Elsevier

European Journal of Cancer

Volume 51, Issue 13, September 2015, Pages 1694-1703
European Journal of Cancer

Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease

https://doi.org/10.1016/j.ejca.2015.05.018Get rights and content

Abstract

Introduction

The advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1st-line regimen for patients with advanced/metastatic biliary tract cancer; patients with bilirubin ⩾1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin.

Methods

Patients with ABC, receiving CisGem with a baseline bilirubin of ⩾1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected.

Results

Thirty-three patients of 545 screened; median age 59 years, range 23–79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55 μmol/L (range 32–286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9 months (95% confidence interval (CI): 4.4–9.0) and median overall survival (OS) 9.5 months (95% CI: 5.7–12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6 months; p = 0.1633 and 9.8 versus 4.4 months, hazard ratio (HR) 0.74; p = 0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9 months, HR 0.49; p = 0.08 and 15.2 versus 5.4 months, HR 0.12 p < 0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS).

Conclusion

For PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.

Introduction

Biliary tract cancers (BTC) are relatively low-incidence (0.7%) malignant tumours including cancers of the gallbladder, cholangiocarcinoma and the ampulla of Vater with a relative frequency of 41%, 42% and 17%, respectively [1]. Its incidence and mortality are increasing, predominantly due to a rise in intrahepatic cholangiocarcinoma [2]; with an annual incidence in England and Wales of approximately 1200 cases [3].

Because of the naturally aggressive behaviour of these neoplasms, most patients (>65%) are diagnosed with inoperable disease (unresectable locally advanced (stage III) and recurrent or metastatic (stage IV)), when palliative chemotherapy or supportive care are appropriate. The prognosis is poor: the five-year overall survival (OS) is 10% and 0% for stage III and IV, respectively [4].

Palliative chemotherapy has shown benefit in advanced/metastatic biliary tract cancer (ABC), improving survival. A study of 90 patients with bile duct or pancreatic carcinomas randomised patients to receive best supportive care with or without chemotherapy (a combination of 5-fluorouracil (5-FU), etoposide and leucovorin) [5]. The median overall survival in the biliary tract subgroup was greater in the chemotherapy arm (6.5 months versus 2.5 months) and although this difference was not statistically significant for the biliary tract subgroup (p-value 0.1), there was a statistically significant improvement in quality of life (33% versus 5%, p-value < 0.01) and quality-adjusted survival (p-value < 0.05) in favour of chemotherapy in the biliary tract cancer patients.

Several phase II trials [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23] followed, defining 5-FU, gemcitabine and platinum analogues as the most active agents [24], [25]. In 2010 a reference regimen for first-line therapy was established based on the prospective, randomised phase III United Kingdom (UK) ABC-02 study [22] which demonstrated an overall survival advantage for the cisplatin and gemcitabine (CisGem) doublet over gemcitabine alone (11.7 versus 8.1 months; hazard ratio 0.64, 95% confidence interval (CI) 0.52–0.80; p < 0.001).

A common (70–84%) presenting symptom of biliary tract malignancies is jaundice, mostly due to biliary tract obstruction [26], [27], which has also been defined as a poor prognostic factor in surgical BTC series [28]. Addressing biliary obstruction and its complications is pivotal in the successful management of these tumours (NCCN guidelines v.1 2015 [29]). However, even with expert interventional stenting, jaundice can persist because of biliary tract obstruction related to luminal disease or extensive liver metastasis and clinicians often forego systemic treatment for fear of toxicity and uncertain benefit in otherwise good performance status patients.

Jaundiced patients (defined as patients with a bilirubin at the time of starting chemotherapy higher than 1.5× upper limit of normal (ULN) were excluded from the randomised ABC-02 clinical trial [22] and no analysis has assessed this specific population to date. Therefore, there are no safety or efficacy data for this patient subgroup who are usually not considered for chemotherapy and are offered supportive care only.

According to the manufacturer’s labelling, no dose adjustment for cisplatin is recommended in patients with hepatic impairment due to its renal elimination (www.fda.gov). In contrast, the gemcitabine summary of product characteristics advices its use ‘with caution’ in patients with hepatic impairment due to its potential hepatotoxicity, but it does not recommend a specific dose reduction [30]. Venook and colleagues performed a phase I clinical trial in patients with liver failure; they recommend starting gemcitabine at a reduced dose (800 mg/m2) in patients with elevated bilirubin levels [31].

Due to lack of knowledge regarding the safety of administering CisGem in the context of liver impairment, other drugs (such as 5-FU alone, or combined with oxaliplatin) could be considered as an alternative in this scenario. However, lack of quality data (no randomised study available) supporting this alternative combination in this setting, makes this approach challenging [32], [33], [34], [35], [36].

This study assessed the safety and efficacy of CisGem, already established as the standard of care in non-jaundiced patients, as first-line chemotherapy in jaundiced patients despite optimal stenting.

Section snippets

Materials and methods

We undertook a retrospective analysis in three specialist UK institutions. Eligible patients (between 2003 and 2013) were those that met the following inclusion criteria: biopsy-proven ABC (gallbladder, cholangiocarcinoma or ampullary); received palliative first-line chemotherapy with 3-weekly CisGem; bilirubin level at the moment of starting chemotherapy ⩾1.5×ULN (⩾30 μmol/L or ⩾1.7 mg/dL); patients with follow-up, response and chemotherapy-related toxicity data available. Patients were

Results

A total of 545 patients who had received CisGem for ABC were screened; 33 met the criteria to be included in this analysis. The median time of follow-up was 8.3 months (range 0.9–36.8); at the end of the follow-up, more than 95% of the patients had progressed or died.

Discussion

Deranged liver function tests and elevated bilirubin are a common problem in patients with biliary tract malignancies; both due to biliary tract obstruction and/or liver metastases. These patients are, by necessity, excluded from phase 3 studies in biliary tract malignancies and therefore, few data are available for its safety or efficacy. In this study we evaluated the benefit of chemotherapy in patients who remained jaundiced despite optimal biliary stenting. We reasoned that for patients

Conclusions

Not all patients with a high bilirubin despite optimal stenting should be denied the option of palliative chemotherapy. A subgroup of patients whose jaundice is related to biliary tract obstruction (luminal disease) may benefit from chemotherapy; in the absence of active infection, there is no need to delay chemotherapy after biliary stenting waiting for the bilirubin to normalise. In contrast, for patients with jaundice secondary to liver metastasis, chemotherapy is not beneficial. CisGem

Conflict of interest statement

None declared.

Acknowledgements

AL is funded by the ESMO Translational Research Programme.

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