Abstract
Background/Aim: The safety and efficacy of anti-angiogenic agents in patients with cancer with proteinuria and a history of proteinuria are not well established. This systematic review aimed to answer these questions. Materials and Methods: We searched three electronic databases for articles published until June 18, 2021. The main outcomes used were “death”, “renal impairment”, and “proteinuria impairment”. Results: After screening 303 references in the PubMed, Cochrane Library, and ICHUSHI-web databases, this review included five studies on renal cell carcinoma (RCC). In patients with metastatic RCC, the hazard ratio of the presence of (or having) proteinuria (1+ or higher) at baseline was 0.82 (0.23-2.97); thus, proteinuria was not significantly associated with the outcome of death. No significant deterioration in kidney function was observed in patients with proteinuria. Although proteinuria at baseline was a significant risk factor for proteinuria progression during and after treatment, most patients maintained grade 1 or 2 proteinuria and continued treatment without dose reduction or discontinuation. Conclusion: While weak evidence suggests that proteinuria at the start of treatment with anti-angiogenic agents might be a risk factor for worsening proteinuria, it was not significantly associated with death or renal impairment.
Recent progress in molecular-targeted agents has contributed to improvements in the prognosis of patients with cancer. In particular, anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) pathway have demonstrated clinical efficacy in the treatment of several cancers (1-3). Among the various side effects (SEs) of VEGF receptor (VEGFR)-targeted agents, proteinuria is relatively common (4), particularly in patients with metastatic colorectal cancer (mCRC) and metastatic renal cell carcinoma (mRCC), and its pathogenesis is multifocal (5-7). Proteinuria due to the use of anti-angiogenic agents may decrease renal function or cause nephrotic syndrome in patients (8). However, limited information is available regarding the safety of VEGFR-targeted agents in patients with proteinuria.
A clinical practice guideline for the management of kidney injury during anticancer drug therapy was established to support improvements in cancer drug therapy outcomes and the patient quality of life through the application of these advances in clinical nephrology and evidence-based treatment. In developing this guideline, we systematically reviewed the pertinent available literature to assess the efficacy and safety of anti-angiogenic agents for treating patients with cancer and proteinuria or a history of proteinuria and reported evidence related to clinical outcomes in these patients.
Materials and Methods
Search strategy. We established a committee for the development of clinical practice guidelines for the management of kidney injury during anticancer drug therapy under the direction of the Japanese Society of Nephrology (JSN), the Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and the Japanese Society of Nephrology and Pharmacotherapy (JSNP).
The guideline committee outlined the initial project scope, key principles, relevant patients/populations, intervention, comparison, and outcome (PICO) questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was employed to combine the results of the systematic review with expert opinions to address the clinical question (9). We and an expert librarian (T. S. mentioned in the acknowledgments) conducted a systematic literature search up to June 18, 2021, using the PubMed (MEDLINE), Cochrane Library, and ICHUSI-Web databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The following search keywords were used: “vascular endothelial growth factor inhibitor”, “VEGF inhibitor”, “proteinuria”, and “kidney”. Table I lists the search syntaxes.
Search strategy.
Eligibility criteria. Any study evaluating the association between outcomes and baseline proteinuria in patients with cancer receiving VEGFR-targeted agents was included. The outcomes included overall survival, progression-free survival, chemotherapy interruption, kidney function, and proteinuria.
Study selection. The eligibility of the selected articles was assessed in two phases. In the first phase of study selection, we evaluated the eligibility of the studies by screening the titles and abstracts. In the second phase, we obtained and screened the full texts of all papers according to our inclusion and exclusion criteria. This systematic review for the PICO question, “Is the use of anti-angiogenic agents recommended for patients with proteinuria or a history of proteinuria?” comprised (P) participants and patients taking anti-angiogenic agents with proteinuria or history of proteinuria; (I) intervention: continued or initiated anti-angiogenic agents; (C) comparison: no discontinuation of anti-angiogenic agents; and (O) outcomes: continued use of anti-angiogenic agents without interruption.
Two investigators independently assessed the methodological quality of the selected reports according to the Minds Manual for Guideline Development 2020 ver. 3.0 (10). Briefly, the investigators independently screened all reports and then performed full-text assessments based on the eligibility criteria, except for those excluded by both. Disagreements in the full-text assessments were resolved through discussion.
Risk of bias assessment. The risk of bias for each observational study was graded as low, moderate, or high for selection, commission, detection, attribution, confounding, and other biases.
Rating the quality of evidence. Two reviewers independently rated the quality of the evidence according to the GRADE approach (11). We used the Cochrane risk-of-bias tool to assess the bias risk (12). The two reviewers evaluated the individually extracted studies and created an “evaluation sheet” for each critical and important outcome, considering the limitations of the study design, integrated bias risk, increasing factors, indirectness (lack of concordance between the PICO elements and the clinical question), and the number of patients/risk patients. Based on the evaluation sheets of all outcomes, the reviewers created the “Body of Evidence” for the clinical question in consideration of the limitations of the study design, risk of bias, inconsistency, indirectness, imprecision, and other factors as proposed by the Minds Tokyo GRADE center as A (strong), B (moderate), C (weak), and D (very weak). The reviewers created a qualitative systematic review and summarized the systematic review reports that they provided to the clinical guideline committee. Under the GRADE approach, a recommendation was made considering the balance between the relative benefits and harms of anti-angiogenic agents, the quality of the evidence, and patients’ preferences. The clinical guideline committee voted on the recommendation and its strength related to the clinical question. Consent was obtained from 75% of the committee members. If a 75% agreement was not obtained in the first vote, the voting members discussed it before revoting. A written explanation was provided for the developed recommendation, which led to the decision of the guideline member responsible for the clinical question.
Conflicts of interest and selection of systematic review members. No specific industry, including the systematic review committee, participated in this consensus meeting. The members of the systematic review committee were invited to join the chair and Clinical Practice Guidelines Development Committee. This article does not contain any studies with human participants performed by any of the Authors. Informed consent was obtained from all study participants by each investigator.
Results
Study characteristics. Of the 303 references that were extracted from the PubMed (n=179), Cochrane Library (n=23), and ICHUSI-Web (n=101) databases in the first screening, after removing duplicate records, we excluded 210 records based on title and abstract screening results. We then analyzed the remaining 91 references for potential inclusion and full-text review, of which five articles were included in the quantitative analysis (Figure 1). Through this analysis, we aimed to determine the outcomes of death, renal impairment, and proteinuria (Table II).
Diagram of study selection, systematic review, and meta-analysis according to Minds guideline handbook 2020 (8).
Characteristics of the five studies remaining after the first and second screenings.
Outcome: death. To evaluate death due to the administration of anti-angiogenic agents, one reference was included with a total of 45 patients in the Japanese cohort (13). In a multivariate Cox proportional hazards model with death as the outcome, the hazard ratio of proteinuria (1+ or higher) at baseline was 0.82 (0.23-2.97), which was not significantly associated with the outcome of death. However, we could not confirm differences in the baseline clinical characteristics between proteinuria-positive and proteinuria-negative patients because proteinuria positivity at the start of treatment with anti-angiogenic agents was not the main exposure in this study.
Outcome: renal impairment. For the quantitative evaluation of renal impairment, we assessed the estimated glomerular filtration rate (eGFR), which is a parameter frequently used to evaluate kidney function. After the first and second screenings, one article described the changes in eGFR before and after treatment in 41 proteinuria-positive patients (8). The study observed no significant deterioration in kidney function in patients with proteinuria, although the cohort consisted of 14 patients who were proteinuria-positive at baseline and 27 patients who became proteinuria-positive after initiating treatment. As the study was limited to patients who had been treated for at least 12 weeks, patients who discontinued anti-angiogenic agents early in the treatment period because of kidney function deterioration might have been excluded, which may have led to a selection bias.
Outcome: proteinuria impairment. To evaluate proteinuria impairment after the administration of anti-angiogenic agents, three studies provided information on baseline proteinuria, defined as proteinuria >2 g/day and proteinuria of any grade (14-16). Despite the differences in the criteria for proteinuria, all reports agreed that proteinuria at baseline was a significant risk factor for disease progression after treatment. One study, which lacked information on baseline proteinuria, also reported that most patients maintained grade 1 or 2 proteinuria and that treatment continued without dose reduction or discontinuation (16).
Discussion
Although the introduction of molecular-targeted agents into clinical settings in recent decades has remarkably improved the prognosis of patients with cancer, these agents may induce various types of SEs, some of which may require intensive medical management, dose reduction, or treatment interruption (1, 2). Among SEs specific to molecular-targeted agents, proteinuria occurs as a dose-related complication in patients receiving VEGFR inhibitors, which inactivates signaling pathways via VEGFR (17).
This systematic review selected five studies to evaluate the efficacy and safety of VEGF inhibitors in mRCC patients with proteinuria or a history of proteinuria (Table II). Miyake et al. reported no significant difference in eGFR values before and after the introduction of axitinib in either group, regardless of the presence of proteinuria (8). Furthermore, the degree of proteinuria and duration of axitinib treatment were not significantly correlated with changes in eGFR following treatment with axitinib. Although proteinuria is considered a risk factor for renal impairment, their findings suggest that anti-angiogenic agent-induced proteinuria may not cause irreversible glomerular injury or worsen renal function.
Tomita et al. showed that preexisting grade 1 proteinuria was associated with a significantly higher risk of any grade and grade 3/4 proteinuria in patients with mRCC receiving axitinib (15). In contrast, Sorich et al. reported no significant association between the baseline eGFR and on-therapy proteinuria in patients with mRCC treated with sunitinib or pazopanib (14). Although a significant unadjusted association between eGFR and any-grade proteinuria was observed, this association was not significant after adjusting for other covariates. In addition to preexisting proteinuria, some studies have reported the associations of diabetes, baseline systolic blood pressure, Asian ethnicity, and prior nephrectomy with a significantly higher risk of developing proteinuria in patients with mCRC and mRCC (14, 18). Interestingly, proteinuria following the initiation of sunitinib or pazopanib treatment has been associated with significantly improved overall survival (14, 19).
Regarding the reduction in the risk of proteinuria, no evidence indicated that the baseline use of angiotensin-converting enzyme inhibitors, other hypertensive drugs, non-steroidal anti-inflammatory drugs, and bisphosphonates significantly altered the risk of proteinuria (14).
Study limitations. First, all five studies included in this review were retrospective observational studies related to patients with mRCC. Further prospective investigations are required to validate our findings in a larger number of patients with multiple cancer types. Second, further research examining the effects of the long-term administration of anti-angiogenic agents is required.
In conclusion, weak evidence suggests that the presence of proteinuria at the start of anti-angiogenic agents may be a risk factor for worsening proteinuria, but was not significantly associated with the more important outcomes of death and renal impairment, suggesting that anti-angiogenic agents can be administered to patients regardless of proteinuria status. After the initiation of anti-angiogenic agents, proteinuria should be monitored appropriately and the benefits or harms of continued anti-angiogenic therapy should be carefully evaluated according to the proteinuria grade.
Acknowledgements
The Authors thank Eiichiro Kanda (Kawasaki Medical School) and Takaaki Suzuki (Nara Medical University Library) for their systematic literature search. The Authors also appreciate the constructive comments of the guideline committee members.
Footnotes
Authors’ Contributions
TK systematically reviewed related literature and drafted the manuscript. SK, TK, YF, and YY systematically reviewed related literature. YA participated in the entire coordinating of this systematic review. All Authors approved the final version of the manuscript for submission and agreed to be accountable for the contents.
Conflicts of Interest
The Authors declare no potential conflicts of interest in relation to this study.
- Received September 25, 2023.
- Revision received October 23, 2023.
- Accepted October 24, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
