Pharmacist–Urologist Collaborative Management for Patients with Renal Cell Carcinoma Receiving Pazopanib Monotherapy

Abstract

Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment due to adverse events (AEs). We established an ambulatory care pharmacy practice that enables pharmacist–urologist collaboration to manage patients with RCC. This study evaluated the usefulness of this collaborative management. We retrospectively reviewed the medical records of 51 consecutive patients with metastatic RCC receiving pazopanib at the Kobe City Medical Center General Hospital between April 2014 and December 2020. Our collaborative management was implemented in October 2016. The time to pazopanib discontinuation was compared between patients who started pazopanib before (n = 30) and after (n = 21) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with pazopanib discontinuation. In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations, and provided 286 suggestions [according to supportive care in pazopanib treatment (214 suggestions) were most frequent], and 236 (82.5%) were accepted by urologists. The median time to discontinuation (6.1 months vs. 2.4 months, p = 0.024) was significantly longer in the after group. Multivariate analysis showed that collaborative management (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.26–0.88, p = 0.017), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47–9.13, p = 0.008) were significantly associated with pazopanib discontinuation. These results suggested that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.

INTRODUCTION

Pazopanib, an inhibitor of multiple kinases such as vascular endothelial growth factor (VEGF) receptors 1–3, platelet derived growth factor receptors (PDGFR) α and β, and stem cell factor receptor (c-KIT), is one of the recommended treatments for metastatic renal cell carcinoma (RCC).^1–3) Despite its effectiveness, patients with RCC often find it difficult to continue pazopanib treatment due to adverse events (AEs), such as appetite loss, fatigue, diarrhea, skin toxicity, and hypertension.^4,5) Therefore, the management of AEs is essential in this treatment option.

We established an ambulatory care pharmacy practice in October 2016 that enables pharmacist–urologist collaboration for the treatment of patients with urologic cancer taking oral anti-cancer medications, such as pazopanib.⁶⁾ Pharmacists meet patients, provide education, evaluate AEs and medication adherence in each patient, and suggest urologists with prescription recommendations based on the medical needs of each patient.^6–8) To date, only few studies have shown the prolongation of treatment duration following pharmacist interventions in patients with cancer receiving molecular targeting agents.^9,10) Todo et al. implemented a comprehensive pharmaceutical care strategy for metastatic RCC outpatients treated with pazopanib, and evaluated the usefulness of the collaborative management.¹⁰⁾ They implemented a pharmacist–urologist collaborative management, and reported that grade 2 or higher nausea and anorexia, adherence to the pazopanib, and the median time to treatment failure were significantly improved after initiating this approach.

For pazopanib, only a retrospective study from a single institute has been reported to date. Accumulation of evidence on the impact of pharmacy collaborating services is essential to improve patient care in cancer treatment. In addition, the aforementioned study did not evaluate the effects of confounding factors, including various patient characteristics; therefore, a detailed analysis that considers these factors is required. Against this background, this study investigated the usefulness of pharmacist–urologist collaboration, considering the potential confounding factors, in patients with RCC being treated with pazopanib monotherapy.

PATIENTS AND METHODS

Implementing Pharmacist–Urologist Collaborative Management for Oral Anticancer Drugs

In October 2016, we extended an ambulatory care pharmacy practice based on pharmacist–physician collaboration to outpatients with urologic cancer receiving oral anticancer drugs. The objectives of our collaborative management were to support urologists in patient care.^6–8) Three board-certified oncology pharmacists in Japan worked in the ambulatory care pharmacy practice. Their average experience as pharmacists was 21.7 and 15.3 years in general practice and oncology, respectively. The scheme of an ambulatory care pharmacy practice has already been reported previously.^6–8) Briefly, before examination by a urologist, patients had a 15-min face-to-face consultation with a pharmacist in the oncology pharmacy, where the pharmacist evaluated: (1) adherence to pazopanib through patient interviews (patients’ self-report based on residual medication tablet counts); (2) any AEs and their grades in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; (3) whether the patient could take appropriate medication for supportive care; (4) any modifications to concurrent medications or supplements from the perspective of drug–drug interactions. The pharmacists then informed the urologists of their findings (evaluations and suggestions) primarily by reporting in the electronic medical record (EMR) system or by phone call if needed. Subsequently, the urologists would refer to the consultation records provided, assess patient symptoms, and prescribe medicine.

Patients

Fifty-one consecutive patients with metastatic RCC who started pazopanib monotherapy at the Department of Urology of the Kobe City Medical Center General Hospital between April 2014 and December 2020 were the study subjects, and were retrospectively evaluated. Thirty patients started pazopanib before the implementation of the collaborative management approach (before group). After October 1, 2016, 21 patients started pazopanib monotherapy (after group). Patients received oral pazopanib at a dose of 800 mg/d on an empty stomach once daily. Dose modification was done at the physician’s discretion. The Ethics Committee at our institution approved the study protocol (Approval Number: zn210736).

Data Collection and Assessment

The primary endpoint was to investigate the efficacy of pharmacist–urologist collaborative management for time to pazopanib discontinuation. The secondary endpoints included suggestions provided to urologists by the oncology pharmacists in the collaborative management group, the incidence of AEs and their grades in the before/after groups, and factors associated with pazopanib discontinuation. The final daily dose was calculated from the mean dose of pazopanib last two weeks before pazopanib discontinuation. Time to pazopanib discontinuation was calculated as the duration between the time pazopanib was started and the date the treatment was discontinued for any reason. All data we obtained from our hospital’s EMR system. The data cut-off date was June 30, 2022.

Statistical Analysis

Categorical variables are shown as the number of patients (n) and their frequencies. To compare categorical data, chi-square tests or Fisher’s exact tests were employed. For continuous data, values were presented as median (interquartile range (IQR)). The Wilcoxon rank-sum test was performed to analyze group differences. To investigate factors associated with time to pazopanib discontinuation, a Cox regression analysis was used, utilizing the patient’s sex, age, body weight, comorbidities, site of metastasis, Eastern Cooperative Oncology Group performance status (ECOG PS), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC) risk group,¹¹⁾ previous treatments, the dose of pazopanib, prior nephrectomy, and before-and-after the implementation of collaborative management as independent variables. Significant variables from the univariate analyses were considered as potential confounders in the subsequent multivariable Cox regression analysis using the forced entry method. To compare the groups, Kaplan–Meier curves were plotted. Patients who were still taking pazopanib and had not progressed were censored at the last follow-up. JMP version 13.2.1 (SAS Institute Inc., Cary, NC, U.S.A.) and EZR 1.41 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) were used for all statistical analyses,¹²⁾ and a two-tailed p-value of 0.05 was used to determine statistical significance.

RESULTS

Baseline Characteristics of Patients

The baseline patient characteristics are summarized in Table 1. The study subjects consisted with 30 and 21 patients with RCC in the before and after groups, respectively. The proportions of male patients were more in the after group (70.0 vs. 90.5%, p = 0.098). The proportion of patients treated with prior immune-check point inhibitors (ICIs) (0 vs. 19.1%, p = 0.024) and median body weight (54.5 vs. 66.8 kg/body, p < 0.001) were significantly higher in the after group. The initial and final daily doses of pazopanib per body weight were (10.8 [8.8–12.8] vs. 11.6 [7.3–13.1] mg/kg/d, p = 0.984), and (10.3 [8.4–12.4] vs. 7.8 [5.7–11.8] mg/kg/d, p = 0.106), respectively, and those were not significantly different between the groups. Other characteristics such as ECOG PS and IMDC risk group were balanced in the both groups.

Table 1. Baseline Patient Characteristics

Characteristics	Implementation of collaborative management		p-Values
	Before (n = 30)	After (n = 21)
Male sex, n (%)	21 (70.0%)	19 (90.5%)	0.098
Age, years, median (IQR)	71 (65–76)	69 (64–76)	0.745
Body weight, kg, median (IQR)	54.5 (45.0–62.0)	66.8 (60.5–71.5)	<0.001
ECOG PS, n (%)			0.855
0	12 (40.0%)	9 (42.9%)
1	13 (43.3%)	10 (47.6%)
2	5 (16.7%)	2 (9.5%)
Histological subtype, clear cell, n (%)			0.217
Clear cell carcinoma	24 (80.0%)	20 (95.2%)
Others	6 (20.0%)	1 (4.8%)
IMDC risk group, n (%)			0.672
Favorable	8 (26.7%)	8 (38.1%)
Intermediate	19 (63.3%)	12 (57.1%)
Poor	3 (12.0%)	1 (4.8%)
Prior nephrectomy, n (%)	23 (76.7%)	17 (81.0%)	1.000
Pre-existing proteinuria, n (%)	11 (36.7%)	6 (28.6%)	0.764
Use of antihypertensive agents, n (%)	18 (60%)	12 (57.1%)	1.000
Comorbid with diabetes, n (%)	8 (26.7%)	6 (28.6%)	1.000
Site of metastasis, n (%)
Lung	21 (70.0%)	17 (81.0%)	0.518
Lymph nodes	9 (30.0%)	5 (23.8%)	0.754
Liver	4 (13.3%)	2 (9.5%)	1.000
Bone	12 (40.0%)	7 (33.3%)	0.771
Brain	2 (6.7%)	0 (0%)	0.516
Line of therapy, n (%)			0.244
1st	17 (56.7%)	15 (71.4%)
2nd	4 (13.3%)	0 (0%)
3rd or later	9 (30.0%)	6 (28.6%)
Prior cytokine therapy, n (%)	11 (36.7%)	6 (28.6%)	0.764
Prior targeted therapy, n (%)
Sunitinib	9 (30.0%)	6 (28.6%)	1.000
Axitinib	10 (33.3%)	6 (28.6%)	0.768
Everolimus	6 (20.0%)	2 (9.5%)	0.445
Sorafenib	1 (3.3%)	0 (0%)	1.000
Temsirolimus	3 (10.0%)	0 (0%)	0.259
Prior ICI, n (%)	0 (0%)	4 (19.1%)	0.024
LDH, U/L, median (IQR)	190 (151–252)	192 (156–226)	0.702
Initial daily dose, n (%)			0.329
800 mg	15 (50.0%)	15 (36.6%)
600 mg	4 (13.3%)	1 (4.8%)
400 mg	11 (36.7%)	5 (23.8%)
Final daily dose, n (%)			0.138
800 mg	10 (33.3%)	10 (47.6%)
600 mg	8 (26.7%)	1 (4.8%)
400 mg or less	12 (40.0%)	10 (47.6%)

ECOG-PS, Eastern Cooperative Oncology Group performance status; ICI, immune-checkpoint inhibitors; IMDC, International Metastatic Renal Cell Carcinoma Data Consortium; IQR, interquartile range.

Clinical Outcomes of Pharmacist–Urologist Collaborative Management on Pazopanib Treatment

As of June 30, 2022, 48 patients had discontinued pazopanib. The Kaplan–Meier curves before and after the implementation of collaborative management are shown in Fig. 1. The time to pazopanib discontinuation (median 6.1 months [95% confidence interval (CI), 3.1–11.9] vs. 2.4 months [95% CI, 1.3–5.6]; p = 0.024) was significantly longer in the after group than in the before group. To evaluate the efficacy of the pharmacist–urologist collaborative management, we conducted a Cox proportional hazards model for the time to pazopanib discontinuation. Collaborative management (hazard ratio [HR] 0.49, 95% CI 0.26–0.88, p = 0.017), and ECOG PS ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47–9.13, p = 0.008) were significantly associated with pazopanib discontinuation (Table 2).

Fig. 1. Time to Pazopanib Discontinuation before and after Implementation of Pharmacist–Urologist Collaborative Management

Kaplan–Meier curves for comparisons of time to pazopanib discontinuation before and after implementation of pharmacist–urologist collaborative management in patients receiving pazopanib. Log-rank tests were performed to compare the differences between the groups.

Table 2. Univariate and Multivariate Cox Proportional Hazard Models for Time to Pazopanib Discontinuation

Variables	Univariate analyses		Multivariate analysis
	HR (95% CI)	p-Value	HR (95% CI)	p-Value
After implementation of collaborative management	0.51 (0.28–0.92)	0.025	0.49 (0.26–0.88)	0.017
ECOG PS ≥2	4.32 (1.70–9.69)	0.004	3.87 (1.47–9.13)	0.008
IMDC risk group (favorable vs. intermediate or poor)	1.68 (0.92–3.26)	0.094	1.51 (0.79–2.99)	0.212
Prior targeted therapy	1.64 (0.89–2.95)	0.114	NE
Prior cytokine treatment	1.04 (0.55–1.87)	0.902	NE
Pre-existing proteinuria	1.41 (0.74–2.61)	0.287	NE
Use of antihypertensive agents	0.80 (0.45–1.44)	0.458	NE
Comorbid with diabetes	0.94 (0.48–1.74)	0.845	NE
Older age	1.02 (0.99–1.06)	0.145	NE
Male sex	0.69 (0.36–1.43)	0.299	NE
Prior nephrectomy	0.79 (0.42–1.64)	0.516	NE
Lung metastasis	0.75 (0.40–1.48)	0.388	NE
Initial dose reduction	1.00 (0.54–1.77)	0.992	NE

CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IMDC, International Metastatic Renal Cell Carcinoma Data Consortium; LDH, lactate dehydrogenase; ULN, upper limit of normal. NE indicates that the covariate was not evaluated in the model because it was not significant in the univariate analyses.

The reasons for discontinuation of pazopanib were varied: in the before group, 16 patients (53.3%) discontinued pazopanib due to disease progression, 11 patients (36.7%) due to AEs, two patients (6.7%) were transferred to another hospital, and one patient (3.3%) due to patient preference. In the after group, 10 patients (47.6%) discontinued due to disease progression, eight (38.1%) due to AEs, and one (4.8%) due to patient preference.

Involvement of Oncology Pharmacists in Pazopanib Treatment

In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations (median [IQR] 8 times [4–19 times]) and made 286 suggestions to urologists (Table 3). Among these, suggestions based on supportive care in pazopanib treatment (214 suggestions) were most frequent, followed by pazopanib dose (43 suggestions), laboratory tests (23 suggestions), and drug interactions (6 suggestions). The most common suggestions for supportive care were gastrointestinal toxicities (129 suggestions), including diarrhea (96 suggestions), followed by skin toxicities (44 suggestions). In terms of pazopanib dose suggestions, temporary interruption (26 suggestions), followed by adjustment of prescription days due to residual pazopanib tablets (7 suggestions) and decrease in dosage (7 suggestions) were most frequent. Of the 286 suggestions from the oncology pharmacists, 236 (82.5%) were accepted by the urologists and reflected in the prescriptions.

Table 3. Number of Suggestions Provided by the Pharmacists and Urologists Responses in 21 Patients Who Were Managed by the Collaborative Management

	Number of suggestions	Number of suggestions accepted by urologists
Supportive care
Diarrhea	96	88 (91.7%)
Other gastrointestinal toxicity	33	27 (81.8%)
Skin toxicity	44	34 (77.3%)
Hypertension	12	9 (75.0%)
Fatigue	10	5 (50.0%)
Pain control	4	3 (75.0%)
Hypothyroidism	3	3 (100%)
Others	12	8 (66.7%)
Subtotal	214	177 (82.7%)
Pazopanib dosage based on patients’ symptoms
Temporary interruption	26	20 (76.9%)
Adjustment of the prescription days due to residue of pazopanib tablets	7	7 (100%)
Decrease the dosage	7	5 (71.4%)
Increase the dosage	2	2 (100%)
Reinitiate the treatment	1	1 (100%)
Subtotal	43	35 (81.4%)
Laboratory tests
Proteinuria	6	5 (83.3%)
Hypothyroidism	5	3 (60.0%)
Cardiac dysfunction	3	3 (100%)
Screening for hepatitis B virus	3	2 (66.7%)
Others	6	5 (83.3%)
Subtotal	23	18 (78.3%)
Drug interaction	6	6 (100%)
TOTAL	286	236 (82.5%)

Safety

The type and grade of AEs associated with pazopanib are shown in Table 4. Other AEs did not significantly differ in severity across the groups. Although no statistically significant differentiation was observed, the incidences of grade ≥3 fatigue (20.0 vs. 4.8%, p = 0.217), hand-foot syndrome (6.7 vs. 0% p = 0.506), anorexia (16.7 vs. 4.8%, p = 0.381), and diarrhea (6.7 vs. 0%, p = 0.506) were relatively reduced in the after group. The proportions of patients who required discontinuation of pazopanib due to diarrhea (10.0 vs. 0%, p = 0.259) was also relatively reduced in the after group. On the other hand, the incidences of grade ≥3 proteinuria [6.7 (1/15) vs. 20.0% (4/20), p = 0.293] and hepatotoxicity (3.3 vs. 14.3%, p = 0.365) were relatively increased in the after group. The proportion of patients who were evaluated for urine protein significantly increased from 50.0% (15/30) to 95.2% (20/21) after implementing collaborative management (p = 0.001).

Table 4. Selected Adverse Events and Laboratory Abnormalities Associated with Pazopanib in before and after Groups

Events	Before (n = 30)			After (n = 21)			p-Values
	Any grades	Grade 2	Grade ≥3	Any grades	Grade 2	Grade ≥3
Adverse events
Fatigue	24 (80.0%)	10 (33.3%)	6 (20.0%)	18 (85.7%)	7 (33.3%)	1 (4.8%)	0.306
Hand-foot syndrome	19 (63.3%)	5 (16.7%)	2 (6.7%)	10 (47.6%)	2 (9.5%)	0 (0%)	0.537
Anorexia	18 (60.0%)	9 (30.0%)	5 (16.7%)	12 (57.1%)	5 (23.8%)	1 (4.8%)	0.392
Hypertension	18 (60.0%)	13 (43.3%)	1 (3.3%)	13 (61.9%)	8 (38.1%)	2 (9.5%)	0.858
Diarrhea	12 (40.0%)	5 (16.7%)	2 (6.7%)	11 (52.3%)	2 (9.5%)	0 (0%)	0.168
Laboratory abnormalities
Proteinuria a)	11/15 (73.3%)	8/15 (53.3%)	1/15 (6.7%)	14/20 (70.0%)	6/20 (30.0%)	4/20 (20.0%)	0.548
Anemia	19 (63.3%)	2 (6.7%)	0 (0%)	14 (66.7%)	2 (9.5%)	0 (0%)	1.000
AST or ALT increased	11 (36.7%)	3 (10.0%)	1 (3.3%)	14 (66.7%)	5 (23.8%)	3 (14.3%)	0.166
Neutropenia	9 (30.0%)	4 (13.3%)	0 (0%)	6 (28.6%)	3 (14.3%)	1 (4.8%)	0.725
Thrombocytopenia	9 (30.0%)	3 (10.0%)	1 (3.3%)	6 (28.6%)	3 (14.3%)	1 (4.8%)	0.736
Hypothyroidism	5 (16.7%)	2 (6.7%)	0 (0%)	4 (19.0%)	2 (9.5%)	0 (0%)	1.000

AST, aspartate aminotransferase; ALT, alanine aminotransferase. a) Among the study subjects, 15 and 1 patients were not examined urine protein dipstick test was not conducted in the before and after groups, respectively. The proportion of patients who were evaluated urine protein was significantly increased from 50.0% (15/30) to 95.2% (20/21) after implemented the collaborative management (p = 0.001).

DISCUSSION

For collaborative management of outpatients with metastatic RCC receiving pazopanib monotherapy, we implemented and assessed an ambulatory care pharmacy practice. The multivariate Cox proportional hazards model revealed that the time to drug discontinuation was significantly prolonged after the implementation this approach. This is the first study to show the prolonged time to drug discontinuation using multivariate analysis by collaborative management of pharmacists and urologists in patients with metastatic RCC receiving pazopanib monotherapy.

Numerous studies have shown the effectiveness of pharmacist-led team care in pharmacotherapies.^{6–10,13–19)} The results of this study also supported the usefulness of pharmacist–urologist collaborative pharmacotherapy management in an ambulatory care setting. In our ambulatory care pharmacy practice, pharmacists performed a variety of responsibilities, including patient education, suggesting appropriate supportive care, suggesting pazopanib dose modifications to physicians if necessary, managing drug–drug interactions, and encouraging patients to take their medication as prescribed. Further, the pharmacists educated patients on how to take supportive care medicines upon initiation of pazopanib treatment. At the second or later visit, the pharmacists assessed the potential adverse drug events (ADEs) and the appropriateness of the supportive care medicines and then suggested prescriptions to urologists. Pharmacists also advised patients on how to take supportive care medication based on their condition. To ensure the effectiveness of the pharmacist–urologist collaboration in pazopanib therapy, it is essential that pharmacists not only educate patients at the start of pazopanib treatment but also support patients and urologists continuously after pazopanib has been initiated to ensure the safe use of and adequate adherence to the prescribed therapy.

Supportive care medications accounted for the majority of the pharmacists’ suggestions, followed by doses of pazopanib and laboratory testing. Urologists accepted most of the 286 suggestions (82.5%). Pharmacists also suggested dose adjustments of pazopanib based on the severity of the patient’s symptoms. The incidences of grade ≥3 diarrhea, hand-foot syndrome, anorexia, and fatigue were all decreased in the after group compared to the before group. In contrast, the incidences of grade ≥3 proteinuria (6.7 vs. 20.0%) and hepatotoxicity (3.3 vs. 14.3%) were relatively higher in the after group. These findings may be due to the prolonged pazopanib treatment after implementing pharmacist–urologist collaborative management. Exacerbation of proteinuria and hepatotoxicity are difficult to prevent without temporal discontinuation of pazopanib and are known to develop in a treatment duration-dependent manner.^4,20,21) For appropriate management of these AEs, early detection by careful monitoring of laboratory abnormalities is essential. Herein, the proportion of patients evaluated for urine protein significantly improved from 50.0% to 95.2% after collaborative management was implemented. Taken together, our results showed that various interventions by pharmacists contributed to prolonging the time to pazopanib discontinuation, and confirmed the previous preliminary evidence which suggested the usefulness of the pharmacist–urologist collaborative work in pazopanib monotherapy.¹⁰⁾

In the multivariate analysis, ECOG PS ≥2 at pazopanib initiation was also significantly associated with pazopanib discontinuation. This result was consisted with the previous studies,^22,23) and showed that poor PS was also significantly associated with drug discontinuation in real-world clinical practice.

Pazopanib is a drug for which an exposure-safety relationship has been demonstrated, and the usefulness of therapeutic drug monitoring is reported.²⁴⁾ In addition, Noda et al. reported that the relationship between trough concentration and incidences of grade ≥3 toxicity.²⁵⁾ Although the median initial and final daily doses per body weight were not significantly different between the investigated groups, there was a marked difference in body weight. Since we did not evaluate pazopanib plasma concentration, we cannot rule out the possibility that pazopanib exposure was influenced by the difference in body weights between the groups.

Our research has several limitations. First, it was a single-center, non-randomized observational study with retrospective assessment of results in historical controls. Second, the sample size was small. Third, because the study participants were limited to patients with RCC who received pazopanib monotherapy, these findings cannot be extrapolated to include other patient groups. The interventions from medical staff including pharmacists in the before group could not be investigated because of the retrospective nature of the study. Lastly, although multivariate analysis showed that pharmacists–urologist collaborative management was significantly associated with pazopanib discontinuation, this study could not fully control the influence of confounding factors.

In conclusion, we developed an ambulatory care pharmacy practice for pharmacist–urologist collaborative management of outpatients with metastatic RCC receiving pazopanib. The findings of this study showed that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.

Conflict of Interest

The authors declare no conflict of interest.

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