Denosumab administration in breast, prostate and lung cancer with chronic kidney disease – a retrospective multicenter Turkish Oncology Group (TOG) study

doi:10.21203/rs.3.rs-5026529/v1

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Denosumab administration in breast, prostate and lung cancer with chronic kidney disease – a retrospective multicenter Turkish Oncology Group (TOG) study

https://doi.org/10.21203/rs.3.rs-5026529/v1

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Background

Denosumab, a RANK-ligand inhibitor, is an effectivetreatmentforfor bone metastasesfromsolidtumors.Unlikethebisphosphonates, it is not excretedbythekidney. Little is known, however, aboutitsefficacyandsafety in patientswith severe chronickidneydisease (CKD).

Methods

Results

A total of 262 patients from 17 centers were included in the study. Toxicitygrade ≥ 3 was seen in a total of 18 patients. Of these 18 patients, 16 had hypocalcemia and the others had eGFR decline. In 42 patients, eGFR was < 60 ml/min. Grade ≥ 3 toxicity (eGFR decrease in 2, hypocalcemia in 11) was detected in 13 of these patients and was statistically significant (p < 0.01).In 6 of 21 patients with pathologic fractures, GFR was < 60 ml/min, which was statistically significant (p = 0.035). In 6 of 21 patients with pathologic fractures, GFR was < 60 ml/min and was found to be statistically significant (p = 0.035). In 4 of 8 patients who underwent bone surgery for SRE, GFR was below 60 ml/min and was significant (p = 0.012).

Conclusion

A high rate of severe hypocalcemiawasobserved in patientswithadvanced CKD treatedwithdenosumab. Ifdenosumab is used in patientswith severe CKD, closemonitoringandaggressivereplacement of calciumandcalcitriol is requiredtoavoidthedevelopment of hypocalcemia.

Bone metastases often occur in advanced cancer patients and bone is one of the most common organs to be affected by metastatic cancer(1). Approximately 90–100% of patients with myeloma, 65–80% of patients with metastatic breast or prostate cancer and 30–40% of patients with advanced lung cancer have bone metastases(2). Many cancers possess the ability to metastasize to bone, but some cancers have greater avidityfor bone than others. Although the reason why some cancers metastasize to bones more often is not fully understood, breast, lung and prostate cancer are the most common cancers that metastasize to bones (3). Bone metastases often occur in advanced cancer patients, and cause skeletal-related events (SREs), including pathological fracture, paralysis from spinal cord compression, hypercalcemia, surgical intervention, and irradiation of thebone. This results in a decline in performance status (PS), activities of daily living (ADL), and quality of life (QOL), and increase the risk of death (4, 5).

In bone metastases, bisphosphonates and denosumab are used to reduce skeletal-related events.Denosumab is a fully human monoclonal antibody against the receptor activator of the nuclear factor-κB ligand, which suppresses osteoclast activation and prevents bone resorption and destruction (6). As denosumab is cleared by the reticuloendothelial system, denosumab can be safely used in chronic kidney disease (CKD).However, the use of denosumab in moderate to advanced CKD (estimated glomerular filtration rate (eGFR) below 30 ml/min) poses a number of complex problems. Not only are clinical studies of denosumab limited in this patient population, but patients frequently have concomitant CKD–mineral and bone disorder (CKD-MBD), which can negatively impact bone density and fracture risk.

Denosumab-associated hypocalcemia (DAH) was reported in several studies in osteoporotic patients in CKD(7, 8).Our knowledge about this is derived from patients with osteoporosis, but denosumab is used more frequently and at higher doses in patients with bone metastases than in osteoporotic patients (120 mg once a month in patients with bone metastases compared to 60 mg every six months in osteoporotic patients). However, data from cancer patients with CKD are very limited. In this study, we aimed to show whether CKD affects the side effects and SRE in cancer patients (with the three most common cancers; breast, prostate and lung)receiving denosumab.

Study design and participants

This study is a retrospective observational study and was conducted as a multicenter study within the scope of the Turkish Oncology Group (TOG) project. Patients with breast, prostate and lung cancer who received denosumab between January 2011 and December 2022 and who were older than 18 years of age were included in the study. We retrospectively extracted patient data for those treated with denosumab from electronic medical charts. Patients who switched from zoledronic acid to denosumab were excluded from this study. Those who were treated for giant cell tumors of the bone, bone metastases from primary bone and soft tissue sarcomas, other solid malignancies and bone lesions from hematologic diseases were also excluded from this study. Moreover, those with incomplete data and < 3 months follow-up, as well as those who did not consent to participation were also excluded.

Treatment procedure

Subcutaneous denosumab (120mg) was administered every four weeks following a diagnosis of metastatic bone tumors. In some patients, physicians decided to extend the period of denosumab administration based on disease status. Denosumab was continued until unacceptable toxic effect, withdrawal of consent, or death.

Procedures

CKD was defined as patients with eGFR below 60 ml/min. SREs inthis study were defined as pathological fractures, spinal cord compressions, surgery to bone, and hypercalcemia. Rates of SREs and surgical interventions were evaluated.Adverse events (AEs)-related to denosumab were also assessed. These included hypocalcemia, hypomagnesemia and hypophosphatemia. In this study, hypomagnesemia and hypophosphatemia weredefined based on a blood sample taken after the start of denosumab treatment and hypocalcemia was defined based on a blood sample taken after the start of denosumab treatment that was below our standard albumin-adjusted calcium level.The grading of patientside effects was based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

For data analysis, in addition to descriptive statistics (mean, standard deviation, medianvalues, and interquartile range), chi-square and Fisher’s exact tests were performed to evaluate the data for categorical variables. The Kolmogorov-Smirnov and Shapiro-Wilk tests were used as appropriate to determine whether continuous variables were compatible with normal distribution. ANOVA, Student’s t-test, Mann-Whitney U test, and Kruskal-Wallis tests were used forthe analysis of the variables indicated by the measurements, according to their distribution. Two-sided p < 0.05 was used to quantify statistical significance.

A total of 262 patients from 17 centers were included in the study. These 262 patients had a median age of 60 years (interquartile range (IQR) 49–71). Of the 262 patients, 164 patients had 1 or more comorbidities. Of the patients, 148 (56.1%) had breast cancer, 60 (22.7%) had prostate cancer and 54 (20.5%) had lung cancer.Toxicitygrade ≥ 3 was seen in a total of 18 patients. Of these 18 patients, 16 had hypocalcemia and the others had eGFR decline. Hypomagnesemia and hypophosphatemia were not detected. Sociodemographic and clinicopathologic characteristics of the patients are summarized in Table 1.

Table 1

Patients’ sociodemographicandclinicopathologicalcharacteristics
Variables	Total (n = 264)
Age, median(percentiles, 25–75), year	60 (49–71)
Age groups, n (%) < 70 ≥ 70	206(%44) 56(%22)
Gender, n (%) Male Female	107(%40.5) 157(% 59.5)
Body-mass Index, n (%) > 18.0 18.0-24.9 25.0–30.0 > 30.0 Missed	2(%0.8) 74(%28.0) 134(%50.8) 53(%20.1) 1(%0.4)
Komorbidity, n(%) CAD COPD DM HT Hemodialysis	32(%12.2) 19(%7.3) 30(%11.5) 82(%31.3) 1(%0.4)
Primarydiagnosis, n (%) Breast Prostate Lung	148 (%56.1) 60 (%22.7) 54 (%20.5)
Metastasis site, n (%) Lung Liver Periton Brain Surrenal	86(%32.6) 60(%22.7) 7(%2.3) 30(%11.4) 20(%7.6)
Frequency of denosumabuse, n (%) Monthly Quarterly	245(%92.8) 10(%7.2)
Toxicity (≥ grade 3), n (%) Yes No Missed	18(%6.8) 237 (%89.8) 9(%3.4)
Toxicitytype, n (%) Hypocalcemia eGFRdecrease	16 (%87.5) 2 (%12.5)

CAD: Coronaryarterialdisease COPD: Chronicobstructivepulmonarydisease DM: DiabetesMellitus HT: Hypertension

In 42 patients, eGFR was < 60 ml/min. Grade ≥ 3 toxicity (eGFR decrease in 2, hypocalcemia in 11) was detected in 13 of these patients and was statistically significant (p < 0.01).In 2 of 9 patients with malignant hypercalcemia, GFR was < 60 ml/min and this was not statistically significant (p = 0.640). In 6 of 21 patients with pathologic fractures, GFR was < 60 ml/min, which was statistically significant (p = 0.035). In 6 of 21 patients with pathologic fractures, GFR was < 60 ml/min and was found to be statistically significant (p = 0.035). In 4 of 8 patients who underwent bone surgery for SRE, GFR was below 60 ml/min and was significant (p = 0.012). Characteristics of denosumab-related toxicities and SRE are summarized in Table 2.

Table 2

Denosumab-relatedtoxicitiesand Skeletal-relatedEventsandtheirfrequency
Malignanthypercalcemia, n (%) Yes No Missed	9(%3.4) 254(%96.2) 1(%0.4)
Pathologicalfracture, n (%) Yes No Missed	30(%11.4) 233(%88.3) 1(%0.3)
Fracture site, n (%) Lowerextremity Vertebra Upperextremity Other	10(%3.8) 17(%6.4) 1(%0.4) 2(%0.8)
Bone surgery, n (%) Yes No Missed	9(%3.4) 226(%85.6) 29(%11.0)
Surgery site, n (%) Lowerextremity Vertebra Upperextremity Other	2(%0.8) 5(%1.9) 1(%0.4) 1(%0.4)
Palliativeradiotherapy, n (%) Yes No Missed	99(%37.5) 155(%58.7) 10 (%3.8)

Grade ≥ 3 toxicity was significantly associated with serum creatinine level (p < 0.01) (Fig. 1).In addition, serum creatinine levels 3 months after diagnosis were also shown to be associated with grade 3 toxicity (p < 0.01) (Fig. 2).Apart from this, other parameters and changes in these parameters were not found to have a significant effect on grade 3 toxicity and SRE.

The median overall survival (OS) of all patients was 161.81 (95% CI 133.09-190.52). The median OS of patients with eGFR < 60 ml/min was 70.14 months (95% CI; 12.15-128.13 months), while the median OS of patients with eGFR > 60 ml/min was 161.81 months (95% CI; 113.43-210.19 months) and statistically significant (p = 0.033) (Fig. 3).The median OS of patients with grade ≥ 3 toxicity was 36.43 months (95% CI; 6.69–66.11 months), while the median OS of patients without grade ≥ 3 toxicity was 165.39 months (95% CI; 118.93-211.84 months), which was statistically significant (p < 0.001) (Fig. 4).

We evaluated denosumab treatment adherence, renal function change, and all-cause mortality using Turkish medical data.In this study, we found a pathologic fracture rate of 11.4% in patients receiving denosumab for metastatic bone disease. The rates of other SREs were malignant hypercalcemia 3.4% and osteonecrosis of the jaw 0.4%. In many studies on this subject, the ratesfor SRE were found to be between 10.5% and 14.4%(9, 10). The rate was similar in our study.Furthermore, in our study, grade 3 toxicity was more common in patients with eGFR < 60 ml/min and this was statistically significant. In all patients in our study, 95% of grade 3 toxicities were hypocalcemia.

Denosumab-associated hypocalcemia in patients with CKD was previously shown in patients with osteoporosis. In a study of patients with osteoporosis, a single dose of 60 mg denosumab reduced serum bone turnover markers in patients with eGFR < 60 ml/min and the reduction in bone turnover markers was associated with hypocalcemia (11). Another population-based study showed that the rate of hypocalcemia reached 42% in patients with end-stage renal disease (ESRD) taking denosumab for osteoporosis. Patients from the same study with stage 3b–5 CKD were reported to be at highest risk (OR 2.92; 95% CI 1.38–6.20) (12).

Patients with bone metastases are at high risk for bone-related complications. The incidence of first and multiple SREs in patients with bone metastasis were up to 0.63 and 3.9(13–15). Zoledronic acid and denosumab are two antiresorptive treatments with differing mechanisms of action, both helping to reduce the likelihood of SREs, which includes pathological fractures. But in patients with CKD, bone turnover is reduced and a condition called adynamic bone disease occurs. Studies ofpatients with eGFR < 60 ml/min with osteoporosis showed that pathologic fractures are more common in these patients than in patients with eGFR > 60 ml/min, but less common than in patients who never received denosumab (16–18).In our study, the incidence of pathologic fractures was higher in patients with eGFR < 60 ml/min. This shows that despite the protective effect of denosumab, it cannot completely reduce the damage caused by CKD tobone(19).

In our study, both hypocalcemia (grade ≥ 3) and pathologic fracture were shown to significantly affect overall survival. However, the number of patients in these patient groups was quite small and the patients were quite heterogeneous, so this reduction should be confirmedinmore homogeneous patient groups includinga larger number of patients. The previous studies on the association of toxins and pathologic fracture with CKD wereconducted with osteoporotic patient groups(18, 20), but the studies with cancer patient groups are case series, single centered and not comparative(21, 22). In our study, this increase was shown to be significant and although the number of patients who developed toxicity and SRE was small, it may have an effect on overall survival.

Our results are limited by the retrospective study design, which interfered with our ability to adequately assess oral calcium supplementation and to consistently identify adverse events as monitoring was atphysician discretion. Other causes of hypocalcemia, including vitamin D levels and/or parathyroid disorders, were not routinely assessed by the healthcare providers. An additional confounder is that the presence of solid tumor malignancy was previouslyshown to be a risk factor for developing hypocalcemia with denosumab use(23).

To our knowledge, this is the first retrospective observational, cross-sectional study to evaluate denosumab use at 120mg in patients with severe renal insufficiency. Our study revealed a higher incidence of grade ≥ 3 hypocalcemia in patients with severe renal impairment (14%) compared to the incidence reported in patients with normal renal function (3.1–9%) (24). This finding strengthens the rationale that denosumab may be the preferred agent in patients with severe renal impairment (CrCl < 30mL/min) for the prevention of SRE in metastatic solid tumor patients with bone metastases. Well-designed prospective clinical trials are warranted to investigate this hypothesis. In current clinical practice, calcium and phosphorus levels should be closely monitored prior to each denosumab dose in this population to identify and promptly address potential toxicities.

Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding Statement: None.

Conflict of interest: The authors declare no potential conflicts of interest.

Ethics approval statement: This study was approved by the Beykoz University Ethics Committee with decision dated 14.08.2020 and numbered 2020 / 1. The study was conducted in accordance with the Declaration of Helsinki.

Author contributions: H.I.E. wrote the main manuscript text, H.I.E. , H.S.S. and T.Y. interpreted the data, H.I.E. prepared all figures and tables, T.Y. and S.T. created the working design and determined the trial concept, F.E, A.P.E, F.K., F.K., E.B., K.K, H.Y.Ç, N.Y., M.K.E., E.T.B, O.A., M.O.,Y.D., T.S., N.A., Y.İ. played a role in organising the dataset and generating the data. The final manuscript was reviewed and approved by all authors.

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No competing interests reported.

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You are reading this latest preprint version

Denosumab administration in breast, prostate and lung cancer with chronic kidney disease – a retrospective multicenter Turkish Oncology Group (TOG) study

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Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Materials and Methods

Study design and participants

Treatment procedure

Procedures

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1