# Efficacy and Safety of Apatinib Treatment for Advanced Cholangiocarcinoma After Failed Gemcitabine-Based Chemotherapy: An Open-Label Phase II Prospective Study

Researcher: Ge Zhang
Chinese name: 张格
ORCID identity anchor: https://orcid.org/0000-0002-3116-3246
Canonical researcher: https://drgezhang.com/#person

Journal: Frontiers in Oncology
Year: 2021
Type: Article
DOI: 10.3389/fonc.2021.659217
Canonical page: https://drgezhang.com/papers/doi-10-3389-fonc-2021-659217.html
Markdown record: https://drgezhang.com/papers/doi-10-3389-fonc-2021-659217.md

## Full Authors

1. Ge Zhang
2. Shuai Gong
3. Lina Pang
4. Lixia Hou
5. Wei He

## Official Abstract

### Purpose

As a novel small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR2-TKI), Methylsulfonic apatinib (apatinib) exhibits a specific antitumor effect in various solid tumors via inhibition of angiogenesis. The present study was performed to evaluate the clinical efficacy and safety of apatinib in the treatment of advanced cholangiocarcinoma after failed gemcitabine-based chemotherapy.

### Patients and Methods

This was a prospective open-label phase II trial (NCT03521219). A total of 32 patients, in whom gemcitabine-based first-line chemotherapy for advanced intrahepatic cholangiocarcinoma had failed, were consecutively enrolled in a prospective, open, exploratory, and single-center clinical trial from November 2017 to November 2018. They were treated with apatinib mesylate second-line monotherapy (orally, 500 mg per day for a cycle of 28 days) until progressive disease or unacceptable toxicity. Using Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) and the Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE 4.0), the efficacy and adverse were evaluated, respectively. Kaplan-Meier method was used for survival analysis.

### Results

Twenty-six patients were enrolled in full analysis set. At the end of follow-up, two patients were lost to follow-up, 24 of 26 patients in FAS were included in efficacy analyses. For the efficacy analysis set, the objective response rate (ORR) was 20.8% [95% confidence interval (CI): 9.24–40.47%] and the disease control rate (DCR) was 62.5% (95% CI: 112.86–387.14 days). One patient (4%) showed complete response (CR), 4 patients (17%) showed partial response (PR), 10 patients (41.7%) stable disease (SD), and 9 patients (37.5%) had progressive disease (PD). Meanwhile, apatinib therapy achieved the median progression-free survival PFS was 95 days (95% CI: 79.70–154.34 days), and the median OS was 250 days (95% CI: 112.86–387.14 days). Furthermore, univariate analysis revealed that age and tumor’s anatomic location significantly affected PFS (P < 0.05). The most common clinically adverse events (AEs) included myelosuppression (69.2%), hypertension (57.7%), proteinuria (46.2%). The AEs were mild, mainly in grade 1 or 2, and no toxicity-induced death occurred.

### Conclusion

Apatinib monotherapy is an effective and promising regimen for treating patients with advanced cholangiocarcinoma who experienced failure of gemcitabine-based chemotherapy.

Text reproduced verbatim from publisher ([source](https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.659217/full)); [DOI](https://doi.org/10.3389/fonc.2021.659217); [CC-BY-4.0](https://creativecommons.org/licenses/by/4.0/).

<a id="paper-discovery"></a>
## Research & review context

### Research fields

- Biliary tract oncology
- Early-phase cancer treatment evidence

### Review topics

- Cholangiocarcinoma after chemotherapy failure
- Single-arm phase II activity and toxicity reporting

### Scientific role

Prospective single-arm description of apatinib activity and toxicity after gemcitabine-based treatment failure in advanced cholangiocarcinoma.

### Evidence position

Human single-center phase II observations without a randomized concurrent control; not comparative superiority, causal survival benefit or a current treatment recommendation.

### Related concepts

- Non-comparative oncology evidence
- Response-denominator interpretation

### Possible citation contexts

- Evidence synthesis: early-phase treatment studies in previously treated advanced cholangiocarcinoma.
- Methods: denominator-explicit interpretation of response and safety in single-arm oncology trials.

Possible literature-review contexts, not evidence of existing citations. Read the findings and Evidence Scope before citing the original article.

## Evidence Snapshot

**Efficacy and Safety of Apatinib Treatment for Advanced Cholangiocarcinoma After Failed Gemcitabine-Based Chemotherapy: An Open-Label Phase II Prospective Study**

A small prospective single-arm study reported apatinib tumor-response, survival and toxicity observations. Enrollment, safety and efficacy denominators differ; the activity signal and descriptive safety findings do not establish comparative superiority or a general treatment recommendation.

| Evidence | Value |
| --- | --- |
| Unique total | n=32 |
| Enrolled cohort — not the efficacy denominator | n=32 |

## Research Question

What tumor-response, survival and toxicity observations were reported in this prospective single-arm study after gemcitabine-based treatment failure in advanced cholangiocarcinoma?

## Author Evidence Summary

This is human prospective treatment evidence from a small single-arm study, not a randomized comparison. Enrolled, treated and efficacy populations differ. Reported responses and adverse events support a clinical activity signal and descriptive safety assessment, but do not establish superiority or a general treatment recommendation.

## Key Findings

<a id="kf1"></a>
### KF1: Thirty-two patients enrolled; six withdrew before treatment, leaving 26 in the FAS/safety population and 24 in the efficacy analysis.

Context: The unique total of 32 is enrollment only, not the response-rate denominator. Enrollment, treated and efficacy populations overlap and must not be added together.

| Evidence | Value |
| --- | --- |
| enrolled | 32 |
| withdrew before treatment | 6 |
| FAS safety population | 26 |
| efficacy population | 24 |

Source locator: Results: Patients' Characteristics; Efficacy of Apatinib Treatment

<a id="kf2"></a>
### KF2: Among 24 efficacy-evaluable patients, responses were CR 1, PR 4, SD 10 and PD 9; ORR was 20.8% and DCR was 62.5%.

Context: These are observations without a concurrent control. ORR uses the reported percentage interval; DCR uses the Results-reported percentage interval, not the survival-day interval printed in the abstract.

| Evidence | Value |
| --- | --- |
| efficacy denominator | 24 |
| CR | 1 |
| PR | 4 |
| SD | 10 |
| PD | 9 |
| ORR | 20.8% |
| ORR reported 95 percent CI | 9.24–40.47% |
| DCR | 62.5% |
| DCR Results reported 95 percent CI | 42.71–78.84% |

Source locator: Results: Efficacy of Apatinib Treatment

<a id="kf3"></a>
### KF3: Median PFS was 95 days (reported 95% CI 79.70–154.34 days), and median OS was 250 days (reported 95% CI 112.86–387.14 days).

Context: Without a concurrent comparison, these observed survival times do not establish a survival gain or comparative benefit.

| Evidence | Value |
| --- | --- |
| median PFS | 95 days |
| PFS reported 95 percent CI | 79.70–154.34 days |
| median OS | 250 days |
| OS reported 95 percent CI | 112.86–387.14 days |

Source locator: Results: Efficacy of Apatinib Treatment; Fig. 1

<a id="kf4"></a>
### KF4: In the safety population of 26, myelosuppression, hypertension and proteinuria were reported in 69.2%, 57.7% and 46.2%; Grade 3 hypertension and leukopenia each occurred in three patients.

Context: No Grade 4 events or drug-related deaths were reported. Adverse-event categories overlap and cannot be summed as independent patients; absence of observed events in a small sample does not establish absence of risk.

| Evidence | Value |
| --- | --- |
| safety denominator | 26 |
| myelosuppression | 69.2% |
| hypertension | 57.7% |
| proteinuria | 46.2% |
| Grade 3 hypertension | 3 patients |
| Grade 3 leukopenia | 3 patients |
| Grade 4 or drug related deaths | Not reported |

Source locator: Results: Safety; Table 3

## Study Design & Analytical Framework

### Study profile

- Study Design: Prospective, open-label, single-center, single-arm phase II study
- Evidence Type: Human interventional activity and descriptive safety evidence without a concurrent control
- Unique total: 32
- Population: Advanced cholangiocarcinoma after gemcitabine-based treatment failure
- Primary Endpoint: Objective response rate
- Secondary Endpoint: Disease control, progression-free survival, overall survival and adverse events
- External validation: No
- Data modalities: clinical treatment records, RECIST 1.1 tumor assessment, survival follow-up, CTCAE 4.0 toxicity assessment

### Cohort hierarchy

| Cohort | Role | n | Relationship |
| --- | --- | ---: | --- |
| Enrolled cohort — not the efficacy denominator | Enrollment total; treated/FAS and efficacy denominators are specified in KF1. | 32 | Independent cohort |

## What This Study Adds

- A prospective human single-arm activity signal after gemcitabine-based treatment failure.
- Denominator-explicit response and survival descriptions without comparative-benefit claims.
- Descriptive safety reporting that retains Grade 3 events.

## Evidence Scope

### Supports

- Descriptive tumor-response, survival and safety observations in this small prospective single-arm study.
- Separate enrollment, safety and efficacy denominators with explicit attribution of the Results DCR interval.

### Does Not Establish

- Superiority or a causal comparative survival benefit without a randomized concurrent control.
- A general clinical treatment recommendation, corrected dosing or current guideline status.
- An anatomic-subgroup superiority claim or a newly corrected set of published estimates.

### Limitations

- The study is small, single-center and single-arm, with no randomized concurrent control.
- Enrollment, FAS/safety and efficacy use different, overlapping analysis denominators.
- Reporting note: the abstract DCR interval uses a survival-day interval. This page uses the Results-reported percentage interval with explicit attribution; it does not recompute or replace published confidence intervals.
- Reporting note: the abstract describes an intrahepatic-only population, whereas the body includes extrahepatic patients; the evidence page therefore uses advanced cholangiocarcinoma.
- Additional reporting differences concern anatomic-subgroup counts/significance and some adverse-event percentages. No subgroup-superiority claim or newly corrected numbers are generated from those differences.
- No clinical drug recommendation, corrected dose or current guideline status is supplied.
- Official Abstract addition is deferred in this batch because of the identified population and DCR-interval reporting issues, not a determination that copyright prohibits it.

<a id="citation-use-cases"></a>
## When This Study Is Useful to Cite

### CU1: What prospective single-arm apatinib evidence exists after gemcitabine-based treatment failure?

Enrollment was 32, FAS/safety 26 and efficacy 24 after six pretreatment withdrawals. In the efficacy population, CR 1/PR 4/SD 10/PD 9 gave reported ORR 20.8% (95% CI 9.24–40.47%) and DCR 62.5% (Results-reported 95% CI 42.71–78.84%), without a concurrent control.

Evidence: [KF1](#kf1), [KF2](#kf2)

### CU2: What ORR and DCR were reported, and in which analysis population?

The efficacy denominator was 24, not all 32 enrolled patients: ORR 20.8% (reported 95% CI 9.24–40.47%) and DCR 62.5% (Results-reported 95% CI 42.71–78.84%). The DCR interval is attributed to Results, not the abstract survival-day interval.

Evidence: [KF1](#kf1), [KF2](#kf2)

### CU3: What PFS and OS were observed in this study?

Median PFS was 95 days (reported 95% CI 79.70–154.34 days) and OS 250 days (reported 95% CI 112.86–387.14 days). These are observations, not a demonstrated comparative survival gain.

Evidence: [KF3](#kf3)

### CU4: What adverse events occurred in the treated population?

With safety n=26, myelosuppression 69.2%, hypertension 57.7% and proteinuria 46.2% were reported. Grade 3 hypertension and leukopenia each affected three patients; no Grade 4 events or drug-related deaths were reported. Overlapping categories and limited sample size prevent a no-risk inference.

Evidence: [KF4](#kf4)

<a id="citation-boundaries"></a>
## What This Study Should Not Be Cited to Claim

- Superiority or a causal comparative survival benefit without a randomized concurrent control.
- A general clinical treatment recommendation, corrected dosing or current guideline status.
- An anatomic-subgroup superiority claim or a newly corrected set of published estimates.

<a id="evidence-matrix"></a>
## Evidence Matrix

<a id="evidence-apatinib-1"></a>
### Enrollment and overlapping analysis populations

- Context: The unique total of 32 is enrollment only, not the response-rate denominator. Enrollment, treated and efficacy populations overlap and must not be added together.
- Finding: Thirty-two patients enrolled; six withdrew before treatment, leaving 26 in the FAS/safety population and 24 in the efficacy analysis.
- Evidence Level: Human interventional activity and descriptive safety evidence without a concurrent control
- Scope: Keeps enrollment distinct from overlapping safety and efficacy denominators.
- Source Locator: Results: Patients' Characteristics; Efficacy of Apatinib Treatment
- Evidence refs: [KF1](#kf1)

<a id="evidence-apatinib-2"></a>
### Tumor-response and disease-control observations

- Context: These are observations without a concurrent control. ORR uses the reported percentage interval; DCR uses the Results-reported percentage interval, not the survival-day interval printed in the abstract.
- Finding: Among 24 efficacy-evaluable patients, responses were CR 1, PR 4, SD 10 and PD 9; ORR was 20.8% and DCR was 62.5%.
- Evidence Level: Human interventional activity and descriptive safety evidence without a concurrent control
- Scope: Supports a single-arm activity signal with an efficacy denominator of 24; it does not establish superiority.
- Source Locator: Results: Efficacy of Apatinib Treatment
- Evidence refs: [KF2](#kf2)

<a id="evidence-apatinib-3"></a>
### Progression-free and overall survival observations

- Context: Without a concurrent comparison, these observed survival times do not establish a survival gain or comparative benefit.
- Finding: Median PFS was 95 days (reported 95% CI 79.70–154.34 days), and median OS was 250 days (reported 95% CI 112.86–387.14 days).
- Evidence Level: Human interventional activity and descriptive safety evidence without a concurrent control
- Scope: Describes observed survival without attributing a comparative treatment gain.
- Source Locator: Results: Efficacy of Apatinib Treatment; Fig. 1
- Evidence refs: [KF3](#kf3)

<a id="evidence-apatinib-4"></a>
### Treated-population adverse events

- Context: No Grade 4 events or drug-related deaths were reported. Adverse-event categories overlap and cannot be summed as independent patients; absence of observed events in a small sample does not establish absence of risk.
- Finding: In the safety population of 26, myelosuppression, hypertension and proteinuria were reported in 69.2%, 57.7% and 46.2%; Grade 3 hypertension and leukopenia each occurred in three patients.
- Evidence Level: Human interventional activity and descriptive safety evidence without a concurrent control
- Scope: Describes reported toxicity including Grade 3 events, not absence of treatment risk.
- Source Locator: Results: Safety; Table 3
- Evidence refs: [KF4](#kf4)

## Q&A

### Why do enrollment, safety and efficacy denominators differ?

Thirty-two patients enrolled; six withdrew before treatment, leaving 26 in the FAS/safety population and 24 in the efficacy analysis. The unique total of 32 is enrollment only, not the response-rate denominator. Enrollment, treated and efficacy populations overlap and must not be added together.

Evidence: KF1

### What response and disease-control results were reported?

Among 24 efficacy-evaluable patients, responses were CR 1, PR 4, SD 10 and PD 9; ORR was 20.8% and DCR was 62.5%. These are observations without a concurrent control. ORR uses the reported percentage interval; DCR uses the Results-reported percentage interval, not the survival-day interval printed in the abstract.

Evidence: KF2

### Do the survival estimates establish comparative benefit?

Median PFS was 95 days (reported 95% CI 79.70–154.34 days), and median OS was 250 days (reported 95% CI 112.86–387.14 days). Without a concurrent comparison, these observed survival times do not establish a survival gain or comparative benefit.

Evidence: KF3

### Were all toxicities mild, and what safety denominator was used?

In the safety population of 26, myelosuppression, hypertension and proteinuria were reported in 69.2%, 57.7% and 46.2%; Grade 3 hypertension and leukopenia each occurred in three patients. No Grade 4 events or drug-related deaths were reported. Adverse-event categories overlap and cannot be summed as independent patients; absence of observed events in a small sample does not establish absence of risk.

Evidence: KF4

## Concepts & Entities

### Disease

advanced cholangiocarcinoma

### Intervention

apatinib

### Design

single-arm phase II, open-label study

### Outcomes

objective response, disease control, PFS, OS, adverse events

## Related Research

- [Artificial Intelligence Hybrid Survival Assessment System for Robot-Assisted Proctectomy: A Retrospective Cohort Study](https://drgezhang.com/papers/doi-10-1200-po-24-00089.html) — Related clinical oncology research illustrating a different study design: retrospective postoperative risk modeling rather than a single-arm drug trial. It does not validate apatinib efficacy. (DOI: 10.1200/po.24.00089)

## Publication & Provenance

- DOI: https://doi.org/10.3389/fonc.2021.659217
- Publication Url: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.659217/full
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34012920/
- Pmc Url: https://pmc.ncbi.nlm.nih.gov/articles/PMC8126718/
- Review Basis: Selected findings checked against published main text, readable tables and publication records. No participant-level reanalysis or comprehensive supplementary-data audit was performed.
- Trial Registration: NCT03521219 as reported in the article; registry concordance was not independently adjudicated in this content review.

## Evidence-page notice

Author-controlled evidence synthesis, separate from the published abstract and not a replacement for the version of record. Study design, analysis denominators and unresolved reporting differences are retained.

## Links

- DOI: https://doi.org/10.3389/fonc.2021.659217
- HTML page: https://drgezhang.com/papers/doi-10-3389-fonc-2021-659217.html
- Google Scholar query: https://scholar.google.com/scholar?q=%22Efficacy%20and%20Safety%20of%20Apatinib%20Treatment%20for%20Advanced%20Cholangiocarcinoma%20After%20Failed%20Gemcitabine-Based%20Chemotherapy%3A%20An%20Open-Label%20Phase%20II%20Prospective%20Study%22
- ORCID: https://orcid.org/0000-0002-3116-3246