This study found that 66% of cases with QV2+ on qualitative tests had low UPCR (UPCR < 2.0); if the UPCR value reflects a more actual urinary proteinuria than the qualitative test result, the QV2+ result may overestimate proteinuria. The CTCAE Grade 2 concordance rate between qualitative and quantitative tests was low, and of the cases judged to be the CTCAE Grade 2 by QV, the CTCAE grade by UPCR was Grade 1 in 40% of these cases. Given the discrepancy in the CTCAE grading derived from the UPCR and QV results, unnecessary treatment interruption may occur when the judgment of continuation of treatment is made on the basis of qualitative proteinuria alone. In the current study, regarding the clinical judgment of whether to continue anti-VEGF/Ri when proteinuria occurred, the UPCR values were found to be more important than the QV status.
The cutoff value of UPCR used for proteinuria management is also an important issue. In CTCAE ver5, UPCR 1.0 and UPCR 3.5 are used as indicators to separate Grade 1 and Grade 2, and Grade 2 and Grade 3, respectively, but there is no rationale behind the use of 1.0 and 3.5 as reference values. In the JO19380 study, a phase I/II study of BV in Japanese patients with colorectal cancer, the drug suspension/discontinuation policy in the study protocol stipulated that BV could be administered if proteinuria was 2 g/24 h or less in a quantitative test by 24-h urine storage.7 Therefore, even in actual clinical practice, a UPCR of ≤ 2.0 is often considered by convention as an index for resuming the administration of angiogenesis inhibitors. However, the rationale for this criterion is unclear, and its contribution to clinical outcomes is unknown. It has also been reported that when a UPCR of 2.4 is used as the cutoff value, the delineating of Grade 2 and Grade 3 proteinuria has a sensitivity of 96.9% and a specificity of 82.5%.8 There is currently no consensus on the UPCR cutoff value that leads to clinical outcomes.
Furthermore, regarding the evaluation of proteinuria in the various clinical trials thus far, it is necessary to pay attention to which version of CTCAE is used for the evaluation. For example, the handling of QV3+ or higher was not described in CTCAE ver 4.0 and earlier versions, but in CTCAE ver 5.0, QV2+ and QV3+ were defined as Grade 2, and QV4+ was defined as Grade 3. In pivotal trials using anti-VEGF/Ri, all adverse events were evaluated with CTCAE ver 4.0 and earlier versions.1–3, 9 Therefore, in these clinical trials, Grade 2 or higher proteinuria assessment may have been inaccurate. In addition, as shown in Figure 3C, there were ten cases (11%) with QV3+ whose UPCR values were ≥ 3.5; therefore, a discrepancy with the UPCR value exists even then using CTCAE ver 5. Regarding proteinuria when using lenvatinib, a multikinase inhibitor with VEGFR 1–3 inhibitory activity, it has also been reported that only 36.4% of the dipstick 3+ samples were UPCR Grade 3.10 Therefore, CTCAE grading has its limits, and it is also necessary to pay attention to the version of CTCAE used in pivotal clinical trials.
This study showed an association between high UPCR and body weight. For BV and Ram, a single dose is prescribed based on body weight, and a single dose of each drug was found to be associated with the worst UPCR.1, 3 Interestingly, there was no correlation between the number of doses or total dose of each drug and worst UPCR (Supplementary Figures S3 and S4), suggesting that higher single doses carry a greater risk of proteinuria, and that a single dose rather than the total dose is a risk of proteinuria. Single doses are common in people with a high body weight, and proteinuria monitoring needs to be enhanced in these cases. In addition, if proteinuria is present, dose reduction of anti-VEGF/Ri may be effective. For example, when BV is used for colorectal cancer, 7.5 mg/kg of BV is used once every 3 weeks in combination with the capecitabine plus oxaliplatin (CapeOX) regimen, whereas 5 mg/kg is used once every 2 weeks in combination with the fluorouracil/folinic acid plus oxaliplatin (FOLFOX) regimen.1 Considering that a single dose of BV poses a risk of proteinuria, a regimen given every 2 weeks rather than every 3 weeks may reduce the risk in cases where proteinuria is a problem. No previous clinical trial has directly compared the rate of proteinuria between BV every 2 weeks and every 3 weeks. According to the sub-analysis of the TRICOLORE study,11 a randomized phase III trial to determine whether S-1 and irinotecan plus BV is noninferior to mFOLFOX6 or CapeOX plus BV as the first-line treatment of metastatic colorectal cancer, the rate of proteinuria of Grade 3 or higher was 4% and 0% triweekly and biweekly, respectively, in the oxaliplatin-based regimen. In contrast, it was 3% and 2% triweekly and biweekly, respectively, in the irinotecan-based regimen. However, the evaluation of proteinuria may be inaccurate given that CTCAE ver 4.0 was used to evaluate adverse events in the TRICOLORE study. Still, it was suggested that the risk of proteinuria differs depending on the base regimen. In the EAGLE study,12 a randomized phase III trial comparing two doses of BV (5 mg/kg and 10 mg/kg) combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting for metastatic colorectal cancer, there was no apparent difference in the rate of Grade 3 or higher proteinuria (1% and 0.5% in 5 mg/kg and 10 mg/kg of BV, respectively). However, the ver 3.0 of CTCAE was used to evaluate adverse events in this EAGLE study, and there was no UPCR information’ therefore, the evaluation of proteinuria was inadequate.
Regarding the administration period up to the worst UPCR, although there was no association found in the cases treated with BV, there was a tendency for worst UPCR to occur early after the start of treatment with Ram (Supplementary Figures S3 and S4). Therefore, when using Ram, careful monitoring is required in the early stages.
There are several limitations to this study. First, this is a retrospective observational study with a small sample size. In particular, as the frequency of UPCR and QV measurement was not specified in advance, it was difficult to grasp the transition of proteinuria over time. However, regarding the decision to continue treatment with anti-VEGF/Ri, it is possible to read from the medical records, and it was found that the UPCR results were more important in clinical practice. When examining the concordance rate between the UPCR and the QV, 1026 samples that could measure both simultaneously were used for analysis, which is a good samples size. Second, there is a lack of information on the factors that are affected by the UPCR. As mentioned above, the UPCR is affected by urine-specific gravity; however, information on urine-specific gravity and muscle mass could not be collected in this study, which is a point to be noted when conducting prospective clinical studies using UPCR in the future. Third, there is insufficient research on risk factors for proteinuria. Our results that body weight was associated with UPCR but not with history of anti-VEGF/Ri use. However, the number of cases in which anti-VEGF/Ri was used as pretreatment was as small as 30 cases, which was insufficient to examine the effects of pretreatment. Interestingly, in 32 patients who did not use anti-VEGF/Ri as a post-treatment of this study, only 5 (16%) had QV2+ proteinuria, whereas in 20 cases who used anti-VEGF/Ri as a post-treatment, proteinuria of QV2+ or higher was observed in 18 patients (90%) (Supplementary Figure S5). That is, although the history of anti-VEGF/Ri use itself does not pose a risk of proteinuria during the continued use of anti-VEGF/Ri, in cases of Grade 2 or higher proteinuria during use of anti-VEGF/Ri, there may be a risk of proteinuria when continuing anti-VEGF/Ri. It was reported that there was no relationship between proteinuria expression and clinical outcomes in patients who used BV.13 However, given that there is a limit to the evaluation method of proteinuria using the CTCAE grade, it is essential to consider how to best evaluate proteinuria by considering the association between proteinuria and clinical outcomes.