Support Care Cancer (2014) 22:1765–1771 DOI 10.1007/s00520-014-2142-2
ORIGINAL ARTICLE
The effects of denosumab on calcium profiles in advanced cancer patients with bone metastases Breanne Lechner & Carlo DeAngelis & Noreen Jamal & Urban Emmenegger & Natalie Pulenzas & Angie Giotis & Parker Sheehan & May Tsao & Gillian Bedard & Edward Chow
Received: 19 December 2013 / Accepted: 22 January 2014 / Published online: 11 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Objective To retrospectively examine the incidence and management of hypocalcemia for patients with bone metastases treated with denosumab. Methods Patients who had a record of filling a prescription of denosumab for treatment of bone metastases at the outpatient pharmacy at the Odette Cancer Centre from May 2011 to February 2013 were included in the analysis. Demographic information, previous bisphosphonate usage, calcium and albumin values, and adverse events were obtained using the Sunnybrook Electronic Patient Record system (EPR) and the Oncology Symptom Control and Information Resource (OSCIR). Hypocalcemia was defined as a calcium value below 2.0 mmol/L within a 28-day±7-day window after the last injection of denosumab based on the Common Terminology Criteria for Adverse Events (CTCAE) grade 2 hypocalcemia. Results A total of 55 patients had record of a prescription for denosumab filled with an average age of 62 years (range 40 to
93 years), 18 (32.7 %) were males and 37 (67.3 %) were females. Twenty-nine (52.7 %) patients had primary breast cancer, 12 (21.8 %) prostate, 10 (18.2 %) lung, and 4 (7.3 %) with other types. Using CTCAE grading of hypocalcemia, 17 (32.7 %) patients experienced grade 1, 4 (7.7 %) patients grade 2, 4 (7.7 %) patients grade 3, and 1 (1.9 %) patient grade 4. The number of injections before the incident of hypocalcemia was a median of one injection (range 1 to 14). Time from the first hypocalcemia lab value to normocalcemia was a median of 33 days. Conclusions This study found that 9 of 52 (17.3 %) patients had at least one incidence of hypocalcemia of grade 2 or higher after receiving denosumab. Cautionary measures should be taken to avoid hypocalcemia in patients receiving denosumab. Keywords Denosumab . Hypocalcemia . Bone metastases
Introduction B. Lechner : N. Pulenzas : P. Sheehan : M. Tsao : G. Bedard : E. Chow (*) Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5 e-mail: [email protected] C. DeAngelis : N. Jamal : A. Giotis Department of Pharmacy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Canada U. Emmenegger Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Canada
Bone metastases are a serious concern for patients with cancer. Nearly 95 to 100 % of patients with myeloma [1], 90 % of patients with prostate [2], 65 to 75 % of patients with breast [1], and 30 to 40 % of patients with lung [1] cancer develop skeletal metastases. One of the most frequent symptoms of bone metastases is pain which is experienced by 60 to 70 % of patients [3]. Serious complications from bone metastases can include pathological fractures, compression of the spinal cord, hypercalcemia, and the need for radiotherapy or surgery to bone [4]. These skeletal-related events (SRE) can negatively impact quality of life for patients with bone metastases. Various systemic therapies can be used in patients with metastatic cancer to treat and prevent the advancement of bone metastases, including bone-targeted pharmacological agents such as bisphosphonates [4]. A recently approved
1766
alternative option for the treatment of bone metastases is the bone-modifying agent denosumab indicated to reduce the risk of developing SRE in patients with bone metastases from solid tumors [4]. Bone destruction is mediated by osteoclasts which are regulated by the receptor activator of nuclear factor-kappaB ligand (RANKL) [5]. Denosumab, a monoclonal antibody, works against RANKL and has been effective in reducing markers of osteolysis and the development of SRE in patients with bone metastases [5]. Clinical benefits of denosumab when compared to other bone-modifying agents include the fact that it is administered subcutaneously and that it is not nephrotoxic [4, 5]. In regard to efficacy, a systematic review of the literature by Ford et al showed that denosumab is superior in delaying time to first SRE and reducing the risk of the first and subsequent SRE when compared with placebo, zoledronic acid, and pamidronate [4]. An additional systematic review found similar results that denosumab significantly reduced the incidence, as well as delayed the onset, of SRE in patients with skeletal metastases when compared to intravenous bisphosphonates [5]. Despite these promising efficacy results, the study also concluded that denosumab-treated patients had an increased likelihood of developing hypocalcemia, including Common Terminology Criteria for Adverse Events (CTCAE) grades 3 and 4 events [5]. Denosumab is associated with adverse events including severe hypophosphatemia (15.4 %), osteonecrosis of the jaw (1.8 %), and hypocalcemia (9.3 %) [6]. Hypocalcemia is a concern as clinical manifestations can include paresthesias affecting the mouth and extremities, muscle stiffness, myalgias, spasms, and prolongation of the QT interval [7]. The potential for the development of hypocalcemia is especially worrisome for advanced cancer patients who may already be experiencing significant symptoms and side effects from their other treatment modalities and the underlying disease. The incidence of hypocalcemia in advanced cancer patients treated with denosumab in clinical trials was reported as 9.3 % [6]. Patients receiving treatment modalities as a part of a clinical trial are often monitored more closely and chosen to meet stringent eligibility criteria; thus, incidences of adverse events may be lower in comparison to actual practice. Severe symptomatic hypocalcemia, including fatal cases, has been reported in patients receiving denosumab in the post-marketing setting [6]. The objective of the present study was to retrospectively examine hypocalcemia trends in terms of incidence and management for patients receiving denosumab in a standard care setting at the Odette Cancer Centre, a comprehensive tertiary referral cancer center.
Methods A retrospective analysis was conducted to examine incidence of hypocalcemia and management trends for patients
Support Care Cancer (2014) 22:1765–1771
receiving denosumab to treat bone metastases. A report was generated from the pharmacy dispensing system to identify all patients that filled a prescription for denosumab from May 2011 to February 2013 at the Odette Cancer Centre outpatient pharmacy. Denosumab received Notice of Compliance from Health Canada in May 2011, and thus, the beginning date of this study was chosen to capture denosumab use at our center since that point [8]. Demographic information including age, gender, and primary cancer site for each of the study patients was collected using the Sunnybrook Electronic Patient Record system (EPR) and the Oncology Symptom Control and Information Resource (OSCIR). For each patient, the denosumabdispensing dates were collected from the pharmacy dispensing system, and administration was confirmed in the Oncology Patient Information System (OPIS), the cancer center’s computerized physician order entry system. Information regarding previous bisphosphonate usage, mention of adverse events related to denosumab treatment, and any other pertinent information regarding denosumab usage was also collected using physician’s dictated notes in EPR. Calcium and albumin levels were collected through EPR and OSCIR. Calcium levels were corrected by applying the formula corrected total calcium (mmol/L)=total calcium (mmol/L)+0.02 [40 (g/L)−albumin (g/L)] [9]. After exclusion of three subjects with incomplete calcium level availability, 52 subjects were included in the analysis. The CTCAE version 4.03 guideline states that grade 1 hypocalcemia is a serum calcium value
ORIGINAL ARTICLE
The effects of denosumab on calcium profiles in advanced cancer patients with bone metastases Breanne Lechner & Carlo DeAngelis & Noreen Jamal & Urban Emmenegger & Natalie Pulenzas & Angie Giotis & Parker Sheehan & May Tsao & Gillian Bedard & Edward Chow
Received: 19 December 2013 / Accepted: 22 January 2014 / Published online: 11 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Objective To retrospectively examine the incidence and management of hypocalcemia for patients with bone metastases treated with denosumab. Methods Patients who had a record of filling a prescription of denosumab for treatment of bone metastases at the outpatient pharmacy at the Odette Cancer Centre from May 2011 to February 2013 were included in the analysis. Demographic information, previous bisphosphonate usage, calcium and albumin values, and adverse events were obtained using the Sunnybrook Electronic Patient Record system (EPR) and the Oncology Symptom Control and Information Resource (OSCIR). Hypocalcemia was defined as a calcium value below 2.0 mmol/L within a 28-day±7-day window after the last injection of denosumab based on the Common Terminology Criteria for Adverse Events (CTCAE) grade 2 hypocalcemia. Results A total of 55 patients had record of a prescription for denosumab filled with an average age of 62 years (range 40 to
93 years), 18 (32.7 %) were males and 37 (67.3 %) were females. Twenty-nine (52.7 %) patients had primary breast cancer, 12 (21.8 %) prostate, 10 (18.2 %) lung, and 4 (7.3 %) with other types. Using CTCAE grading of hypocalcemia, 17 (32.7 %) patients experienced grade 1, 4 (7.7 %) patients grade 2, 4 (7.7 %) patients grade 3, and 1 (1.9 %) patient grade 4. The number of injections before the incident of hypocalcemia was a median of one injection (range 1 to 14). Time from the first hypocalcemia lab value to normocalcemia was a median of 33 days. Conclusions This study found that 9 of 52 (17.3 %) patients had at least one incidence of hypocalcemia of grade 2 or higher after receiving denosumab. Cautionary measures should be taken to avoid hypocalcemia in patients receiving denosumab. Keywords Denosumab . Hypocalcemia . Bone metastases
Introduction B. Lechner : N. Pulenzas : P. Sheehan : M. Tsao : G. Bedard : E. Chow (*) Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5 e-mail: [email protected] C. DeAngelis : N. Jamal : A. Giotis Department of Pharmacy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Canada U. Emmenegger Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Canada
Bone metastases are a serious concern for patients with cancer. Nearly 95 to 100 % of patients with myeloma [1], 90 % of patients with prostate [2], 65 to 75 % of patients with breast [1], and 30 to 40 % of patients with lung [1] cancer develop skeletal metastases. One of the most frequent symptoms of bone metastases is pain which is experienced by 60 to 70 % of patients [3]. Serious complications from bone metastases can include pathological fractures, compression of the spinal cord, hypercalcemia, and the need for radiotherapy or surgery to bone [4]. These skeletal-related events (SRE) can negatively impact quality of life for patients with bone metastases. Various systemic therapies can be used in patients with metastatic cancer to treat and prevent the advancement of bone metastases, including bone-targeted pharmacological agents such as bisphosphonates [4]. A recently approved
1766
alternative option for the treatment of bone metastases is the bone-modifying agent denosumab indicated to reduce the risk of developing SRE in patients with bone metastases from solid tumors [4]. Bone destruction is mediated by osteoclasts which are regulated by the receptor activator of nuclear factor-kappaB ligand (RANKL) [5]. Denosumab, a monoclonal antibody, works against RANKL and has been effective in reducing markers of osteolysis and the development of SRE in patients with bone metastases [5]. Clinical benefits of denosumab when compared to other bone-modifying agents include the fact that it is administered subcutaneously and that it is not nephrotoxic [4, 5]. In regard to efficacy, a systematic review of the literature by Ford et al showed that denosumab is superior in delaying time to first SRE and reducing the risk of the first and subsequent SRE when compared with placebo, zoledronic acid, and pamidronate [4]. An additional systematic review found similar results that denosumab significantly reduced the incidence, as well as delayed the onset, of SRE in patients with skeletal metastases when compared to intravenous bisphosphonates [5]. Despite these promising efficacy results, the study also concluded that denosumab-treated patients had an increased likelihood of developing hypocalcemia, including Common Terminology Criteria for Adverse Events (CTCAE) grades 3 and 4 events [5]. Denosumab is associated with adverse events including severe hypophosphatemia (15.4 %), osteonecrosis of the jaw (1.8 %), and hypocalcemia (9.3 %) [6]. Hypocalcemia is a concern as clinical manifestations can include paresthesias affecting the mouth and extremities, muscle stiffness, myalgias, spasms, and prolongation of the QT interval [7]. The potential for the development of hypocalcemia is especially worrisome for advanced cancer patients who may already be experiencing significant symptoms and side effects from their other treatment modalities and the underlying disease. The incidence of hypocalcemia in advanced cancer patients treated with denosumab in clinical trials was reported as 9.3 % [6]. Patients receiving treatment modalities as a part of a clinical trial are often monitored more closely and chosen to meet stringent eligibility criteria; thus, incidences of adverse events may be lower in comparison to actual practice. Severe symptomatic hypocalcemia, including fatal cases, has been reported in patients receiving denosumab in the post-marketing setting [6]. The objective of the present study was to retrospectively examine hypocalcemia trends in terms of incidence and management for patients receiving denosumab in a standard care setting at the Odette Cancer Centre, a comprehensive tertiary referral cancer center.
Methods A retrospective analysis was conducted to examine incidence of hypocalcemia and management trends for patients
Support Care Cancer (2014) 22:1765–1771
receiving denosumab to treat bone metastases. A report was generated from the pharmacy dispensing system to identify all patients that filled a prescription for denosumab from May 2011 to February 2013 at the Odette Cancer Centre outpatient pharmacy. Denosumab received Notice of Compliance from Health Canada in May 2011, and thus, the beginning date of this study was chosen to capture denosumab use at our center since that point [8]. Demographic information including age, gender, and primary cancer site for each of the study patients was collected using the Sunnybrook Electronic Patient Record system (EPR) and the Oncology Symptom Control and Information Resource (OSCIR). For each patient, the denosumabdispensing dates were collected from the pharmacy dispensing system, and administration was confirmed in the Oncology Patient Information System (OPIS), the cancer center’s computerized physician order entry system. Information regarding previous bisphosphonate usage, mention of adverse events related to denosumab treatment, and any other pertinent information regarding denosumab usage was also collected using physician’s dictated notes in EPR. Calcium and albumin levels were collected through EPR and OSCIR. Calcium levels were corrected by applying the formula corrected total calcium (mmol/L)=total calcium (mmol/L)+0.02 [40 (g/L)−albumin (g/L)] [9]. After exclusion of three subjects with incomplete calcium level availability, 52 subjects were included in the analysis. The CTCAE version 4.03 guideline states that grade 1 hypocalcemia is a serum calcium value
