Original Article
Does gastric acid suppression affect sunitinib efficacy in patients with advanced or metastatic renal cell cancer?
J Oncol Pharm Practice 2015, Vol. 21(3) 194–200 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214527145 opp.sagepub.com
Vincent H Ha1,2,*, Margaret Ngo2,3,*, Michael P Chu4, Sunita Ghosh5, Michael B Sawyer4 and Carole R Chambers1
Abstract Introduction: Renal cell cancer is a chemotherapy-insensitive cancer treated by vascular endothelial growth factor receptor antagonists. Recently, a question has arisen on whether there is an interaction between tyrosine kinase inhibitors, such as sunitinib, and acid suppressing agents. Methods: A retrospective chart review was conducted for patients at two tertiary care centers who received sunitinib between 1 January 2006 and 31 March 2013. Using electronic systems and a province-wide electronic health records database, medication dispensing records were obtained. A univariate Cox’s proportional hazard model determined if acid suppression had effects on progression-free survival and overall survival. Results: Of 383 patient charts reviewed, 231 were included in the study. Patients on intermittent acid suppression, lost to follow-up or received sunitinib for less than one week were excluded from the study. The median age of the study population was 65. Patients who received no acid suppression (n ¼ 186) had a median progression-free survival of 23.6 weeks (95% CI, 19.0–31.9 weeks) and patients who received continuous acid suppression (n ¼ 45) had a median progression-free survival of 18.9 weeks (95% CI, 11.0–23.7 p ¼ 0.04). A median overall survival of 62.4 weeks (95% CI, 42.0–82.7 weeks) was observed in the group with no acid suppression, while a median overall survival of 40.9 weeks (95% CI, 26.1–74.4 weeks) was observed in the continuous acid suppression group (p ¼ 0.02). Conclusion: There was a significant difference in progression-free survival and overall survival between the acid suppressed and no acid suppression groups. Further research is required to confirm this potential interaction.
Keywords Sunitinib, proton pump inhibitors, renal cell cancer, progression-free survival, overall survival
Introduction Renal cell cancer (RCC) is a common cancer which is estimated to affect 5900 Canadians in 2013.1 RCC was one of the most chemotherapy-insensitive forms of cancer until development of vascular endothelial growth factor receptor (VEGFR) antagonists. Over the last few years, VEGFR antagonist tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, have become first-line agents for treating metastatic RCC (mRCC). However, a recent review article has questioned whether there is a significant interaction between TKIs and acid suppressing agents.2 With TKIs being fairly new to the clinic, interactions between TKIs and acid suppressing agents have scarcely been studied
and are not documented in interaction databases such as Medscape, LexiComp and MicromedexÕ .3–5 1
Pharmacy Department, Cross Cancer Institute, Canada Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Canada 3 Pharmacy Department, Tom Baker Cancer Centre, Canada 4 Department of Medical Oncology, Cross Cancer Institute, Canada 5 Experimental Oncology Department, Cross Cancer Institute, Canada 2
*Vincent H Ha and Margaret Ngo equally contributed in collecting the data and writing the manuscript Corresponding author: Michael B Sawyer, Department of Medical Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada. Email: [email protected]
Ha et al. Unfortunately, these interaction databases are heavily relied upon by frontline staff. Given the large proportion of stage IV disease at the time of RCC diagnosis, these novel agents are of significant value in extending progression-free survival (PFS) and it is important to determine if acid suppressing therapy could interfere with TKIs. Sunitinib malate (SutentÕ ) is an oral multi-targeted receptor TKI used to treat mRCC.6 Motzer et al.7 established sunitinib’s role as frontline therapy through a randomized, phase III trial comparing it to interferon-a (IFN-a).7 The median PFS was 11 months for sunitinib and 5 months for IFN-a.7 The median overall survival (OS) was 26.4 months for sunitinib and 21.8 months for IFN-a.7 Sunitinib is metabolized by cytochrome P450 3A4 and has a pKa of 9.0.2 Its solubility is pH-dependent and only soluble within a pH range of 1.2–6.8. Once pH exceeds 6.8, sunitinib solubility decreases drastically and will not be absorbed properly.2 Although many different medications may increase intragastric pH, patients suffering acid reflux symptoms may actively pursue acid suppressing agents. This places the individual at risk of cancer progression due to inadequate systemic concentrations of the anticancer drug. Budha et al.2 noted that from their database of 2.8 million cancer patients, 20–55% received acid-reducing agents. With the high prevalence of gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), acid-reducing agents may decrease drug absorption and subsequently affect cancer control. Histamine-2 receptor antagonists (H2RA), antacids and proton pump inhibitors (PPI) are common acid-suppressing agents accessible to cancer patients. Although there are different agents for acid suppression, PPIs are of particular concern because of their long duration of action. PPIs are prodrugs which irreversibly bind to hydrogen potassium ATPase pumps (H+/K+ ATPase), reducing production of gastric acid.8 Although the halflife may be short, irreversible binding results in long duration of acid inhibition ranging from 10.1 to 14.1 hours.9 With a long duration of action, luminal pH may be elevated from a pH of 1–2 to as high as a pH of 6–7, ultimately affecting drug solubility.8 On top of high GERD incidences, sunitinib can cause abdominal pain (39%) and GERD/reflux (12%).10 These adverse effects may potentiate use of acid-reducing agents by physician prescribing PPIs to alleviate these side effects for patients taking sunitinib. Many TKIs have been studied and shown to have diminished effects in an environment with an increased pH.2 In another chart review, we found a clinical significance in the PFS of patients who co-administered acid suppression with erlotinib (PFS 70 vs. 40 days).11 In comparison with other TKIs, sunitinib lacks
195 published evidence to definitively establish whether there is an interaction between sunitinib and acid suppressors. Our study aims to retrospectively examine patients with mRCC who have received sunitinib treatment with co-administration of acid suppression and compare PFS between patients who have and have not received acid suppression therapy.
Methods Study design In this retrospective study, all stage-IV RCC patients treated with sunitinib at the Cross Cancer Institute and Tom Baker Cancer Centre in Alberta, Canada, between 1 January 2006 and 31 March 2013 were reviewed. Prior to initiation of the study, the ethics board approved the study. Due to the nature of a retrospective chart review, patient consent was not required.
Patients Further inclusion criteria required patients to have a valid personal health number (PHN) to allow access to community pharmacy dispensing records on the provincial electronic health record database Netcare. Patients who were excluded were those lost to followup due to moving out of province or out of country, patients who received intermittent acid suppression therapy and patients who received less than 1 week of sunitinib therapy. Intermittent suppression was defined as inconsistent PPI refills (greater than 1 month with unsupplied medications as per refill dates), beginning acid suppression therapy after initiation of sunitinib, or discontinuing acid suppression before sunitinib therapy ended. Suppression, in this study, was defined as patients who received an acid suppressing agent continuously throughout their sunitinib therapy. No suppression was classified as patients who did not receive or fill any acid suppressing agents during their sunitinib therapy. Other databases used for this study included the computerized entry system Aria, which documents physician orders and progress notes, and Centricity, the database for pharmacy dispensing records for both of these tertiary care centers.
Data collection Using our electronic databases Aria and Netcare, we were able to gather information through physician progress notes, CT scan results and pathology reports. Patient demographics that were collected include: date of birth, gender, RCC subtype, date of diagnosis, stage at diagnosis, date disease progressed to stage IV, Eastern Cooperative Oncology Group (ECOG)
196
Journal of Oncology Pharmacy Practice 21(3)
performance status. Sunitinib administration information including lines of treatment, dates and duration of treatment, dose reductions, and evidence of progression and treatment cessation were documented. Co-administration of acid suppression was then noted including type of acid suppression, dosage of acid suppression, continuous or as needed acid suppression. PFS and OS were identified as primary and secondary endpoints. Information gathered was then recorded in an Excel spreadsheet. The date that the patient received sunitinib was documented in Centricity, and other information was gathered through physician documentation notes in Aria. Acid-suppression information and dispensing records were gathered through Netcare. With this system, we were able to report patients who have taken prescription acid suppressors such as PPIs. In some instances, pharmacies also uploaded information about non-prescription acid suppressors such as H2RAs and calcium carbonate. Data were analyzed using Statistical Analysis Systems (SAS Institute Inc., Cary, NC) version 9.3. Survival data collected were
analyzed through a univariate Cox’s proportional hazard model using the PHREG procedure and Kaplan-Meier estimates were obtained using LIFETEST procedure. Our primary endpoint for the study was PFS and the log rank test was used to compare between patients receiving sunitinib and acid suppression concomitantly and patients receiving sunitinib without acid suppression. A secondary endpoint, OS, was also analyzed for these populations. A significance level of
Does gastric acid suppression affect sunitinib efficacy in patients with advanced or metastatic renal cell cancer?
J Oncol Pharm Practice 2015, Vol. 21(3) 194–200 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214527145 opp.sagepub.com
Vincent H Ha1,2,*, Margaret Ngo2,3,*, Michael P Chu4, Sunita Ghosh5, Michael B Sawyer4 and Carole R Chambers1
Abstract Introduction: Renal cell cancer is a chemotherapy-insensitive cancer treated by vascular endothelial growth factor receptor antagonists. Recently, a question has arisen on whether there is an interaction between tyrosine kinase inhibitors, such as sunitinib, and acid suppressing agents. Methods: A retrospective chart review was conducted for patients at two tertiary care centers who received sunitinib between 1 January 2006 and 31 March 2013. Using electronic systems and a province-wide electronic health records database, medication dispensing records were obtained. A univariate Cox’s proportional hazard model determined if acid suppression had effects on progression-free survival and overall survival. Results: Of 383 patient charts reviewed, 231 were included in the study. Patients on intermittent acid suppression, lost to follow-up or received sunitinib for less than one week were excluded from the study. The median age of the study population was 65. Patients who received no acid suppression (n ¼ 186) had a median progression-free survival of 23.6 weeks (95% CI, 19.0–31.9 weeks) and patients who received continuous acid suppression (n ¼ 45) had a median progression-free survival of 18.9 weeks (95% CI, 11.0–23.7 p ¼ 0.04). A median overall survival of 62.4 weeks (95% CI, 42.0–82.7 weeks) was observed in the group with no acid suppression, while a median overall survival of 40.9 weeks (95% CI, 26.1–74.4 weeks) was observed in the continuous acid suppression group (p ¼ 0.02). Conclusion: There was a significant difference in progression-free survival and overall survival between the acid suppressed and no acid suppression groups. Further research is required to confirm this potential interaction.
Keywords Sunitinib, proton pump inhibitors, renal cell cancer, progression-free survival, overall survival
Introduction Renal cell cancer (RCC) is a common cancer which is estimated to affect 5900 Canadians in 2013.1 RCC was one of the most chemotherapy-insensitive forms of cancer until development of vascular endothelial growth factor receptor (VEGFR) antagonists. Over the last few years, VEGFR antagonist tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, have become first-line agents for treating metastatic RCC (mRCC). However, a recent review article has questioned whether there is a significant interaction between TKIs and acid suppressing agents.2 With TKIs being fairly new to the clinic, interactions between TKIs and acid suppressing agents have scarcely been studied
and are not documented in interaction databases such as Medscape, LexiComp and MicromedexÕ .3–5 1
Pharmacy Department, Cross Cancer Institute, Canada Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Canada 3 Pharmacy Department, Tom Baker Cancer Centre, Canada 4 Department of Medical Oncology, Cross Cancer Institute, Canada 5 Experimental Oncology Department, Cross Cancer Institute, Canada 2
*Vincent H Ha and Margaret Ngo equally contributed in collecting the data and writing the manuscript Corresponding author: Michael B Sawyer, Department of Medical Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada. Email: [email protected]
Ha et al. Unfortunately, these interaction databases are heavily relied upon by frontline staff. Given the large proportion of stage IV disease at the time of RCC diagnosis, these novel agents are of significant value in extending progression-free survival (PFS) and it is important to determine if acid suppressing therapy could interfere with TKIs. Sunitinib malate (SutentÕ ) is an oral multi-targeted receptor TKI used to treat mRCC.6 Motzer et al.7 established sunitinib’s role as frontline therapy through a randomized, phase III trial comparing it to interferon-a (IFN-a).7 The median PFS was 11 months for sunitinib and 5 months for IFN-a.7 The median overall survival (OS) was 26.4 months for sunitinib and 21.8 months for IFN-a.7 Sunitinib is metabolized by cytochrome P450 3A4 and has a pKa of 9.0.2 Its solubility is pH-dependent and only soluble within a pH range of 1.2–6.8. Once pH exceeds 6.8, sunitinib solubility decreases drastically and will not be absorbed properly.2 Although many different medications may increase intragastric pH, patients suffering acid reflux symptoms may actively pursue acid suppressing agents. This places the individual at risk of cancer progression due to inadequate systemic concentrations of the anticancer drug. Budha et al.2 noted that from their database of 2.8 million cancer patients, 20–55% received acid-reducing agents. With the high prevalence of gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), acid-reducing agents may decrease drug absorption and subsequently affect cancer control. Histamine-2 receptor antagonists (H2RA), antacids and proton pump inhibitors (PPI) are common acid-suppressing agents accessible to cancer patients. Although there are different agents for acid suppression, PPIs are of particular concern because of their long duration of action. PPIs are prodrugs which irreversibly bind to hydrogen potassium ATPase pumps (H+/K+ ATPase), reducing production of gastric acid.8 Although the halflife may be short, irreversible binding results in long duration of acid inhibition ranging from 10.1 to 14.1 hours.9 With a long duration of action, luminal pH may be elevated from a pH of 1–2 to as high as a pH of 6–7, ultimately affecting drug solubility.8 On top of high GERD incidences, sunitinib can cause abdominal pain (39%) and GERD/reflux (12%).10 These adverse effects may potentiate use of acid-reducing agents by physician prescribing PPIs to alleviate these side effects for patients taking sunitinib. Many TKIs have been studied and shown to have diminished effects in an environment with an increased pH.2 In another chart review, we found a clinical significance in the PFS of patients who co-administered acid suppression with erlotinib (PFS 70 vs. 40 days).11 In comparison with other TKIs, sunitinib lacks
195 published evidence to definitively establish whether there is an interaction between sunitinib and acid suppressors. Our study aims to retrospectively examine patients with mRCC who have received sunitinib treatment with co-administration of acid suppression and compare PFS between patients who have and have not received acid suppression therapy.
Methods Study design In this retrospective study, all stage-IV RCC patients treated with sunitinib at the Cross Cancer Institute and Tom Baker Cancer Centre in Alberta, Canada, between 1 January 2006 and 31 March 2013 were reviewed. Prior to initiation of the study, the ethics board approved the study. Due to the nature of a retrospective chart review, patient consent was not required.
Patients Further inclusion criteria required patients to have a valid personal health number (PHN) to allow access to community pharmacy dispensing records on the provincial electronic health record database Netcare. Patients who were excluded were those lost to followup due to moving out of province or out of country, patients who received intermittent acid suppression therapy and patients who received less than 1 week of sunitinib therapy. Intermittent suppression was defined as inconsistent PPI refills (greater than 1 month with unsupplied medications as per refill dates), beginning acid suppression therapy after initiation of sunitinib, or discontinuing acid suppression before sunitinib therapy ended. Suppression, in this study, was defined as patients who received an acid suppressing agent continuously throughout their sunitinib therapy. No suppression was classified as patients who did not receive or fill any acid suppressing agents during their sunitinib therapy. Other databases used for this study included the computerized entry system Aria, which documents physician orders and progress notes, and Centricity, the database for pharmacy dispensing records for both of these tertiary care centers.
Data collection Using our electronic databases Aria and Netcare, we were able to gather information through physician progress notes, CT scan results and pathology reports. Patient demographics that were collected include: date of birth, gender, RCC subtype, date of diagnosis, stage at diagnosis, date disease progressed to stage IV, Eastern Cooperative Oncology Group (ECOG)
196
Journal of Oncology Pharmacy Practice 21(3)
performance status. Sunitinib administration information including lines of treatment, dates and duration of treatment, dose reductions, and evidence of progression and treatment cessation were documented. Co-administration of acid suppression was then noted including type of acid suppression, dosage of acid suppression, continuous or as needed acid suppression. PFS and OS were identified as primary and secondary endpoints. Information gathered was then recorded in an Excel spreadsheet. The date that the patient received sunitinib was documented in Centricity, and other information was gathered through physician documentation notes in Aria. Acid-suppression information and dispensing records were gathered through Netcare. With this system, we were able to report patients who have taken prescription acid suppressors such as PPIs. In some instances, pharmacies also uploaded information about non-prescription acid suppressors such as H2RAs and calcium carbonate. Data were analyzed using Statistical Analysis Systems (SAS Institute Inc., Cary, NC) version 9.3. Survival data collected were
analyzed through a univariate Cox’s proportional hazard model using the PHREG procedure and Kaplan-Meier estimates were obtained using LIFETEST procedure. Our primary endpoint for the study was PFS and the log rank test was used to compare between patients receiving sunitinib and acid suppression concomitantly and patients receiving sunitinib without acid suppression. A secondary endpoint, OS, was also analyzed for these populations. A significance level of
