cholangiocarcinomas are perihilar, while smaller proportions have distal and intrahepatic locations (5). Risk factors for cholangiocarcinoma include primary sclerosing cholangitis, choledochal cysts, parasitic infections, inflammatory bowel disease, diabetes, obesity, and alcohol use (1, 3). The prognosis for patients with cholangiocarcinoma is dismal, with a 5-year overall survival (OS) of <20% (6). This is also related to the fact that these tumors are usually diagnosed at advanced stages and surgery with curative intent and adjuvant therapy is only feasible for a small proportion of patients.

Treatment is driven by surgical management whenever possible depending on the site of the tumor, although few patients are candidates for a hepatic graft (1). If a patient is ineligible for surgery or in case of recurrence, chemotherapy can be considered (1). Based on the results of the ABC-02 trial, combination of cisplatin plus gemcitabine (CG) was established as first-line therapy for patients with advanced cholangiocarcinoma (7). Patients with disease progression following cisplatin plus gemcitabine typically have poor OS of less than 6 months (8). Recently, the results of the TOPAZ-1 trial investigating gemcitabine/cisplatin plus durvalumab appear to be promising (9, 10). This phase 3 randomized, double-blind, placebo-controlled study randomized patients to CG plus durvalumab for eight cycles followed by durvalumab only or placebo. Median OS was 12.8 months vs. 11.5 months (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p = 0.021), median PFS was 7.2 months vs. 5.7 months (HR, 0.75; 95% CI, 0.64–0.89; p = 0.001), and ORR (26.7% vs. 18.7%) was superior with gemcitabine/cisplatin plus durvalumab compared to gemcitabine/cisplatin plus placebo. These results are encouraging and will lead to a change in first-line standard, paving the way toward other combinations and translational research in the near future.

The role of second-line chemotherapy after progression on cisplatin and gemcitabine remains debatable, with very limited clinical data (11). Recently, however, the ABC-06 trial reported that as second-line chemotherapy the FOLFOX (folinic acid, fluorouracil, and oxaliplatin) regimen is associated with improved OS in patients with advanced cholangiocarcinoma (12). In particular, at 12 months, the rate of OS was in patients receiving active symptom control was 11.4% compared to 25.9% in those receiving active symptom control and FOLFOX. Accordingly, it was proposed that FOLFOX should be the standard for second-line chemotherapy in patients with advanced cholangiocarcinoma. This conclusion has been reinforced after the recent presentation of quality of life (QoL) result for ABC-06, showing that active chemotherapy does not impact negatively on QoL measures (13). Moreover, alternative combinations with fluorouracil and liposomal irinotecan (Nal-Iri) did not confirm preliminary findings of potential benefit among pretreated patients (14–16), confirming that further studies are warranted in order to optimize systemic treatment beyond first-line progression.

Today, molecular biology and next-generation sequencing techniques are playing an increasingly important role in choice of therapy. In fact, the ESMO Precision Medicine Working Group has recommended that clinical research centers adopt multigene sequencing to screen patients who are eligible for clinical trials and to accelerate drug development, as well as prospectively collect data that may provide additional information on the use of this methodology in the future (17). For cholangiocarcinomas in particular, molecular techniques can evaluate the possibility to target actionable genomic alterations with approved agents such as include ivosidenib for tumors harboring IDH1 mutations, and infigratinib and pemigatinib for those with FGFR2 fusions (18). Ivosidenib, for example, has been associated with a favorable benefit for OS vs placebo in patients whose tumor harbors aberrations in IDH1 (19). Similarly, pemigatinib appears to be beneficial in previously treated patients with cholangiocarcinoma with FGFR2 fusions or rearrangements (20).

Analysis of survival trends over recent decades is important in order to understand the efficacy of chemotherapy in patients with advanced cholangiocarcinoma. Herein, we present survival trends over a long time period spanning almost 20 years in patients with advanced cholangiocarcinoma receiving systemic chemotherapy. The analysis was also divided into different time frames to better understand differences in survival following the introduction of cisplatin plus gemcitabine as a preferred regimen for first-line chemotherapy.

The present analysis of patients with advanced cholangiocarcinoma undergoing first- and second-line chemotherapy compared outcomes during three time periods, 2000-2009, 2010-2013, and 2014-2017. As expected, we observed a shift in the use of cisplatin plus gemcitabine after 2010, following the publication of the ABC-02 trial (7), which was administered to 26% of patients in 2010-2013 and to 35% in 2014-2017. PFS did not show a significant association with the time period of starting first-line therapy, but the high percentage of patients receiving a treatment other than cisplatin + gemcitabine and the retrospective nature of the analyses could partly explain this finding. However, for OS at 12 months a trend was observed towards increased survival at later time periods, increasing progressively from 38.3% in 2000-2009 to 49.5% in 2014-2017. Despite a more than 10% increase in OS, the differences did not reach statistical significance after adjusting for confounding factors. However, it should be pointed out that only about one-third of patients received cisplatin plus gemcitabine, and broadly similar proportions received GemOx or gemcitabine alone. Taken together, our results confirm that CG rapidly entered the clinical scenario after publication of ABC-02, even though a large number of patients still receive regimens different from CG (possibly due to suboptimal general conditions, physician preference or other reasons not captured by our database). Moreover, we confirm that alternative options beyond CG are eagerly needed in advanced cholangiocarcinoma: in this regard, we are conducting an observational study within the G.I.C.O. group with the aim of estimating the real-world impact of the addition of durvalumab to first-line CG compared to the TOPAZ-1 study.

For the group of patients undergoing second-line chemotherapy, in line with the limited clinical evidence available at the time of treatment initiation, a wide variety of regimens were administered. The most widely administered regimen was fluoropyrimidine monotherapy, although FOLFOX or FOLFIRI had been administered to about one-fifth of patients. Response rates were low and 45.2% of the patients showed progressive disease following second-line chemotherapy. Overall, our data indicate the limited value of second-line chemotherapy in a large proportion of patients, as previously highlighted (21).

In our analysis, PFS and OS were numerically higher in patients receiving one of the COMBINED (cisplatin + gemcitabine, gemox, gemcitabine + capecitabine or others) therapies compared to FOLFOX or FOLFIRI or monotherapy, although the differences did not reach statistical significance. Of note, OS at 12 months in ABC-02 was 25.9% (7) compared to 33.1% in the last time period analyzed in the present study. Thus, we conclude that, even if the benefits of second-line therapy are limited among unselected patients in the real-world practice, they might be significant in some subgroups of patients (22, 23). Interestingly, subgroup analysis by age at second-line therapy showed that in patients ≤60 and 61-70 years, compared with those starting therapy in 2002-2009 risk reduction of progression was found in those starting second-line therapy in 2010-2013 and 2014-2017, while the opposite was seen in patients ≥71 years. Therefore, even if a definitive conclusion about the optimal management of pre-treated elderly patients with cholangiocarcinoma cannot be derived from our analysis, overall benefit of second-line therapies should not be overestimated and some caution is warranted when facing frail patients with pre-treated disease (for whom active symptoms control is still an option on the basis of ABC-06). Median age was 65 years but upper age limit was as high as 84 years in ABC-06: since subgroup analysis according to age was not presented in the publication, it could be of interest to better explore the actual impact on OS and QoL of salvage chemotherapy for these higher-risk patients.

Similar to first-line chemotherapy, a difference in OS at 12 months was apparent in the three time periods, increasing from 24.3% in 2002-2009 to 33.1% in 2014-2017, although these differences did not reach statistical significance. Taken together, our data confirm the findings of randomized trials, such ABC-02 and others (14–16). This is relevant since real-world outcomes appear to be similar to those seen in clinical trials (24), although prognosis still remains dismal (25).

Cholangiocarcinoma is emerging as a promising candidate for precision medicine in light of the multiple potentially targetable molecular alterations identified, especially for the intrahepatic subset. Among these, FGFR2 rearrangements and IDH1 mutations have already entered the clinical scenario. In our study we did not collect data about molecular profiling, but we can speculate that only a limited proportion of patients treated in more recent years had their disease profiled for druggable alterations and received targeted treatment. Therefore, together with information about the use of durvalumab plus CG in first-line, we are currently collecting data about the prevalence of patients with cholangiocarcinoma assessed for molecular alterations in Italian practice and about the potential impact of target treatment in molecularly-defined patient subsets. Preliminary findings on ivosidenib are encouraging (26).

In summary, in our clinical experience the benefits of first- and second-line chemotherapy appear to be limited in patients with advanced choangiocarcinoma overall, although some impact may be seen in some subgroups of patients that remain to be better defined. Over the years, therapeutic techniques have undoubtedly improved (e.g. for biliary stenting), but at present it is difficult to quantify their impact on outcomes in the absence of specific studies. In line with other reports (27), our study further underlines the aggressiveness of biliary tract cancers, and the need for better treatment options as well as specialized management in trained centers: this could contribute to offering effective palliative measures, with the aim of increasing the chances of receiving active therapeutic options in the advanced setting. Future therapeutic combinations with novel agents and the routine introduction of individualized therapy with targeted agents has the potential to improve overall outcomes in selected subgroups of patients. In this regard, the results of the TOPAZ-1 trial on gemcitabine/cisplatin plus durvalumab are likely to change clinical practice in the near future (9, 10).

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.

LFo and AC-G: creators. All other authors: investigators. All authors contributed to the article and approved the submitted version.