Abstract
Background
This study aimed to assess whether postoperative adjuvant chemoimmunotherapy could lead to better clinical outcomes for high-risk patients with perihilar cholangiocarcinoma (pCCA).
Methods
In the cohort study, we retrospectively reviewed patients who received surgical resection for pCCA with curative intent from January 2018 to December 2021 at the Sun Yat-sen Memorial Hospital.
The patients at high risk for relapse were further analyzed. Among them, 20 patients received adjuvant chemoimmunotherapy, 28 patients received adjuvant chemotherapy, and 33 patients received surgery alone. The oncological outcomes and drug-associated adverse events were evaluated.
Results
The 2-year overall survival (OS) rates in patients treated with adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone were 80.0%, 49.4% and 22.6%, respectively. Univariable and multivariable Cox analyses showed that the treatment regimen and TNM stage were associated with adverse OS. Adjuvant chemoimmunotherapy led to an increase in OS compared with adjuvant chemotherapy [hazard ratio (HR) = 3.253; 95% confidence interval (CI) 1.072–9.870; P = 0.037] or surgery alone (HR = 7.560; 95% CI 2.508–22.785; P < 0.001). The median recurrence-free survival was 22.0 months for the adjuvant chemoimmunotherapy group, 17.0 months for the adjuvant chemotherapy group, and 13.2 months for the surgery alone group (P = 0.177); these differences were not significant. The chemoimmunotherapy group was associated with more frequent hematological side effects than the chemotherapy group, but the difference was not statistically significant.
Conclusion
Postoperative adjuvant chemoimmunotherapy for resected pCCA patients showed improved OS compared with adjuvant chemotherapy or surgery alone, and further prospectively randomized controlled trials are necessary to validate these results.
Keywords: Postoperative adjuvant therapy, Chemoimmunotherapy, Chemotherapy, Perihilar cholangiocarcinoma, High-risk patients
Introduction
Perihilar cholangiocarcinoma (pCCA) is perceived as one of the most aggressive malignant tumors with an exceedingly unfavorable prognosis [1]. The reported 5-year overall survival (OS) rate for resected pCCA is 11–48.9% [2–5]. Radical surgical resection remains the main curative option for pCCA. Despite improvements in tumor diagnosis and surgical techniques, the long-term survival outcomes remain abysmal due to high rates of recurrence and metastasis [6, 7]. In light of the refractory and aggressive nature of pCCA, effective adjuvant therapy strategies are needed to achieve better clinical outcomes.
Currently, a few clinical trials have investigated the potential role of adjuvant chemotherapy in resected biliary tract tumors; nevertheless, there is inconsistent evidence regarding the benefits of adjuvant chemotherapy and optimal adjuvant regimens for aggressive tumors. [8] According to the results of two previously published phase III trials, gemcitabine-based adjuvant chemotherapy failed to demonstrate OS and recurrence-free survival (RFS) advantages [9, 10]. Furthermore, the adjuvant gemcitabine group showed no significant survival advantage compared with the observation group among patients with lymph node metastasis and positive resection margins. [9] However, in a retrospective study of 924 patients who received surgical resection for pCCA, the postoperative adjuvant chemotherapy group showed better median OS than the surgery alone group (28.2 months vs. 19.9 months, P < 0.001). [11] The conflicting evidence on the potential beneficial role of adjuvant therapy may be explained by different subtypes of biliary tract tumors and diverse adjuvant therapeutic regimens. Consequently, the optimal adjuvant therapy for the management of resected cholangiocarcinoma has yet to be identified.
In recent years, immune checkpoint inhibitors (ICIs) have shown remarkable promise for advanced solid tumors [12, 13]. The findings from KEYNOTE-158 and KEYNOTE-028 trials demonstrated that pembrolizumab achieved an ORR of 5.8% and 13% in advanced biliary tract cancer (BTC) [14]. Combined chemotherapy and immunotherapy for advanced BTC have been investigated in numerous clinical studies, displaying promising antitumor efficacy [15–17]. Despite the synergetic effects of combined systemic regimens for unresectable BTC in the clinical setting, the potential role of combined postoperative adjuvant therapies is poorly defined [14, 16].
Therefore, the current study aimed to explore whether adjuvant chemoimmunotherapy provides additional survival benefits for pCCA patients with a high risk of tumor recurrence compared with adjuvant chemotherapy or surgery alone.
Methods
Patients
Consecutive patients who received surgical resection for pCCA with curative intent from January 1, 2018, to December 31, 2021, at the Sun Yat-sen Memorial Hospital were reviewed. The inclusion criteria were as follows: 18 years or older; postoperatively, histopathologically confirmed with pCCA; Child–Pugh class A or B; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; normal organ and bone marrow function; and cases with at least one risk factor for relapse (lymph node metastasis, microvascular invasion, perineural invasion, R1 resection, or poor or undifferentiated differentiation).The exclusion criteria were as follows: patients with other malignant tumors or autoimmune diseases; patients with a previous history of chemotherapy or immunotherapy; and patients with incomplete follow-up. All relevant information, including age, sex, CA19-9, CEA, tumor size, Bismuth‒Corlette classification, TNM stage, T stage, lymph node metastasis, microvascular invasion, perineural invasion, margin status, and differentiation, was collected through detailed medical record reviews. 9 pCCA patients (6 men, 3 women; mean age 58.4 ± 14.4 years) who met the criteria except for above risk factors for recurrence were inspected. After a median follow-up of 30.8(25.0–43.1) months, all patients were alive without a recurrent event.
Treatments
The surgery for pCCA was planned according to the tumor location. The majority of the patients received major hepatectomy, including right or left (extended) hemihepatectomy or right or left trisectionectomy with total caudate lobectomy. Extrahepatic bile duct resection alone was performed in a small number of cases. All patients received routine regional lymphadenectomy during the surgery. Chemotherapy regimens included gemcitabine plus cisplatin, gemcitabine plus oxaliplatin, gemcitabine plus albumin-bound paclitaxel, gemcitabine plus S-1, oxaliplatin plus S-1 and S-1, and chemotherapy was repeated every 3 weeks. In the combined-therapy group, a PD-1 inhibitor was administrated in combination with chemotherapy. For each treatment cycle, pembrolizumab, sintilimab, camrelizumab, or tislelizumab was given at a dose of 200 mg intravenously, and toripalimab was prescribed at a dose of 240 mg intravenously. Dose adjustments or schedule delays due to serious AEs were permitted until AEs resolved to grade ≤ 2. Treatment was withdrawn for unacceptable AEs, patient refusal, tumor progression, or death.
Clinical outcomes
Overall survival (OS) was regarded as the primary outcome, and secondary outcomes consisted of recurrence-free survival (RFS) and adverse events (AEs). OS was measured from the time of surgical resection to patient death or the end of follow-up. RFS was determined as the duration between the date of surgical resection and the date of relapse, death, or the end of follow-up.
Statistical analysis
All data were displayed as composition ratios with percentages and the two treatment groups were compared using Pearson’s χ2 test or Fisher's exact test. OS and RFS were analyzed with Kaplan–Meier plots, and the two groups were compared using the log-rank test. Each variable was tested for significance in a univariate Cox regression model for the primary outcomes. Variables associated with survival in the univariate analysis (P < 0.10) were further incorporated into a multivariable model. A P value of 0.05 or less was deemed statistically significant. SPSS 25.0 software was utilized to carry out all statistical analyses.
Results
Clinical characteristics
81 patients who received surgical resection for pCCA were reviewed, and 64 (79.0%) patients underwent extensive hepatectomy. 34 (42.0%) patients received left hemihepatectomy, 26 (32.1%) patients received right hemihepatectomy, 2 (2.5%) patients received right trisectionectomy, and 2 (2.5%) patients received left trisectionectomy. Major hepatectomy combined with pancreatoduodenectomy was performed in 2 (2.5%) patient. Among them, 20 received adjuvant chemoimmunotherapy, 28 received adjuvant chemotherapy, and 33 received surgery alone. Table 1 shows the baseline demographic and clinical features. Across all groups, the mean age was 61.1 ± 10.2 years. There were 35(43.2%) cases with lymph node metastasis, 34(42.0%) cases with microvascular invasion, 69(85.2%) patients with perineural invasion, 30(37.0%) cases with R1 resection, and 22(27.2%) cases with poor or undifferentiated differentiation. The median number of treatment cycles was 4.0 [interquartile range (IQR) 2.0–6.0)] in the adjuvant chemoimmunotherapy group and 4.0 (IQR 1.3–5.8) in the adjuvant chemotherapy group, respectively (P = 0.568).
Table 1.
The baseline patient characteristics
| Variables | All patients | Adjuvant chemoimmunotherapy | Adjuvant chemotherapy | Surgery alone | P value |
|---|---|---|---|---|---|
| n = 81 | n = 20 | n = 28 | n = 33 | ||
| Age, years | 0.367 | ||||
| ≤ 60 | 37 (45.7%) | 10 (50.0%) | 15 (53.6%) | 12 (36.4%) | |
| > 60 | 44 (54.3%) | 10 (50.0%) | 13 (46.4%) | 2 (63.6%) | |
| Sex | 0.353 | ||||
| Male | 47 (58.0%) | 13 (65.0%) | 18 (64.3%) | 16 (48.5%) | |
| Female | 34 (42.0%) | 7 (35.0%) | 10 (35.7%) | 17 (51.5%) | |
| CA19-9, U/ml | 0.236 | ||||
| ≤ 37 | 10 (12.3%) | 2 (10.0%) | 6 (21.4%) | 2 (6.1%) | |
| > 37 | 71 (87.7%) | 18 (90.0%) | 22 (78.6%) | 31 (93.9%) | |
| CEA, ng/mL | 0.370 | ||||
| ≤ 5 | 60 (74.1%) | 13 (65.0%) | 20 (71.4%) | 27 (81.8%) | |
| > 5 | 21 (25.9%) | 7 (35.0%) | 8 (28.6%) | 6 (18.2%) | |
| Tumor size, cm | 0.409 | ||||
| ≤ 3 cm | 54 (66.7%) | 11 (55.0%) | 19(67.9%) | 24 (72.7%) | |
| > 3 cm | 27 (33.3%) | 9 (45.0%) | 9 (32.1%) | 9 (27.3%) | |
| Bismuth-Corlette classification | 0.159 | ||||
| I + II + III | 53 (65.4%) | 10 (50.0%) | 18 (64.3%) | 25 (75.8%) | |
| IV | 28 (34.6%) | 10 (50.0%) | 10 (35.7%) | 8 (24.2%) | |
| TNM stage | 0.786 | ||||
| I + II | 28 (34.6%) | 6 (30.0%) | 11 (39.3%) | 11 (33.3%) | |
| III + IV | 53 (65.4%) | 14 (70.0%) | 17 (60.7%) | 22 (66.7%) | |
| T stage | 0.519 | ||||
| I + II | 53 (65.4%) | 12 (60.0%) | 17 (60.7%) | 24 (72.7%) | |
| III + IV | 28 (34.6%) | 8 (40.0%) | 11 (39.3%) | 9 (27.3%) | |
| Lymph node metastasis | 0.581 | ||||
| NO | 46 (56.8%) | 10 (50.0%) | 18 (64.3%) | 18 (54.5%) | |
| Yes | 35 (43.2%) | 10 (50.0%) | 10 (35.7%) | 15 (45.5%) | |
| Microvascular invasion | 0.165 | ||||
| NO | 47 (58.0%) | 15 (75.0%) | 16 (57.1%) | 16 (48.5%) | |
| Yes | 34 (42.0%) | 5 (25.0%) | 12 (42.9%) | 17 (51.5%) | |
| Perineural invasion | 0.300 | ||||
| NO | 12 (14.8%) | 1 (5.0%) | 6 (21.4%) | 5 (15.2%) | |
| Yes | 69 (85.2%) | 19 (95.0%) | 22 (77.6%) | 28 (84.8%) | |
| Margin status | 0.916 | ||||
| R0 | 51 (63.0%) | 13 (65.0%) | 18 (64.3%) | 20 (60.6%) | |
| R1 | 30 (37.0%) | 7 (35.0%) | 10(35.7%) | 13(39.4%) | |
| Differentiation | 0.543 | ||||
| Well + Moderate | 59 (72.8%) | 16 (80.0%) | 21 (75.0%) | 22 (66.7%) | |
| Poor + Undifferentiated | 22 (27.2%) | 4(20.0%) | 7 (25.0%) | 11 (33.3%) | |
| Type of hepatectomy | 0.090 | ||||
| S1,2, 3, 4 | 34 (42.0%) | 7 (35.0%) | 17 (60.7%) | 10 (30.3%) | |
| S1, 5, 6, 7, 8 | 26 (32.1%) | 9 (45.0%) | 8 (28.6%) | 9 (27.3%) | |
| S1, 2, 3, 4, 5, 8 | 2 (2.5%) | 1 (5.0%) | 0 (0.0%) | 1 (3.0%) | |
| S1, 4, 5, 6, 7, 8 | 2 (2.5%) | 0 (0.0%) | 1 (3.6%) | 1 (3.0%) | |
| S1,4,5,8/S1,4,5/S1,5.8/S1 | 13 (16.0%) | 3 (15.0%) | 2 (7.1%) | 8 (24.2%) | |
| Without hepatectomy | 4 (4.9%) | 0 (0.0%) | 0 (0.0%) | 4 (12.1%) |
CA19-9 carbohydrate antigen 19–9; CEA carcinoembryonic antigen
Survival outcomes
The survival outcomes of the three treatment groups were estimated (Fig. 1). The median time of clinical follow-up was 18.4 (IQR 11.8–24.2) months. The 1-year and 2-year OS rates of the entire group were 81.0% and 45.6%, respectively. The median OS for patients treated with adjuvant chemoimmunotherapy, patients treated with adjuvant chemotherapy, and patients treated with surgery alone was not reached, 23.1, and 13.2 months, respectively. (P < 0.001). The 1-year OS rates were 100% in the adjuvant chemoimmunotherapy group, 85.7% in the adjuvant chemotherapy group, and 64.6% in the surgery alone group; the corresponding 2-year OS rates were 80.0%, 49.4% and 22.6%, respectively. (Fig. 1A). Recurrent events (recurrent or died) occurred in 9 (45.0%) of 20 cases in the adjuvant chemoimmunotherapy group, 19 (67.9%) of 28 patients in the adjuvant chemotherapy group, and 22 (66.7%) of 33 patients in the surgery alone group. The median RFS was 22.0 months (95% CI 15.1–28.9) in the adjuvant chemoimmunotherapy group, 17.0 months (95% CI 2.1–31.9) in the adjuvant chemotherapy group, and 13.2 months (95% CI 11.5–14.9) in the surgery alone group. For adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone, the 1-year RFS rates were 75.0%, 57.1%, and 63.1%, respectively, and the 2-year RFS rates were 35.7%, 42.3%, and 20.2%, respectively. However, no significant difference was found in RFS between the treatment groups (P = 0.177) (Fig. 1B). The treatment regimen and TNM stage were independent factors for pCCA in the multivariable model after adjusting for age and lymph node metastasis. Adjuvant chemoimmunotherapy provided increased an OS benefit over adjuvant chemotherapy (HR = 3.253, 95% CI 1.072–9.870; P = 0.037) or surgery alone (HR = 7.560, 95% CI 2.508–22.785; P < 0.001) (Table 2).
Fig. 1.
Overall survival (OS); (A) and recurrence-free survival (RFS) B curves of patients in the adjuvant chemoimmunotherapy, adjuvant chemotherapy groups, and surgery alone group
Table 2.
Univariable and multivariable cox regression analysis of OS
| Variables | Univariate | P value | Multivariate | P value |
|---|---|---|---|---|
| Hazard ratio (95% CI) | Hazard ratio (95% CI) | |||
| Age, years | 0.073 | |||
| ≤ 60 | Reference | Reference | ||
| > 60 | 1.767(0.948–3.295) | 1.549(0.817–2.937) | 0.180 | |
| Sex | 0.894 | |||
| Male | Reference | |||
| Female | 1.042(0.567–1.916) | |||
| CA19-9, U/ml | 0.790 | |||
| ≤ 37 | Reference | |||
| > 37 | 0.889(0.374–2.112) | |||
| CEA, ng/mL | 0.969 | |||
| ≤ 5 | Reference | |||
| > 5 | 1.014(0.496–2.073) | |||
| Tumor size, cm | 0.809 | |||
| ≤ 3 cm | Reference | |||
| > 3 cm | 1.084(0.562–2.093) | |||
| Bismuth-Corlette classification | 0.817 | |||
| I + II + III | Reference | |||
| IV | 0.927(0.488–1.761) | |||
| TNM stage | 0.020 | |||
| I + II | Reference | Reference | ||
| III + IV | 2.336(1.144–4.769) | 3.013(1.204–7.538) | 0.018 | |
| T stage | 0.622 | |||
| I + II | Reference | |||
| III + IV | 1.172(0.623–2.206) | |||
| Lymph node metastasis | 0.039 | |||
| NO | Reference | Reference | ||
| Yes | 1.914(1.033–3.548) | 1.039(0.469–2.300) | 0.926 | |
| Microvascular invasion | 0.225 | |||
| NO | Reference | |||
| Yes | 1.455(0.793–2.670) | |||
| Margin status | 0.133 | |||
| R0 | Reference | |||
| R1 | 1.601(0.867–2.956) | |||
| Perineural invasion | 0.595 | |||
| NO | Reference | |||
| Yes | 0.790(0.332–1.881) | |||
| Differentiation | 0.229 | |||
| Well + moderate | Reference | |||
| Poor + undifferentiated | 1.499(0.775–2.899) | |||
| Treatment Regime | ||||
| Adjuvant chemoimmunotherapy | Reference | Reference | ||
| Adjuvant chemotherapy | 2.942(0.982–8.818) | 0.054 | 3.253(1.072–9.870) | 0.037 |
| Surgery alone | 6.312(2.160–18.441) | 0.001 | 7.560(2.508–22.785) | < 0.001 |
OS overall survival; CI confidence interval; CA19-9 carbohydrate antigen 19–9; CEA carcinoembryonic antigen
Adverse events
The details of drug-related adverse events are shown in Table 3. The most common AEs of any grade were anemia, neutropenia, thrombocytopenia, leukopenia, and fever in the adjuvant chemoimmunotherapy group, and anemia, thrombocytopenia, and nausea/vomiting in the adjuvant chemotherapy group. The most frequent grade 3–4 AEs were anemia, neutropenia, and thrombocytopenia in the adjuvant chemoimmunotherapy group, and thrombocytopenia in the adjuvant chemotherapy group. Although the adjuvant chemoimmunotherapy group was associated with increased frequency of hematological toxicity, the association was not significant. Most of the AEs were mild to moderate (grade 1 or 2) and resolved with appropriate treatment. The rate of serious AEs leading to dose reductions or temporary interruption was comparable in the adjuvant chemoimmunotherapy group and the adjuvant chemotherapy group (50.0% vs. 32.1%, P = 0.212). No drug-related deaths occurred in either group.
Table 3.
Adverse events
| Adverse events | Any grade | Grade 3/4 | ||||
|---|---|---|---|---|---|---|
| Adjuvant chemoimmunotherapy | Adjuvant chemotherapy | P value | Adjuvant chemoimmunotherapy | Adjuvant chemotherapy | P value | |
| Leukopenia | 7 (35.0%) | 4 (14.3%) | 0.182 | 1 (5.0%) | 0 (0.0%) | 0.417 |
| Neutropenia | 9 (45.0%) | 6 (21.4%) | 0.082 | 3 (15.0%) | 1 (3.6%) | 0.377 |
| Anemia | 11 (55.0%) | 11 (39.3%) | 0.281 | 5 (25.0%) | 1 (3.6%) | 0.077 |
| Thrombocytopenia | 8 (40.0%) | 7 (25.0%) | 0.269 | 3 (15.0%) | 3 (10.7%) | > 0.999 |
| AST/ALT elevation | 1 (5.0%) | 3 (10.7%) | 0.860 | 1 (5.0%) | 2 (7.1%) | > 0.999 |
| Rash | 1 (5.0%) | 0 (0.0%) | 0.864 | 0 (0.0%) | 0 (0.0%) | – |
| Fatigue | 1 (5.0%) | 1 (3.6%) | > 0.999 | 0 (0.0%) | 0 (0.0%) | – |
| Nausea/vomiting | 2 (10.0%) | 7 (25.0%) | 0.348 | 0 (0.0%) | 0 (0.0%) | – |
| Diarrhea | 2 (10.0%) | 1 (3.6%) | 0.762 | 0 (0.0%) | 1 (3.6%) | > 0.999 |
| Abdominal pain | 1 (5.0%) | 1 (3.6%) | > 0.999 | 0 (0.0%) | 0 (0.0%) | – |
| Abdominal distension | 0 (0.0%) | 1 (3.6%) | > 0.999 | 0 (0.0%) | 0 (0.0%) | – |
| Stomatitis | 1 (5.0%) | 0 (0.0%) | 0.864 | 0 (0.0%) | 0 (0.0%) | – |
| Oral ulcer | 3 (15.0%) | 0 (0.0%) | 0.066 | 1 (5.0%) | 0 (0.0%) | 0.417 |
| Fever | 7 (35.0%) | 6 (21.4%) | 0.297 | 0 (0.0%) | 0 (0.0%) | – |
| Biliary tract infection | 2 (10.0%) | 2 (7.1%) | > 0.999 | 2 (10.0%) | 2 (7.1%) | > 0.999 |
| Proteinuria | 1 (5.0%) | 1 (3.6%) | > 0.999 | 0 (0.0%) | 0 (0.0%) | – |
| Pneumonia | 2 (10.0%) | 2 (7.1%) | > 0.999 | 2 (10.0%) | 2 (7.1%) | > 0.999 |
| Gastrointestinal hemorrhage | 2 (10.0%) | 2 (7.1%) | > 0.999 | 2 (10.0%) | 1 (3.6%) | 0.762 |
| Hypothyroidism | 1 (5.0%) | 0 (0.0%) | 0.417 | 0 (0.0%) | 0 (0.0%) | – |
Treatment toxicities were estimated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0)
Discussion
Surgical resection is the most felicitous therapeutic modality for pCCA, but the clinical outcome remains dismal regarding potential residual tumor and postoperative recurrence [18]. Although numerous studies have addressed the role of postoperative adjuvant therapy, the standardized adjuvant treatment regimen for BTC remains uncertain [19, 20]. In an attempt to clarify this issue, the current study assessed the potential value of postoperative adjuvant chemoimmunotherapy for pCCA. The results indicated that postoperative adjuvant therapy was associated with prolonged overall survival in comparison with surgery alone when delivered as either chemoimmunotherapy or chemotherapy. The addition of adjuvant immunotherapy to chemotherapy was well accepted, and the rate of treatment-related adverse events was equivalent to chemotherapy. The present results of the study provide an opportunity to understand promising adjuvant therapeutic strategies and advance our understanding of the roles of adjuvant chemoimmunotherapy in the management of resected pCCA among patients at high risk for recurrence.
The clinical benefits of postoperative adjuvant chemotherapy and immunotherapy for pCCA were assessed in this study. Even though the difference in RFS did not indicate statistical significance, the adjuvant chemoimmunotherapy group was superior to the adjuvant chemotherapy group or surgery alone group in terms of OS. There are limited studies regarding the advantages of adjuvant treatment for resected BTC. A retrospective study demonstrated that adjuvant chemotherapy or chemoradiotherapy prolonged postoperative OS in patients with resected pCCA [21]. However, a recent meta-analysis of two randomized trials concluded that adjuvant gemcitabine-based chemotherapy failed to show significant survival benefit for BTC [22]. A randomized multicenter study by Kobayashi et al. revealed that patients with BTC may benefit from postoperative adjuvant S-1 therapy compared with adjuvant gemcitabine therapy [23]. The inconsistency may be due to the heterogeneity within each subtype of BTC and different adjuvant therapeutic agents. Our study focused exclusively on pCCA at high risk for recurrence and incorporated immunotherapy in the adjuvant setting. Nevertheless, these promising initial results were based on real-world evidence, highlighting the need for more exploratory studies to determine appropriate therapeutic regimes.
Unfortunately, no significant RFS benefit was observed in favor of adjuvant chemoimmunotherapy. This finding may have been due to the limited number of cases, heterogeneous postoperative adjuvant therapeutic regimens, and diverse individual responses to adjuvant therapy. The inherent restrictions involved in the retrospective study might impede access to accurate RFS with nonstandardized radiological evaluation and an unregular follow-up schedule. Indeed, the unavoidable patient selection bias and patient compliance are notable concerns when elucidating the actual efficacy of adjuvant chemoimmunotherapy. The reasonable explanation for the discrepancy in OS and RFS observed in our study might be attributed to the slow but sustained antitumor efficacy of immunotherapy even after drug discontinuation. Gauci et al. evaluated the durable effects of immunotherapy in patients with a complete response to immunotherapy and demonstrated that responding patients receiving immunotherapy for less than 12 months had a higher relapse rate and an earlier relapse probability than those receiving immunotherapy for more than 12 months [24]. Additionally, RFS might underestimate the long-lasting efficacy of immunotherapy throughout the entire disease course, since a proportion of patients could remain alive for a long time with disease progression after the initiation of immunotherapy [24]. The rationale of durable efficacy relative to immunotherapy lies in the antitumor immunological memory elicited by tumor antigens, which eliminated the potential cancer cells and prevented further rapid progression [25]. As described above, there is still a long way to do to fully elucidate the clinical role of immunotherapy in the postoperative adjuvant setting, and further research is needed to determine the appropriate subpopulation and individual therapeutic schedule.
The study indicated that patients with perihilar cholangiocarcinoma at high risk of relapse might benefit from adjuvant chemoimmunotherapy. A large cohort study, including 4872 patients with extrahepatic cholangiocarcinoma, revealed that adjuvant therapy was correlated with improved OS in subgroups of patients with hilar tumors, and chemoradiotherapy provided an OS benefit in high-risk patients with positive surgical margins [26]. In another study, adjuvant S-1 monotherapy offered survival benefits in patients with node-positive pCCA, when compared with adjuvant gemcitabine monotherapy [27]. Kamarajah et al. [11] demonstrated that adjuvant chemotherapy following liver resection for pCCA exhibited survival superiority even in patients with negative lymph nodes or tumor-free margins. Our primary findings provide insights into postoperative adjuvant regimens for resected pCCA. Notwithstanding, the limited numbers of pCCA patients and selection bias should be considered in the interpretation of these results. Further studies with larger cohorts are warranted to establish effective individualized regimens.
Currently, immunotherapy has gained tremendous attention in cancer therapy. Nonetheless, ICI monotherapy in advanced BTC achieved disappointing results with poor tumor response. Accordingly, immunotherapy in combination with other antitumor therapies exhibited promising clinical efficacy against unresectable BTC. The efficacy of combined durvalumab and chemotherapy (gemcitabine plus cisplatin, GemCis) in advanced BTC has been explored in a phase III randomized controlled trial [28]. Compared with placebo plus GemCis, this combination therapy demonstrated more favorable results. The median OS was 12.8 months, the median progression-free survival (PFS) was 7.2 months, and the ORR was 26.7%. In a phase II study, the efficacy of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) for advanced BTC was encouraging, achieving a median OS of 11.8 months, a median PFS of 6.1 months, and an ORR of 73.3%. [15]
Adjuvant immunotherapy has been investigated in various solid tumors. For instance, atezolizumab after adjuvant chemotherapy showed DFS benefits for resected stage II-IIIA non-small cell lung cancer [29]. Adjuvant nivolumab led to prolonged DFS in patients with resected esophageal or gastroesophageal junction cancer who underwent neoadjuvant chemoradiotherapy [30]. The current evidence on adjuvant immunotherapy in resected BTC is limited. These preliminary findings hinted that the additional administration of immunotherapy to adjuvant chemotherapy could contribute to favorable survival outcomes for resected pCCA.
Chemotherapy combined with immunotherapy was well tolerated, exhibiting an accepted safety profile comparable to chemotherapy alone in patients with advanced BTC [31, 32]. Consistent with previous studies, the hematological toxicity in our study was the most common side effect in combined chemotherapy and immunotherapy [21]. The higher frequency of hematological toxicity in the combined-therapy group might be due to the addition of immunotherapy. Most treatment-related AEs were mild or moderate and could be relieved with appropriate treatment. The current study still suffers from a few limitations. First, this study was based on a single-center experience and retrospective design. Second, the relatively short duration of follow-up should be considered when interpreting these results. Third, the results were limited by the small number of participants, which may introduce some potential bias. Given the limitations described above, our study provides preliminary guidance for postoperative pCCA management.
In summary, chemotherapy plus immunotherapy as postoperative adjuvant treatment exhibited favorable survival outcomes with acceptable AEs in patients with resected pCCA. Further randomized controlled trials are necessitated to support the results of our study.
Author contributions
QQL, RZ, and CL designed the research. QQL, JXM, JLW, SLC, and YH wrote the protocol. QQL and XDS collected the data. QQL, XDS, and YFY analyzed the data. QQL, XDS,and YFY wrote the manuscript. QBT, HML, XHY, RZ, and CL revised the manuscript. All authors have reviewed and approved the manuscript
Funding
This work was supported by the Special Research Foundation of the National Nature Science Foundation of China (82273476, 81972262, 81972255, 82173195); Grant [2013] 163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology; Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes; Grant from Guangdong Science and Technology Department (2015B050501004, 2017B030314026); Sun Yat-sen University Clinical Research 5010 Program (2018008).
Declarations
Conflicts of Interest
The authors declare that they have no conflict of interest.
Footnotes
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Contributor Information
Rui Zhang, Email: zhangr95@mail.sysu.edu.cn.
Chao Liu, Email: liuchao3@mail.sysu.edu.cn.
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