Hydroxychloroquine Fails to Boost Chemotherapy Response in Pooled Cancer Trial Analysis

Adding hydroxychloroquine to conventional chemotherapy did not significantly improve tumor response outcomes in cancer patients, according to a systematic review and meta-analysis published on 30 September 2026 in Future Journal of Pharmaceutical Sciences. The analysis pooled seven studies comprising 383 patients with malignant neoplasms and found no statistically significant difference between chemotherapy plus hydroxychloroquine and chemotherapy alone or placebo across complete response, partial response, stable disease, progressive disease, or objective response. The only statistically significant difference the authors detected was in Eastern Cooperative Oncology Group (ECOG) 1 performance status, and reported adverse events such as headache and nausea and vomiting were comparable between the treatment groups.

The review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two reviewers independently searched PubMed, the Cochrane Library, Scopus, Web of Science, and EMBASE from database inception through August 2025, combining Medical Subject Headings terms and free-text keywords including hydroxychloroquine, chloroquine, chemotherapy, cancer, malignancy, autophagy inhibition, and clinical trial. Reference lists of eligible studies and relevant review articles were also screened manually. Only English-language studies involving human participants were considered, and preclinical or animal experiments, in vitro studies, case reports, review articles, editorials, and conference abstracts without sufficient outcome data were excluded, as were studies evaluating hydroxychloroquine without concomitant chemotherapy and those involving pediatric patients.

Eligible studies included adult patients with histologically or cytologically confirmed malignant neoplasms receiving systemic anticancer therapy, in which hydroxychloroquine was added to chemotherapy and compared with chemotherapy alone or placebo. Acceptable designs included randomized controlled trials, prospective or retrospective cohort studies, and interventional clinical trials. Each study had to report at least one clinically relevant outcome, such as tumor response, ECOG performance status, survival outcomes, or treatment-related adverse events. The seven studies that met these criteria encompassed a total of 383 participants, with publication years spanning from 2006 to 2025. The average age in the investigated groups was 57.4 years, with a range from 28 to 65 years, and sex was documented in six studies, comprising 146 females and 178 males.

The rationale for testing hydroxychloroquine in oncology rests on its established pharmacological profile outside cancer medicine. Hydroxychloroquine is an antimalarial and immunomodulatory drug widely used in the management of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. Its hypothesized anticancer effect is attributed primarily to the inhibition of autophagy, an evolutionarily conserved intracellular process that maintains cellular homeostasis by recycling damaged proteins, macromolecular complexes, or whole organelles into lysosomes. Under conditions of nutrient deprivation or stress, autophagy is stimulated to supply cells with an alternative energy source, promoting temporary survival. By blocking this process, hydroxychloroquine is theorized to prevent tumor cells from recycling damaged organelles and surviving the stress induced by chemotherapy, thereby sensitizing them to cytotoxic agents.

Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool for randomized controlled studies and the Newcastle–Ottawa Scale for observational investigations, with risk of bias characterized as unclear, low, or high. The meta-analysis was performed using Review Manager version 5.4. Dichotomous outcomes were expressed as odds ratios with 95 percent confidence intervals. Heterogeneity was assessed with the I2 statistic and the chi-square test, and a fixed-effect model was applied when heterogeneity was insignificant, meaning an I2 below 50 percent; otherwise a random-effects model was used. Statistical significance was set at a p value below 0.05.

Across the response outcomes, the pooled estimates consistently favored neither arm. Complete response, reported by two studies, yielded a combined odds ratio of 0.46 (95 percent confidence interval, 0.08 to 2.61; p = 0.38). Partial response, reported by three studies, produced an odds ratio of 0.75 (95 percent confidence interval, 0.36 to 1.56; p = 0.44). Stable disease, from two studies, gave an odds ratio of 1.01 (95 percent confidence interval, 0.42 to 2.46; p = 0.97). Progressive disease, reported by four studies, showed an odds ratio of 2.07 (95 percent confidence interval, 0.91 to 4.73; p = 0.08), and objective response, from two studies, an odds ratio of 0.67 (95 percent confidence interval, 0.30 to 1.46; p = 0.31). All of these analyses used fixed-effect models, with heterogeneity reported as insignificant in each case.

Performance status results showed a single statistically significant finding. Five studies reported ECOG 0, with a combined odds ratio of 0.69 (95 percent confidence interval, 0.37 to 1.28; p = 0.24), and three studies reported ECOG 2, with an odds ratio of 0.60 (95 percent confidence interval, 0.28 to 1.29; p = 0.19), both statistically insignificant. For ECOG 1, however, five studies produced a combined odds ratio of 1.93 (95 percent confidence interval, 1.10 to 3.40; p = 0.02), a statistically significant difference between groups.

Safety findings were reassuring with respect to added toxicity. Two studies reported headache, yielding a combined odds ratio of 1.30 (95 percent confidence interval, 0.35 to 4.89; p = 0.70), and two studies reported nausea and vomiting, with an odds ratio of 1.11 (95 percent confidence interval, 0.42 to 2.94; p = 0.83), both statistically insignificant. The authors concluded that hydroxychloroquine was generally well tolerated without additional toxicity when combined with standard-dose chemotherapy. The discussion section compared these pooled results with individual trials, including studies of hydroxychloroquine with radiotherapy in high-grade glioma, chloroquine with chemotherapy in platinum-sensitive relapsed ovarian cancer, hydroxychloroquine with imatinib in chronic-phase chronic myeloid leukemia, radiosensitization with chloroquine in brain metastases, and hydroxychloroquine added to chemotherapy in small-cell lung cancer, all of which reported statistically insignificant differences in the response outcomes examined.

The authors acknowledged several limitations. The relatively small number of included studies and participants may have limited the statistical power of the analyses, and the included studies varied in cancer types, chemotherapy regimens, hydroxychloroquine doses, and follow-up durations, which may have affected the pooled results. Survival outcomes were inconsistently reported, limiting a comprehensive evaluation of the long-term efficacy of hydroxychloroquine. The team concluded that adding hydroxychloroquine to conventional anticancer therapy failed to improve response rates in patients with neoplasia, and that further large-scale randomized studies are required to clarify its therapeutic role. Until such trials are completed, the pooled evidence indicates that the hypothesized autophagy-blocking benefit of hydroxychloroquine, when added to standard chemotherapy in adults with malignancy, did not translate into significantly better tumor response in the studies available through August 2025.

Subject of Research: A meta-analysis of hydroxychloroquine added to chemotherapy for cancer treatment outcomes and toxicity

Article Title: Hydroxychloroquine as an adjunct to chemotherapy in neoplastic diseases: a systematic review and meta-analysis of clinical outcomes and toxicity profiles meta-analysis

Article References: Al-Talqani, A. F., Elnady, I., Rabea, H., Abu El-Ela, R. Y., Abdelrahim, M. E. A., & Kassem, A. B. (2026). Hydroxychloroquine as an adjunct to chemotherapy in neoplastic diseases: a systematic review and meta-analysis of clinical outcomes and toxicity profiles meta-analysis. Future Journal of Pharmaceutical Sciences, 12(1), Article 92. https://doi.org/10.1186/s43094-026-01019-1

Image Credits: AI Generated

DOI: 10.1186/s43094-026-01019-1

Keywords: hydroxychloroquine, chemotherapy, cancer, meta-analysis, autophagy, drug repurposing, ECOG performance status, adverse events, tumor response, systematic review, oncology, pharmacology