Keywords
biliary tract cancers - first-line palliative chemotherapy - gemcitabine–cisplatin
- India - unresectable cholangiocarcinoma
Dr Anant Ramaswamy
Introduction
Biliary tract cancers (BTCs) are a rare group of tumors, with wide geographical variance
in prevalence.[1] India is one of the regions with a high incidence of gallbladder cancers (GBCs)
and there are a large number of epidemiological and clinical studies which have reported
on these measures in GBC.[2]
[3]
[4]
[5] However, there is limited evidence as to the epidemiological factors as well as
clinical outcomes in patients with advanced cholangiocarcinomas (CCAs) in India.
Advanced CCAs are treated with palliative first-line chemotherapy (CT1), usually a
gemcitabine-based doublet, though there is some evidence for the use of external beam
radiotherapy concurrent with chemotherapy in unresectable but nonmetastatic CCAs.[6]
[7]
[8]
[9]
A recently published study from India highlighted outcomes in CCA with the gemcitabine–carboplatin
regimen and showed reasonable tolerance and outcomes.[10] With this background, we conducted a retrospective study evaluating outcomes of
patients with CCA treated with CT1.
Materials and Methods
Data for this study were extracted from a prospective database of all patients with
BTC. Patients between January 2014 and March 2019 were screened from the database.
The study was conducted according to the principles of the Declaration of Helsinki,
and guidelines for good clinical practice.
The decision on unresectability and/or metastatic disease of CCA was made by a dedicated
team comprising a surgical oncologist, medical oncologist, radiation oncologist, and
radiologist.
Patients satisfying all the following criteria were included in the analysis:
-
Histologically proven CCA. In cases where histology was not feasible despite repeated
attempts, patients were treated based on clinical presentation and radiological evaluation.
-
ECOG (Eastern Cooperative Oncology Group) PS 0–2.
-
Metastatic or unresectable CCA.
-
Administered at least one cycle of CT1 in our hospital.
First-line chemotherapeutic regimens, toxicity assessment, and responses were retrieved
from database. Toxicity assessment was recorded as per NCI-CTCAE (National Cancer
Institute- Common Terminology Criteria for Adverse Events) version 4.0 and grades
3 and 4 toxicities are reported. Responses to treatment were evaluated three to four
cycles of chemotherapy or earlier as per physician decision. Responses were calculated
by response evaluation criteria in solid tumors RECIST (Response Evaluation Criteria
in Solid Tumors) criteria, with responses reported as complete response (CR), partial
response (PR), stable disease (SD), progressive disease (PD), where feasible. If RECIST
was not calculable, then the response was quantified based on collusion between treating
physician and the GI radiologist as follows: CR—disappearance of all baseline lesions;
PR—significant regression of lesions at baseline; SD—no significant regression of
baseline lesions and no new lesions; PD—appearance of new lesions or significant increase
in baseline lesions. Response rates and clinical benefit rate (CBR) were reported
as percentages.
Progression-free survival (PFS) was calculated from date of diagnosis to date of progression,
cessation of chemotherapy due to adverse events, withdrawal from therapy or death
(in case of no documented progression). Overall survival (OS) was calculated from
date of diagnosis to date of death. Patients who were lost to follow-up were considered
as dead for the purpose of statistical evaluation of OS.
Clinical Data Collection and Statistics
Demographic and clinical data were entered into SPSS version 25 with descriptive statistics
being used to measure median and frequencies for categorical variables. Median EFS
and OS were calculated using Kaplan–Meier’s estimates. Potential prognostic variables
assessed by chi-square test for significance on univariate analysis included the presence
versus absence of obstructive jaundice, intrahepatic cholangiocarcinoma (iCCA) versus
others, and unresectable nonmetastatic disease versus metastatic disease.
Results
Baseline Characteristics
A total of 140 patients satisfied the inclusion criteria for analysis. Briefly, median
age of patients was 57 years (range: 32–80). Eighty-seven patients (62.1%) had iCCA,
35 patients (25%) had perihilar cholangiocarcinoma (pCCA), and 14 patients (10%) had
distal cholangiocarcinoma (dCCA). Other characteristics are detailed in [Table 1].
Table 1
Baseline characteristics
|
Characteristic
|
Number (%)
|
|
Median age (y)
|
57 (range: 32–80)
|
|
Gender
|
|
Women
|
58 (41.4)
|
|
Men
|
82 (58.6)
|
|
Location of tumor
|
|
Intrahepatic cholangiocarcinoma
|
87 (62.1)
|
|
Perihilar cholangiocarcinoma
|
35 (25)
|
|
Distal cholangiocarcinoma
|
14 (10)
|
|
Multifocal
|
4 (2.9)
|
|
Disease status
|
|
Unresectable, nonmetastatic
|
28 (20)
|
|
Metastatic
|
112 (80)
|
|
Previous history of radical resection
|
|
Yes
|
11 (7.9)
|
|
No
|
129 (92.1)
|
|
Presence of obstructive jaundice at baseline
|
|
Yes
|
43 (30.7)
|
|
No
|
97 (69.3)
|
|
Sites of metastasis
|
|
Hepatic
|
87 (62.1)
|
|
Nonregional nodes
|
70 (50)
|
|
Pulmonary
|
15 (10.7)
|
|
Peritoneal
|
15 (10.7)
|
|
Osseous
|
3 (2.1)
|
|
Adrenal
|
2 (1.4)
|
Chemotherapeutic Regimens and Toxicities
The most common regimens used as CT1 were gemcitabine–cisplatin (GC) in 89 patients
(63.5%) and gemcitabine–oxaliplatin (GO) in 34 patients (24.3%). Concurrent chemoradiation
was administered in 11 patients (7.9%). Sixty-three patients (45%) of patients received
a second-line chemotherapeutic regimen postprogression, the commonest of which was
capecitabine–irinotecan (62%; n = 63).
Common grades 3 and 4 toxicities with first-line chemotherapy included vomiting in
25 patients (17.9%), diarrhea in 23 patients (16.4%), and thrombocytopenia in 22 patients
(15.7%). Other details are mentioned in [Table 2].
Table 2
Chemotherapeutic regimens and toxicity profiles
|
Characteristics
|
Number (%)
|
|
First-line chemotherapeutic regimens
|
|
Gemcitabine–cisplatin
|
89 (63.5)
|
|
Gemcitabine–oxaliplatin
|
34 (24.3)
|
|
Gemcitabine
|
12 (8.6)
|
|
Others
|
5 (3.5)
|
|
Grades 3 and 4 toxicity
|
|
Vomiting
|
25 (17.9)
|
|
Stomatitis/oral mucositis
|
5 (3.6)
|
|
Diarrhea
|
23 (16.4)
|
|
Neutropenia
|
20 (14.3)
|
|
Febrile neutropenia
|
8 (5.7)
|
|
Thrombocytopenia
|
22 (15.7)
|
|
Anemia
|
13 (9.3)
|
|
Neuropathy (grades 2 and 3)
|
13 (9.3)
|
Response Rates and Survival Outcomes
Radiological responses were available in 123 patients. Fifty-one patients (36.4%)
had PR, and 35 patients (25%) had SD as best response on first-line chemotherapy,
for a CBR of 61.4%. Thirty-seven patients (26.4%) had PD as best response on first-line
chemotherapy.
With a median follow-up of 27 months, 123 patients had PD, resulting in a median PFS
of 7.56 months (95% confidence interval [CI]: 6.23–8.88). Of the cohort of 140 patients,
111 patients had expired due to disease progression, 17 patients were alive, and 12
patients were lost to follow-up. The median OS of the entire cohort was 12.16 months
(95% CI: 10.08–14.24). There was no difference in OS between patients with unresectable
nonmetastatic disease and patients with metastatic disease (13.6 vs. 11.7 months,
p = 0.47), presence versus absence of obstructive jaundice (13.6 vs. 11.7 months; p = 0.36), and iCCA versus others (12.9 vs. 12 months; p = 0.722).
Discussion
A majority of CCAs present with advanced disease (55–90%), thereby ruling out surgery
or liver transplant as treatment options. Systemic therapy, predominantly chemotherapy
remains the major modality of management in such tumors. The results of the ABC-02
and BT-22 trials, showing superiority of GC over gemcitabine alone in advanced BTC,
remain the gold standard in terms of systemic therapy for patients with these malignancies.[6]
[11] Various monoclonal antibodies have systematically failed to show survival benefit
above chemotherapy alone, while there has also been a dearth of viable targetable
mutations identified in these cancers.[12] This, coupled with the rarity of CCAs in India, means retrospective data on first-line
chemotherapy still has value in terms of adding to existing literature.
The current study, to our knowledge, is the largest of its kind with respect to advanced
CCA from India. Though the CCAs are usually clubbed together in terms of treatment
strategies, it is interesting to note that the commonest subtype in our cohort was
the iCCAs (62%). A similar pattern was noted in the Japanese BT-22 study as well.[11] Obstructive jaundice is a common presentation in pCCAs and dCCAs and was seen in
30.7% of patients in the study,
As expected, a gemcitabine–platinum combination (GC or GO) was the most commonly used
regimen in this study, with a handful of patients receiving other protocols such as
mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) and gemcitabine–capecitabine.
Despite small studies showing good tolerance to intensive regimens such as FOLFIRINOX
in advanced BTC, the lack of larger randomized studies means these protocols are rarely
used in clinical practice.[13]
The median PFS (7.56 months) and OS (12.16 months) seen in the current study are very
similar to those seen in the seminal ABC-02 (median PFS—8 months; median OS—11.7 months)
and BT-22 (median PFS—5.8 months; median OS—11.2 months) studies. This is heartening
to note, considering the real-world nature of the patients in the current study. The
survivals are superior to those seen with advanced GBC previously published from our
institution (median OS—7.65 months) and are consistent with evidence that CCAs survive
longer than advanced GBCs.[14] An additional point of note is the percentage of patients who were able to receive
second-line chemotherapy (45%). This is a fair proportion, considering the lack of
standardization or known efficacy of second-line regimens in advanced BTC.[15] It is also indicative of the relatively maintained general condition and fitness
of patients with CCA on radiological progression, as opposed to advanced GBCs where
deterioration is more rapid. The common CT2 used in our institution is capecitabine–irinotecan
and we have published data on the same previously.[16]
The chemotherapy-related side-effect profile in the current study cannot be attributed
to a single regimen because a significant proportion received GC or GO. Besides grade
3/4 vomiting (15.7%), which is higher compared with published data, other side effects
were in the expected range.
While the survivals seen with CCA in this study are acceptable, they are still in
the range of ~12 months only. There is an urgent need to find better treatment strategies
in these rare tumors and BTCs as a whole. Some encouraging results have been seen
with first-line triplet GC-nab-paclitaxel regimen, ivosidenib in IDH1 mutated multiply
pretreated CCA and pemigatinib in FGFR rearranged iCCAs.[17]
[18] The gains seen in these studies have been modest but are a step in the right direction.
Conclusion
In conclusion, the current study in advanced CCAs is the largest of its nature from
India. The common regimens used as first line were GC and GO. Tolerance and OS appear
similar to previously published data. Further studies are required to improve survivals
in this cancer which is relatively rare in India.
