Abstract
AIM: To determine the impact (morbidity/mortality) of biliary stent-related events (SRE) (cholangitis or stent obstruction) in chemotherapy-treated pancreatico-biliary patients.
METHODS: All consecutive patients with advanced pancreatobiliary cancer and a biliary stent in-situ prior to starting palliative chemotherapy were identified retrospectively from local electronic case-note records (Jan 13 to Jan 15). The primary end-point was SRE rate and the time-to-SRE (defined as time from first stenting before chemotherapy to date of SRE). Progression-free survival and overall survival were measured from the time of starting chemotherapy. Kaplan-Meier, Cox and Fine-Gray regression (univariate and multivariable) analyses were employed, as appropriate. For the analysis of time-to-SRE, death was considered as a competing event.
RESULTS: Ninety-six out of 693 screened patients were eligible; 89% had a metal stent (the remainder were plastic). The median time of follow-up was 9.6 mo (range 2.2 to 26.4). Forty-one patients (43%) developed a SRE during follow-up [cholangitis (39%), stent obstruction (29%), both (32%)]. There were no significant differences in baseline characteristics between the SRE group and no-SRE groups. Recorded SRE-consequences were: none (37%), chemotherapy delay (24%), discontinuation (17%) and death (22%). The median time-to-SRE was 4.4 mo (95%CI: 3.6-5.5). Patients with severe comorbidities (P < 0.001) and patients with ≥ 2 baseline stents/biliary procedures [HR = 2.3 (95%CI: 1.2-4.44), P = 0.010] had a shorter time-to-SRE on multivariable analysis. Stage was an independent prognostic factor for overall survival (P = 0.029) in the multivariable analysis adjusted for primary tumour site, performance status and development of SRE (SRE group vs no-SRE group).
CONCLUSION: SREs are common and impact on patient’s morbidity. Our results highlight the need for prospective studies exploring the role of prophylactic strategies to prevent/delay SREs.
Keywords: Advanced biliary tract cancer, Pancreatic cancer, Biliary obstruction, Biliary stent, Stent-related event
Core tip: Most patients diagnosed with advanced malignancies of the pancreas or bile ducts present with biliary obstruction; this requires biliary stenting before starting treatment with palliative chemotherapy. The impact of developing stent-related events (SRE) such as cholangitis or stent obstruction (and the potential role of prophylactic treatment in order to reduce the risk of developing SREs) has not been explored in this patient population. Our results have identified that SREs are common and adversely impact on patient’s morbidity (and possibly mortality) and support the need for prospective studies investigating the role of prophylaxis in this population.
INTRODUCTION
Both pancreatic and biliary tract malignancies are known to have a poor prognosis, mainly due to late presentation of patients who experience non-specific symptoms for some time. Because of this delay, the majority of patients (around 80%) are diagnosed with advanced-stage cancer, which is not amenable to curative resection[1,2]. In the context of advanced pancreatobiliary malignancies, chemotherapy is considered the standard of care treatment and cornerstone of patients management; while the role of radiotherapy is not clearly stablished (even for locally advanced disease), at least in the first-line setting. Chemotherapy is given with palliative intent, its aim being to increase survival and reduce cancer-related symptoms thereby improving quality of life. Systemic treatment for patients with advanced biliary tract cancer includes gemcitabine alone or given in combination with cisplatin[3]. In patients with advanced pancreatic adenocarcinoma, chemotherapy may consist of monotherapy (gemcitabine) or combination therapy [gemcitabine-nab-paclitaxel doublet or FOLFIRINOX (5-fluorouracil, oxaliplatin and irinotecan)][4,5]. However, even with the newer chemotherapy combinations, the prognosis remains poor, with a median overall survival of less than 12 mo[5].
For patients presenting with biliary obstruction, re-establishment of biliary drainage prior to starting palliative chemotherapy is mandatory [via endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC)][6]. Two main types of biliary stents are usually employed: (1) plastic stents which have a small diameter and are used for potentially-resectable tumours which are then removed when the curative surgery is performed; and (2) metallic stents that are usually chosen for patients with unresectable cancers because of their larger diameter[7-9] and therefore, longer patency[10].
Unfortunately, despite successful first biliary stenting, some patients will develop a stent-related event (SRE) such as recurrence of biliary obstruction (with development of new obstructive jaundice) or infection (cholangitis)[11,12]. The median patency time of metallic biliary stents is estimated to be around 3.5 to 4.0 mo, although it varies depending on the diameter and type of the stent inserted (stent patency drops to 1.6 mo with plastic biliary stents)[10,13,14]. The development of a SRE has been postulated to be detrimental in many ways for the patient population with pancreatobiliary cancer receiving palliative chemotherapy, leading to shorter survival (due to SRE-related life-threatening complications) and negative impact on patients’ quality of life (due to repeat hospitalisation). Moreover, chemotherapy dose intensity may be compromised as a result of admission-related treatment delays or discontinuations (for example, in patients with permanent deterioration of their performance status after hospitalisation).
The aim of this study was to analyse the incidence (measured as SRE rate and time-to-SRE) and impact of SREs in patients with advanced biliary tract and pancreatic malignancies receiving palliative chemotherapy and, in doing so, to provide reference data in order to design an adequately-powered clinical trial to investigate the role of prophylaxis for the prevention or delay of SREs in patients with biliary stents who are due to commence chemotherapy.
MATERIALS AND METHODS
Patients were identified retrospectively from local electronic case-note records at a single institution (The Christie NHS Foundation Trust, Manchester, United Kingdom). All consecutive patients diagnosed with hepato-pancreato-biliary (HPB) malignancies referred between January 2013 and January 2015 were screened. The local audit committee approved this study (CE15/1400).
Eligible patients were those meeting the following inclusion criteria: advanced (unresectable or metastatic) biliary tract malignancy [gallbladder, bile duct (cholangiocarcinoma) or ampullary] or pancreatic cancer (adenocarcinoma); had an in-situ biliary stent for biliary obstruction at the time of starting palliative chemotherapy; and went on to receive standard first-line palliative chemotherapy. Patients with hepatocellular carcinoma were excluded.
Demographic data [including fitness at baseline assessed by Eastern Cooperative Oncology Group Performance Status score (ECOG-PS)], characteristics of the primary tumour (tumour site and stage (AJCC 7th Edition[15]) and details of the treatment administered were collected from the local records. Radiological response to treatment was assessed 3-monthly as per Response Evaluation Criteria In Solid Tumours (RECIST v.1.1)[16]. Comorbidities in addition to the index cancer were classified according to the Adult Comorbidity Evaluation (ACE)-27 index which is systematically used in our institution[17]. Characteristics of the biliary stent fitted at baseline and details of any SRE (if any) were collected. Patients who developed at least one SRE during the follow-up were included in the SRE group, while those who did not were included in the no-SRE group.
The primary objective of this study was to assess the SRE rate and the time-to-SRE in a population of patients with a diagnosis of biliary or pancreatic cancer receiving palliative chemotherapy. Secondary objectives included analysis of the impact of the development of a SRE on the patient’s planned chemotherapy schedule, progression-free survival (PFS) and overall survival (OS).
A stent-related event (SRE) was defined as any one or more of the following: (1) any episode of jaundice which was considered significant enough for new stenting or medical treatment and was confirmed by radiological imaging to be associated with biliary dilatation; (2) any episode of infection which was clinically in keeping with cholangitis (bile duct infection) requiring antibiotic therapy; (3) bacteraemia with isolation in blood cultures of bacteria suspected to have originated in the biliary tract; and (4) any episode of cholecystitis or gallbladder perforation.
The following were not considered SREs: (1) jaundice related to high tumour burden liver disease with no significant change in biliary dilatation compared with previous imaging; (2) episodes of neutropenic or non-neutropenic fever with no identified biliary focus; and (3) patients with non-clinically significant biliary occlusion or biliary dilatation (i.e., radiological evidence only with no jaundice, increasing bilirubin, increasing liver function tests (LFTs), fever or evidence of infection) who required no action (no new stenting or no new antibiotic therapy).
Time on follow-up was defined as the time from first biliary stent insertion to date of last follow-up available. Time-to-SRE was defined as the period between the date of the first biliary stenting and the date of the first evidence (clinical or radiological) of SRE. The median time-to-SRE was calculated in patients developing a SRE during follow-up. The risk of developing a SRE at different time-points was estimated for all patients, using the Kaplan-Meier method. For the analysis of time-to-SRE, death was considered a competing event; thus, Fine-Gray regression was employed for identification of factors related to longer/shorter time-to-SRE. For multivariable analysis of factors impacting time-to-SRE, those variables which showed statistically significant P-value in the univariate analysis (P < 0.05) were included.
In order to provide data regarding the impact of chemotherapy in PFS and OS, PFS and OS were defined as the time from starting chemotherapy to the time of progression (radiological or clinical) and the date of death/last follow-up, respectively. Median PFS and OS were estimated by the Kaplan-Meier method. The log-rank test and univariate/multivariable Cox regression models were used to identify potential prognostic factors for both PFS and OS. For assessment of factors with an impact on OS, variables considered of interest [such as site of primary tumour, stage, ECOG-PS and development of SRE (SRE group vs no-SRE group)] and those variables which showed statistically significant P in the univariate analysis (P < 0.05) were included in multivariable analysis.
Statistical t-test, χ2 test and the Mann-Whitney test (in case of non-normal distribution as per Shapiro-Wilk test) were applied as appropriate. Two-sided significance test with a P of < 0.05 was considered significant. Stata version 12.0 software was employed for the statistical analysis.
RESULTS
A total of 693 patients diagnosed with HPB malignancies were screened; 96 met the criteria for inclusion (Figure 1). The median time of follow-up was 9.6 mo (range 2.2 to 26.4). By the end of the follow-up period, 45% and 69% of the patients had progressed and died, respectively. There were no significant differences (P = 0.1308) in median follow-up between the SRE group [10.5 mo (range: 2.1-26.4)] and the no-SRE group [8.5 mo (range 3.2-18.9)]. The rate of patients who died and progressed was also similar between both groups [rate of death: 71% (SRE group) vs 67% (no-SRE group); P = 0.825] [rate of progression: 54% (SRE group) vs 38% (no-SRE group); P = 0.151].
Figure 1.
Patient flow. Ninety-six out of the 693 patients screened were found to be eligible. HPB: Hepato-pancreato-biliary cancer; Jan: January; Pts: Patients.
Patient demographics
The median age at the time of commencing palliative chemotherapy was 66.6 years (range 26-83.8) with a similar proportion of males (56%) and females (44%). The primary tumour site was as follows: 78% pancreas, 18% bile duct (cholangiocarcinoma), 3% ampulla and 1% gallbladder cancer. Most patients (60%) had locally advanced disease. All patients were fit for chemotherapy and started first-line systemic treatment as per clinician discretion. The median time between first stenting and start of chemotherapy was 1.8 mo (range: 0.1-12.6). The most frequently used chemotherapy schedules were single agent gemcitabine (39%) followed by gemcitabine and capecitabine combination (26%). The median time of chemotherapy duration was 3.2 mo (range 0.1-7.6); there were no differences in baseline characteristics between the SRE group and the no-SRE group (see detail in Table 1). None of the patients included were on long-term antibiotics or ursodeoxycholic acid.
Table 1.
Demographic characteristics of patients included in the study
| Variables | All patients (n = 96) | SRE group (n = 41; 43%) | no-SRE group (n = 55; 57%) | P-value for distribution within baseline parameter (χ2 test), SRE vs no-SRE groups | |
| Gender | Female | 42 (44) | 20 (49) | 22 (40) | 0.391 |
| Male | 54 (56) | 21 (51) | 33 (60) | ||
| Age1 | Median (range) | 66.6 (26-83.8) | 64.9 (26-84) | 67.6 (42.4-83.2) | 0.88332 |
| Primary tumour site | Ampulla | 3 (3) | 1 (2) | 2 (4) | 0.3803 |
| Bile duct (cholangiocarcinoma) | 17 (18) | 10 (24) | 7 (13) | ||
| Intrahepatic | 5 (31) | 3 (33) | 2 (29) | 1.0004 | |
| Extrahepatic | 11 (69) | 6 (67) | 5 (71) | ||
| Gallbladder | 1 (1) | 0 (0) | 1 (2) | ||
| Pancreas | 75 (78) | 30 (73) | 45 (82) | ||
| Head | 66 (89) | 26 (90) | 40 (89) | 1.0005 | |
| Body | 8 (11) | 3 (10) | 5 (11) | ||
| Stage | Locally advanced | 58 (60) | 22 (54) | 36 (65) | 0.294 |
| Metastatic | 38 (40) | 19 (46) | 19 (35) | ||
| ECOG-PS | 0 | 17 (18) | 9 (22) | 8 (15) | 0.547 |
| 1 | 51 (53) | 22 (54) | 29 (53) | ||
| ≥ 2 | 28 (29) | 10 (24) | 18 (33) | ||
| Diabetic | No | 68 (71) | 29 (71) | 39 (71) | 1.000 |
| Yes | 28 (29) | 12 (29) | 16 (29) | ||
| Comorbidities | None | 31 (32) | 14 (34) | 17 (31) | 0.428 |
| Mild | 41 (43) | 18 (44) | 23 (42) | ||
| Moderate | 20 (21) | 9 (22) | 11 (20) | ||
| Severe | 4 (4) | 0 (0) | 4 (7) | ||
| Line of palliative chemotherapy | First | 96 (100) | 41 (100) | 55 (100) | 1.000 |
| Type of chemotherapy | FOLFIRINOX | 11 (11) | 4 (10) | 7 (13) | 0.605 |
| Cisplatin Gemcitabine | 13 (14) | 8 (20) | 5 (9) | ||
| Gemcitabine Nab-paclitaxel | 7 (7) | 2 (5) | 5 (9) | ||
| Gemcitabine +/- TH302 | 2 (2) | 0 (0) | 2 (4) | ||
| Gemcitabine Capecitabine | 25 (26) | 12 (29) | 13 (24) | ||
| Gemcitabine single agent | 37 (39) | 15 (37) | 22 (40) | ||
| FOLFOX | 1 (1) | 0 (0) | 1 (2) | ||
| Time from first stent to starting chemotherapy1 | Median (range) | 1.8 (0.1-12.6) | 1.6 (0.6-5.8) | 1.9 (0.1-12.6) | 0.18242 |
| Time of chemotherapy duration1 | Median (range) | 3.2 (0.1-7.6) | 3.8 (0.1-7.2) | 3.1 (0.1-7.6) | 0.45202 |
No differences were identified between SRE group and the no-SRE group.
Variables do not meet a normal distribution (as per Shapiro-Wilks test);
Mann-Whitney P-value has been provided for variables not meeting normal distribution criteria;
the P for χ2 test for comparison of distribution of primary tumour [ampulla vs bile duct (cholangiocarcinoma) vs gallbladder vs pancreas] between SRE group and no-SRE group;
the P for χ2 test for comparison of distribution of primary tumour [type of bile duct tumour (cholangiocarcinoma): intrahepatic vs extrahepatic] between SRE group and no-SRE group;
The P for χ2 test for comparison of distribution of primary tumour (site of pancreatic cancer: head vs body) between SRE group and no-SRE group. SRE: Stent-related event; ECOG-PS: ECOG performance status; FOLFIRINOX: 5-fluorouracil, oxaliplatin and irinoetecan combination; FOLFOX: 5-fluorouracil and oxaliplatin combination.
Biliary stenting characteristics at baseline
Most of patients had one (73%) or two (22%) biliary stents fitted at the time of starting systemic chemotherapy; only 3 patients and 1 patient had three and four stents in-situ, respectively. In 85 patients (89%), stents were metallic. A higher proportion of patients in the SRE group when compared to the no-SRE group had ≥ 2 biliary stents or biliary procedures [41% (SRE group) vs 15% (no-SRE group); P = 0.004]. See Table 2.
Table 2.
Characteristics of the baseline biliary stenting and stent-related event
| Variables | All patients (n = 96) | SRE group (n = 41; 43%) | no-SRE group (n = 55; 57%) | P-value for distribution within baseline parameter (χ2 test), SRE vs no-SRE groups | |
| Stents at baseline | 1 | 70 (73) | 24 (59) | 46 (84) | 0.008 |
| 2 | 21 (22) | 13 (32) | 8 (14) | ||
| 3 | 3 (3) | 3 (7) | 0 (0) | ||
| 4 | 1 (1) | 1 (2) | 0 (0) | ||
| Not specified | 1 (1) | 0 (0) | 1 (2) | ||
| Number of stents/biliary interventions at baseline | 1 previous stent/intervention | 70 (73) | 24 (59) | 46 (84) | 0.004 |
| ≥ 2 previous stent/intervention | 25 (26) | 17 (41) | 8 (15) | ||
| Not specified | 1 (1) | 0 (0) | 1 (1) | ||
| Type of stent (baseline) | Metal | 85 (89) | 37 (90) | 48 (87) | 0.170 |
| Plastic | 7 (7) | 4 (10) | 3 (5) | ||
| Not specified | 4 (4) | 0 (0) | 4 (7) | ||
| Type of SRE (SRE group only) | Cholangitis | 16 (17) | 16 (39) | - | - |
| Stent obstruction | 12 (13) | 12 (29) | - | ||
| Both | 13 (14) | 13 (32) | - | ||
| Consequence of SRE (SRE group only) | None | 15 (16) | 15 (37) | - | - |
| Chemotherapy delayed | 10 (10) | 10 (24) | - | ||
| Chemotherapy stopped | 7 (7) | 7 (17) | - | ||
| Death | 9 (9) | 9 (22) | - | ||
| Further SRE (SRE group only) | No | 27 (28) | 27 (66) | - | - |
| Yes | 14 (15) | 14 (34) | - | ||
Forty-three percent of patients developed a SRE during the follow-up. SRE: Stent-related event.
Stent-related events rate and its consequences
During follow-up, 41 (43%) patients developed a SRE; the type of SRE was as follows: cholangitis (16 patients; 39%), stent obstruction (12; 29%) and combination of both (13; 32%). Moreover, in 14 out of the 41 patients with a first SRE (34%), further SREs were documented. Development of at least one SRE during the follow-up led to the following consequences: a delay in chemotherapy (10 patients; 24%), interruption of chemotherapy (7; 17%) and death (9; 22%). In 15 of the patients (37%), there was no significant SRE-related repercussion. No relationship was found between type of stent and type of SRE (P = 0.815; full data not show); nor between the type of SRE and its consequence (P = 0.166; full data not shown). See Table 2.
Time to stent-related event
The median time-to-SRE was 4.4 mo (95%CI: 3.6-5.5) when calculated for the SRE group only. Table 3 summarises the estimated risk of SRE for all patients (SRE group and no-SRE group) at different time-points during the follow up, showing a cumulative risk of developing SRE during the time on follow-up. Figure 2 represents each of the patients included in this study, showing the time to SRE in the context of other clinically significant events.
Table 3.
Risk of development of stent-related event increased with longer follow-up period in the absence of competing event (death)
| Time-point of follow-up since first biliary stenting | Estimated risk of development of SRE rate for all patients |
| 3 mo | 11.5% (95%CI: 6.5-19.7) |
| 6 mo | 32.0% (95%CI: 23.5-42.7) |
| 12 mo | 48.6% (95%CI: 37.5-61) |
| 18 mo | 59.9% (95%CI: 44-76.5) |
| 24 mo | 79.9% (95%CI: 48.03-98.1) |
SRE: Stent-related event.
Figure 2.
Graphical representation of each of the patient’s follow-up included in this study, time on chemotherapy, and time of radiological progression and development of a stent-related event.
Patients with severe comorbidities (vs patients with no comorbidities) (P < 0.001) and patients with ≥ 2 stent/biliary procedure before starting chemotherapy (vs 1) had shorter time-to-SRE on multivariable analysis (HR = 2.3, 95%CI: 1.2-4.44, P = 0.010). See Table 4.
Table 4.
Univariate and multivariable analysis looking for factors related with time-to-stent-related event
| Time-to-SRE | Univariate analysis (Fine-Gray regression) |
Multivariable analysis (Fine-Gray regression) |
|||
| HR (95%CI) | P-value | HR (95%CI) | P-value | ||
| Primary | BTC | Ref | X | ||
| Pancreas | 0.8 (0.4-1.5) | 0.407 | |||
| Stage | Locally advanced | Ref | X | ||
| Metastatic | 1.4 (0.8-2.6) | 0.251 | |||
| ECOG-PS | 0/1 | Ref | X | ||
| ≥ 2 | 0.8 (0.4-1.5) | 0.435 | |||
| Comorbidities | None | Ref | Ref | ||
| Mild | 0.8 (0.4-1.7) | 0.605 | 1.1 (0.5-2.2) | 0.844 | |
| Moderate | 0.9 (0.4-1.9) | 0.734 | 1.1 (0.5-2.2) | 0.986 | |
| Severe | 3.6 × 10-8 (1.2 × 10-8-1.1 × 10-7) | < 0.001 | 9.4 × 10-7 (2.9 × 10-7-3.1 × 10-6) | < 0.001 | |
| Number of stents/biliary interventions at baseline | 1 | Ref | Ref | ||
| ≥ 2 | 2.5 (1.4-4.6) | 0.003 | 2.3 (1.2-4.44) | 0.010 | |
| Type of the most recent stent | Metal | Ref | X | ||
| Plastic | 2.1 (0.7-6.5) | 0.182 | |||
Fine-Gray Regression; competing event: Death. BTC: Biliary tract cancer; ECOG-PS: ECOG performance status.
Progression-free survival
Only nine patients (9%) were still receiving first-line chemotherapy at the time of the analysis: eight in the no-SRE group and one in the SRE group. The most frequent reason for stopping chemotherapy was toxicity (46%), followed by completion of planned treatment (27%), progressive disease (17%) or death (1%). Estimated median PFS was 6.7 mo (95%CI: 4.4-7.8), with similar results in both SRE group and no-SRE group [6.7 (95%CI: 4.3-8.7) and 6.8 (95%CI: 3.9-7.8), respectively] [HR = 0.9 (95%CI: 0.6-1.5), P = 0.7666]. There were no statistically significant differences with respect to the reason for chemotherapy discontinuation between the SRE group and the no-SRE group (P = 0.058; full data not shown).
Overall survival
The estimated median OS was 8.6 mo (95%CI: 6.8-9.8). Even though there seemed to be a trend for longer survival in the SRE group [median OS 9.8 mo (95%CI: 7.4-11.6)] than in the no-SRE group [median OS 7.6 mo (95%CI: 5.7-9.6)] differences were not statistically significant (Log-rank test P = 0.0947). When the impact on OS of the SRE-related consequence was analysed, we identified a longer OS in the group of patients with mild consequences [none/chemotherapy delay; median OS 11.6 mo (95%CI: 9.8-20)] compared to those with severe consequences [interruption of chemotherapy or death; median OS 4.4 mo (95%CI: 2.6-8.7)]; [HR = 3.8 (95%CI: 1.7-8.2), P = 0.001] (Figure 3). Stage was an independent prognostic factor for OS [HR = 1.8 (95%CI: 1.06-2.9), P = 0.029)] in multivariable analysis adjusted for primary tumour, ECOG-PS and development of SRE (SRE group vs no-SRE group) (Table 5).
Figure 3.
Kaplan Meier graphic. Overall survival and type of stent-related event (SRE)-related consequence [mild (none/chemotherapy delayed) vs severe (chemotherapy interrupted/death)].
Table 5.
Univariate and multivariable analysis looking for factors related with overall survival (Cox Regression)
| Overall survival | Univariate analysis (Cox regression) |
Multivariable analysis (Cox regression) |
|||
| HR (95%CI) | P-value | HR (95%CI) | P-value | ||
| Primary site | BTC | Ref | Ref | ||
| Pancreas | 1.6 (0.8-2.9) | 0.153 | 1.5 (0.8-2.8) | 0.205 | |
| Stage | Locally advanced | Ref | Ref | ||
| Metastatic | 1.6 (0.99-2.9) | 0.067 | 1.8 (1.06-2.9) | 0.029 | |
| ECOG-PS | 0/1 | Ref | Ref | ||
| ≥ 2 | 0.9 (0.5-1.6) | 0.748 | 0.9 (0.5-1.6) | 0.716 | |
| Stent-related event | No-SRE group | Ref | Ref | ||
| SRE group | 0.7 (0.4-1.1) | 0.098 | 0.6 (0.4-1.01) | 0.205 | |
For assessment of factors with an impact on OS, variables considered of interest [such as site of primary tumour, stage, ECOG-PS and development of SRE (yes/no)] and those variables which showed statistically significant P-value in the univariate analysis were included in multivariable analysis. BTC: Biliary tract cancer; ECOG-PS: ECOG performance status.
DISCUSSION
In patients with advanced/inoperable cancers of the pancreas or biliary tract receiving chemotherapy and with an indwelling biliary stent at the start of treatment, we observed a high rate of SREs; moreover two-thirds of patients had some kind of consequence from the SRE (chemotherapy delay, discontinuation or early death). In addition, one-third of patients with a first SRE developed further events, highlighting the importance of close follow-up for early detection and management of such events. Although we observed no significant relationship between the type of stent and type of SRE, this may be explained by the small proportion of patients (11%) with plastic stents. Finally, there were no differences between the type of SRE developed (obstruction, infection or both) and its consequences; be it mortality, chemotherapy delay or discontinuation rate. Therefore all SREs should be considered as a medical emergency and early management is essential, due to the potentially life-threatening consequences.
Stent-related events occurred early with a median time-to-SRE of only 4.4 mo. Moreover, the risk increases with time rising 3-fold between month 3 and month 6 and up to 80% in patients alive at 24 mo. This highlights the importance of clinician (including primary and secondary care) and patient (and their cares) awareness of early detection and treatment of a SRE. Although some guidelines suggest replacement of plastic stents every six months[18] there are no such recommendations for metallic stents.
The only factor associated with a higher rate of SRE was the number of biliary stents or procedures at baseline (1 vs ≥ 2); none of the other baseline characteristics had this impact, including disease stage or site of primary tumour, highlighting the challenge that clinicians face in identifying patients at increased risk of a SRE. In addition to the number of stents at baseline, the presence of severe comorbidity was associated with earlier development of a SRE (i.e., earlier time-to-SRE). The fact that stage had no impact on time-to-SRE is likely to reflect the fact that stent occlusion arises from the primary (stented) disease rather than metastases, in the vast majority of patients.
The development of a SRE may be expected to be more frequent in patients receiving chemotherapy due to its known myelosuppressive effect[13] and particularly in patients receiving highly myelosuppressive treatment, such as FOLFIRINOX[5]. This was not confirmed in this study although this may again be due to the small number of patients receiving this regimen, and the fact that prophylactic granulocyte-colony stimulating factor (G-CSF) was routinely prescribed for these patients to reduce duration of neutropenia. The median time-to-SRE in our study was similar to previously published data in a non-chemotherapy population[13], suggesting that chemotherapy may not have as much as an impact on SREs as might be expected. Neither did we observe a higher rate of SREs if chemotherapy was delayed at baseline (due to potentially greater risk of tumour in-growth).
The development of a SRE did not impact on PFS; however there was a non-significant trend towards longer OS in the SRE group, compared with the no-SRE group. This cannot be interpreted as a causality effect (patients with SRE live longer) but rather a “time-at-risk” effect (patients who live longer have more time to develop a SRE). This was the main reason for including death as a “competing event” in the statistical analysis for time-to-SRE. In fact, the development of a SRE did not impact on survival in the multivariable analysis for OS, confirming this approach. Importance of “time-at-risk” in the development of a SRE is also supported by the following: a higher number of patients still receiving chemotherapy at the data cut-off point in the no-SRE group (8 patients vs 1 patient in the SRE group); and longer (though statistically non-significant) follow-up in the SRE group.
Our study population is representative of the population of interest when comparing characteristics such as rate of locally advanced patients; higher rate of biliary obstruction in patients with locally advanced disease[18]; predominance of pancreatic cancer compared to biliary malignancies[19]; median PFS and median OS (in keeping with a non-trial population). Moreover, the fact that tumour stage was identified as a prognostic factor in the multivariable analysis for OS was reassuring. The majority of patients with metallic stents at baseline is in keeping with international standards for palliative patients who are expected to be treated with chemotherapy (i.e., have an estimated survival of > 3 mo) in whom a plastic stent should not be considered as a standard[20]. The small number of patients with ECOG ≥ 2 is the likely reason why ECOG-PS did not impact on OS as chemotherapy is usually considered only for patients of good performance status (PS 0-1 and selected PS 2 patients).
There are limitations associated with our retrospective series; although all consecutive patients with a diagnosis of advanced pancreatobiliary malignancy were included, the patients were already pre-selected by fitness and comorbidities for referral for consideration for chemotherapy. Moreover, retrospective collection of data may be subject to reporting bias. In addition, patients with different primary tumour sites were included who were in receipt of differing chemotherapeutic agents; however completeness of data and inclusion of patients from a recent era makes our findings credible. Our series did not include any non-stented patients and therefore comparisons of SRE rate between stented and not-stented populations, which could be useful for assessing whether the combination of chemotherapy and biliary stent increased the risk of SRE, are not possible. Finally, most of our patients had a metal stent in situ; making our data not representative of population with plastic biliary stents.
To date, there is no evidence supporting the use of prophylactic therapy, such as antibiotics or ursodeoxycholic acid, aimed at reducing or delaying SREs in these patients; thus clinicians currently treat rather than prevent SREs[33]. One purpose of our study was to generate data to inform the design of future clinical trials exploring the role of prophylaxis for the prevention or delay of SREs in this specific population. This rationale has already been investigated by some studies (summarised in Table 6): overall, these trials are under-powered and involved patients with both benign and malignant biliary strictures who had plastic stents in-situ. No adequately-powered studies have been performed; neither has this question been addressed in patients with metal stents (now considered the standard of care in the palliative setting) or in a population receiving chemotherapy for advanced pancreas/biliary cancer. In 2002 the Cochrane collaboration concluded that well-designed studies with sufficient statistical power were essential to address this issue[33]. Our results highlight the importance of performing adequately-powered prospective studies looking for prevention of these events.
Table 6.
Summary of the available literature exploring the role of prophylactic treatment for stent-related event
| Disease | Ref. | Randomised | Type of stent | Total number of patients | Number of patients per arm | Treatment arm(s): Stent insertion plus…. | Investigation and result |
| Benign | Sciumè et al[21], 2004 | Yes | Plastic | 90 | 49/41 | Ursodeoxycholic acid and levofloxacin vs Ursodeoxycholic acid alone | Longer stent patency with lower cholangitis and admission rate. |
| (not blinded) | |||||||
| Katsinelos et al[22], 2008 | Yes | Plastic | 41 | 21/20 | Ursodeoxycholic acid vs Placebo | Common bile duct stones. No reduction in the bile duct stone size. | |
| (blinded) | |||||||
| Han et al[23], 2009 | No | Plastic | 28 | 28 | Ursodeoxycholic acid and terpene | Gallstones in elderly patients. Size of gallstones was reduced. | |
| Lee et al[24], 2011 | No | Plastic | 51 | 51 | Ursodeoxycholic acid | Gallstones in elderly patients. No benefit of adding Ursodeoxycholic acid. | |
| Nishizawa et al[25], 2013 | No | Plastic | 36 patients, 63 procedures | Non-randomised, two arms: 20/43 procedures | Ursodeoxycholic acid vs Observation | Bile duct stones. Longer patency time and reduction in gallstone size in the intervention cohort. | |
| Malignant | Ghosh et al[26], 19941 | Yes | Plastic | 70 | 31/39 | Ursodeoxycholic acid + antibiotic (ampicillin, metronidazole, ciprofloxacin) vs Observation | No differences in stent occlusion rate. |
| (not blinded) | |||||||
| Barrioz et al[27], 19941 | Yes | Plastic | 20 | Not specified | Ursodeoxycholic acid and norfloxacin vs Observation | Longer stent patency, prolonged median survival and shorter mean hospital stay. | |
| (not blinded) | |||||||
| Luman et al[28], 19991 | Yes | Not specified | 40 | 20/20 | Ciprofloxacin and rowachol vs Observation | Similar rate of obstruction and time to event. | |
| (not blinded) | |||||||
| Sung et al[29], 19991 | Yes | Plastic | 58 | Not specified | Ursodeoxycholic acid vs Observation | Similar rate of obstruction and time to event. | |
| (not blinded) | |||||||
| De Lédinghen et al[30], 20001 | Yes | Plastic | 62 | 33/29 | Ursodeoxycholic acid and norfloxacin vs Observation | Stopped after the interim analysis. No differences in stent patency. | |
| (not blinded) | |||||||
| Halm et al[31], 20012 | Yes | Plastic | 52 | 26/26 | Ursodeoxycholic acid and ofloxacin vs Ursodeoxycholic acid alone | Similar rate of obstruction and times to stent obstruction. | |
| (not blinded) | |||||||
| Chan et al[32], 20052 | Yes | Plastic | 94 | 50/44 | Ciprofloxacin vs Placebo | No differences in stent patency. Lower rate of cholangitis, but there was improvement in quality of life. | |
| (double blinded) |
Stent-related events can result in life-threatening complications in patients with advanced pancreatobiliary cancer who are receiving palliative chemotherapy; 43% of patients in our series developed a SRE and 63% of them had a SRE-related impact on delivery of chemotherapy or resulting in death. The risk of developing SREs increases with prolonged time on treatment and/or follow-up; moreover, risk is higher in patients with severe comorbidities and patients with ≥ 2 biliary stent or biliary procedures at baseline. Thus, close monitoring for early diagnosis and treatment is required. Our data will inform the design of future, prospective clinical trial(s) to evaluate how the risk of SREs and their sequelae can be reduced; as well as the clinical and socio-economic impact of doing so.
COMMENTS
Background
Despite successful first biliary stenting, some patients with biliary and pancreatic malignancies will develop a stent-related event (SRE) such as recurrence of biliary obstruction (with development of new obstructive jaundice) or infection (cholangitis). Development of these events is detrimental, especially in a chemotherapy-treated population.
Research frontiers
The aim of this study was to analyse the incidence (measured as SRE rate and time-to-SRE) and impact of SREs in patients with advanced biliary tract and pancreatic malignancies receiving palliative chemotherapy and, in doing so, to provide reference data in order to design an adequately-powered clinical trial to investigate the role of prophylaxis for the prevention or delay of SREs in patients with biliary stents who are due to commence chemotherapy.
Innovations and breakthroughs
In patients with advanced/inoperable cancers of the pancreas or biliary tract receiving chemotherapy and with an indwelling biliary stent at the start of treatment, the authors observed a high rate of SREs; moreover, in two-thirds of these patients there was a direct consequence from the SRE (chemotherapy delay, discontinuation or early death). Therefore all SREs should be considered as a medical emergency and early management is essential, due to their potentially life-threatening consequences.
Applications
Although the authors have demonstrated that SREs are frequent and may be associated with adverse outcomes, there is, to date, no evidence supporting the use of prophylactic therapy, such as antibiotics or ursodeoxycholic acid, aimed at reducing or delaying SREs in these patients; thus clinicians currently treat rather than prevent SREs. One purpose of our study was to generate data to inform the design of future clinical trials exploring the role of prophylaxis for the prevention or delay of SREs in this specific population.
Terminology
Stent-related events: recurrence of biliary obstruction with stent obstruction (with development of new obstructive jaundice) or infection (cholangitis) following successful first biliary stenting.
Peer-review
The authors explored the occurrence and consequences of stent-related events in a retrospective cohort of patients with pancreatico-biliary cancer stented for biliary obstruction. They showed that 43% patients developed a stent-related during the follow-up, which could lead to chemotherapy delay or discontinuation, or death.
Footnotes
Supported by Pancreatic Cancer Research Fund and Spanish society of Medical Oncology (Lamarca A).
Institutional review board statement: The study was reviewed and approved by The Christie NHS Foundation Trust (Manchester, United Kingdom); institutional approval number CE15/1400.
Informed consent statement: Not applicable to this study.
Conflict-of-interest statement: Authors declare no conflict-of-interest related to this manuscript.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Peer-review started: December 24, 2015
First decision: January 28, 2016
Article in press: March 2, 2016
P- Reviewer: Meyer J S- Editor: Ma YJ L- Editor: A E- Editor: Ma S
References
- 1.Valle JW. Advances in the treatment of metastatic or unresectable biliary tract cancer. Ann Oncol. 2010;21 Suppl 7:vii345–vii348. doi: 10.1093/annonc/mdq420. [DOI] [PubMed] [Google Scholar]
- 2.Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–1617. doi: 10.1056/NEJMra0901557. [DOI] [PubMed] [Google Scholar]
- 3.Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–1281. doi: 10.1056/NEJMoa0908721. [DOI] [PubMed] [Google Scholar]
- 4.Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703. doi: 10.1056/NEJMoa1304369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825. doi: 10.1056/NEJMoa1011923. [DOI] [PubMed] [Google Scholar]
- 6.Ballinger AB, McHugh M, Catnach SM, Alstead EM, Clark ML. Symptom relief and quality of life after stenting for malignant bile duct obstruction. Gut. 1994;35:467–470. doi: 10.1136/gut.35.4.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Davids PH, Groen AK, Rauws EA, Tytgat GN, Huibregtse K. Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet. 1992;340:1488–1492. doi: 10.1016/0140-6736(92)92752-2. [DOI] [PubMed] [Google Scholar]
- 8.Faigel DO. Preventing biliary stent occlusion. Gastrointest Endosc. 2000;51:104–107. doi: 10.1016/s0016-5107(00)70403-2. [DOI] [PubMed] [Google Scholar]
- 9.Costamagna G, Mutignani M, Rotondano G, Cipolletta L, Ghezzo L, Foco A, Zambelli A. Hydrophilic hydromer-coated polyurethane stents versus uncoated stents in malignant biliary obstruction: a randomized trial. Gastrointest Endosc. 2000;51:8–11. doi: 10.1016/s0016-5107(00)70378-6. [DOI] [PubMed] [Google Scholar]
- 10.Speer AG, Cotton PB, MacRae KD. Endoscopic management of malignant biliary obstruction: stents of 10 French gauge are preferable to stents of 8 French gauge. Gastrointest Endosc. 1988;34:412–417. doi: 10.1016/s0016-5107(88)71407-8. [DOI] [PubMed] [Google Scholar]
- 11.Libby ED, Leung JW. Prevention of biliary stent clogging: a clinical review. Am J Gastroenterol. 1996;91:1301–1308. [PubMed] [Google Scholar]
- 12.Gilbert DA, DiMarino AJ, Jensen DM, Katon RM, Kimmey MB, Laine LA, MacFaydyen BV, Michaletz-Onody PA, Zuckerman G. Status evaluation: biliary stents. American Society for Gastrointestinal Endoscopy. Technology Assessment Committee. Gastrointest Endosc. 1992;38:750–752. [PubMed] [Google Scholar]
- 13.Lofts FJ, Evans TR, Mansi JL, Glees JP, Knight MJ. Bile duct stents: is there an increased rate of complications in patients receiving chemotherapy? Eur J Cancer. 1997;33:209–213. doi: 10.1016/s0959-8049(96)00365-6. [DOI] [PubMed] [Google Scholar]
- 14.Ge PS, Hamerski CM, Watson RR, Komanduri S, Cinnor BB, Bidari K, Klapman JB, Lin CL, Shah JN, Wani S, et al. Plastic biliary stent patency in patients with locally advanced pancreatic adenocarcinoma receiving downstaging chemotherapy. Gastrointest Endosc. 2015;81:360–366. doi: 10.1016/j.gie.2014.08.020. [DOI] [PubMed] [Google Scholar]
- 15.Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, Editors . AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010. [Google Scholar]
- 16.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed] [Google Scholar]
- 17.Adult Comorbidity Evaluation-27 index. Available from: http://www.docin.com/p-690761619.html.
- 18.Seufferlein T, Bachet JB, Van Cutsem E, Rougier P. Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii33–vii40. doi: 10.1093/annonc/mds224. [DOI] [PubMed] [Google Scholar]
- 19.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29. doi: 10.3322/caac.21254. [DOI] [PubMed] [Google Scholar]
- 20.Boulay BR, Parepally M. Managing malignant biliary obstruction in pancreas cancer: choosing the appropriate strategy. World J Gastroenterol. 2014;20:9345–9353. doi: 10.3748/wjg.v20.i28.9345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Sciumè C, Geraci G, Pisello F, Facella T, Li Volsi F, Modica G. [Prevention of clogging of biliary stents by administration of levofloxacin and ursodeoxycholic acid] Chir Ital. 2004;56:831–837. [PubMed] [Google Scholar]
- 22.Katsinelos P, Kountouras J, Paroutoglou G, Chatzimavroudis G, Zavos C. Combination of endoprostheses and oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones. Dig Liver Dis. 2008;40:453–459. doi: 10.1016/j.dld.2007.11.012. [DOI] [PubMed] [Google Scholar]
- 23.Han J, Moon JH, Koo HC, Kang JH, Choi JH, Jeong S, Lee DH, Lee MS, Kim HG. Effect of biliary stenting combined with ursodeoxycholic acid and terpene treatment on retained common bile duct stones in elderly patients: a multicenter study. Am J Gastroenterol. 2009;104:2418–2421. doi: 10.1038/ajg.2009.303. [DOI] [PubMed] [Google Scholar]
- 24.Lee TH, Han JH, Kim HJ, Park SM, Park SH, Kim SJ. Is the addition of choleretic agents in multiple double-pigtail biliary stents effective for difficult common bile duct stones in elderly patients? A prospective, multicenter study. Gastrointest Endosc. 2011;74:96–102. doi: 10.1016/j.gie.2011.03.005. [DOI] [PubMed] [Google Scholar]
- 25.Nishizawa T, Suzuki H, Takahashi M, Kaneko H, Suzuki M, Hibi T. Effect of ursodeoxycholic acid and endoscopic sphincterotomy in long-term stenting for common bile duct stones. J Gastroenterol Hepatol. 2013;28:63–67. doi: 10.1111/jgh.12012. [DOI] [PubMed] [Google Scholar]
- 26.Ghosh S, Palmer KR. Prevention of biliary stent occlusion using cyclical antibiotics and ursodeoxycholic acid. Gut. 1994;35:1757–1759. doi: 10.1136/gut.35.12.1757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Barrioz T, Ingrand P, Besson I, de Ledinghen V, Silvain C, Beauchant M. Randomised trial of prevention of biliary stent occlusion by ursodeoxycholic acid plus norfloxacin. Lancet. 1994;344:581–582. doi: 10.1016/s0140-6736(94)91967-4. [DOI] [PubMed] [Google Scholar]
- 28.Luman W, Ghosh S, Palmer KR. A combination of ciprofloxacin and Rowachol does not prevent biliary stent occlusion. Gastrointest Endosc. 1999;49:316–321. doi: 10.1016/s0016-5107(99)70007-6. [DOI] [PubMed] [Google Scholar]
- 29.Sung JJ, Sollano JD, Lai CW, Ismael A, Yung MY, Tumala I, Chung SC. Long-term ciprofloxacin treatment for the prevention of biliary stent blockage: a prospective randomized study. Am J Gastroenterol. 1999;94:3197–3201. doi: 10.1111/j.1572-0241.1999.01518.x. [DOI] [PubMed] [Google Scholar]
- 30.De Lédinghen V, Person B, Legoux JL, Le Sidaner A, Desaint B, Greef M, Moesch C, Grollier G, Ingrand P, Sautereau D, et al. Prevention of biliary stent occlusion by ursodeoxycholic acid plus norfloxacin: a multicenter randomized trial. Dig Dis Sci. 2000;45:145–150. doi: 10.1023/a:1005429914955. [DOI] [PubMed] [Google Scholar]
- 31.Halm U, Schiefke WE, Mössner J, Keim V. Ofloxacin and ursodeoxycholic acid versus ursodeoxycholic acid alone to prevent occlusion of biliary stents: a prospective, randomized trial. Endoscopy. 2001;33:491–494. doi: 10.1055/s-2001-14963. [DOI] [PubMed] [Google Scholar]
- 32.Chan G, Barkun J, Barkun AN, Valois E, Cohen A, Friedman G, Parent J, Love J, Enns R, Baffis V, et al. The role of ciprofloxacin in prolonging polyethylene biliary stent patency: a multicenter, double-blinded effectiveness study. J Gastrointest Surg. 2005;9:481–488. doi: 10.1016/j.gassur.2004.10.008. [DOI] [PubMed] [Google Scholar]
- 33.Galandi D, Schwarzer G, Bassler D, Allgaier HP. Ursodeoxycholic acid and/or antibiotics for prevention of biliary stent occlusion. Cochrane Database Syst Rev. 2002;(3):CD003043. doi: 10.1002/14651858.CD003043. [DOI] [PMC free article] [PubMed] [Google Scholar]