Katherine Kelly, PharmD, BCOP

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.^1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.^7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.⁴ Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.

Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.⁹ The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.¹⁰

The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.^11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.

METHODS

This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.

Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.

Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.

 

 

RESULTS

A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.

The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.

These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.

DISCUSSION

More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.^5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.⁵ The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.⁵ Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.⁶ The most common reason for prescription modifications was prescription error.

Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.

Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.^13,14

Limitations

This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.

Conclusions

VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.

These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.

The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.^1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.^7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.⁴ Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.

Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.⁹ The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.¹⁰

The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.^11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.

METHODS

This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.

Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.

Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.

 

 

RESULTS

A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.

The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.

These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.

DISCUSSION

More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.^5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.⁵ The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.⁵ Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.⁶ The most common reason for prescription modifications was prescription error.

Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.

Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.^13,14

Limitations

This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.

Conclusions

VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.

These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.

The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.^1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.^7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.⁴ Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.

Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.⁹ The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.¹⁰

The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.^11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.

METHODS

This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.

Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.

Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.

 

 

RESULTS

A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.

The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.

These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.

DISCUSSION

More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.^5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.⁵ The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.⁵ Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.⁶ The most common reason for prescription modifications was prescription error.

Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.

Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.^13,14

Limitations

This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.

Conclusions

VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.

These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.