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Subcutaneous clodronate: A study evaluating efficacy in hypercalcemia of malignancy and local toxicity
Annals of Oncology 8: 915-916, 1997. O 1997 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Subcutaneous clodronate: A study evaluating efficacy in hypercalcemia of malignancy and local toxicity P. Walker, S. Watanabe, P. Lawlor, J. Hanson, J. Pereira & E. Bruera Palliative Care Program, Grey Nuns Community Hospital & Health Centre, Cross Cancer Institute, Edmonton, Canada
Summary
The logistics of administering intravenous bisphosphonates may be problematic in the care of advanced cancer patients, especially in the home setting. Hypodermoclysis is a convenient method of administering fluid via subcutaneous infu-
Introduction Bisphosphonates have extremely poor oral bioavailability resulting in recommendations for intravenous administration for the treatment of hypercalcemia of malignancy [1] and bone pain [2, 3]. We have published our initial experience with subcutaneous (sc) clodronate as a proposed alternative [4].
Patients and methods Thirty-seven inpatients underwent 45 clodronate infusions (Table 1). All were diagnosed with terminal cancer, defined as locally recurrent or metastatic cancer showing no response to antineoplastic therapy. Clodronate 1500 mg in 1 litre of normal saline was administered via a # 2 3 gauge x 3/4 inch butterfly needle placed in the sc tissue. Initial infusions utilized 300 units of hyaluronidase injected into the sc site prior to infusion. This was later followed by infusions utilizing 150 units, and then infusions without hyaluronidase. Standard, non-portable hospital infusion pumps were initially used, followed by infusions utilizing gravity alone. Progressively, the infusions were requested to be given over 24 hours, 12 hours, and then 6 hours duration. The actual duration of infusion could vary from that requested, at the nurse's discretion. Evaluation of the sc sites was obtained from the parenteral fluid record, in which nurses prospectively recorded their assessment of the site at a minimum frequency of every eight hours. Any additional information describing site toxicity was also included. Data was collected for three days following infusion of clodronate. The volume of hydration with parenteral fluids was recorded for the week prior to clodronate administration. Normal saline or 2/3 D 5 W 1/3 N.S. were administered via hypodermoclysis or intravenously. Criteria for evaluating the efficacy of sc clodronate included: parenteral fluid hydration of a minimum volume of 1 litre/day for a duration of at least 1 day, corrected serum calcium values following hydration ^2.7 mmol/1 (day - 1 to 0), and a minimum of two serum calcium determinations between day 2 to day 10 post clodronate. Patients receiving antineoplastic or other medications that may reduce serum calcium levels were eliminated from the efficacy evaluation. Corrected
sion, presently used in the domiciliary setting. Results of the administration of clodronate via this route are reported. Key words: biphosphonates, clodronate, hypercalcemia, hypodermoclysis
serum calcium values were obtained from the following formula: Ca (corrected) mmol/1 = (40-albumin g/1) 0.02 + Ca (measured) mmol/1. The efficacy of sc clodronate on pain intensity was not assessed because of the open uncontrolled nature of the study. Chi-square test was used for the comparison of proportions. Descriptive statistics and data analysis were performed using the SAS system [5],
Results The observed site toxicity was as follows: none in 32 infusions (71%), local pain in eight (18%), swelling in six (13%), redness in five (11%), bruising in three (7%) and allergic reaction in one (2%). All pain, swelling and redness resolved within a few hours. The three cases of nontender bruising resolved spontaneously in two to three days. The majority of the sc sites were in the anterior chest, abdomen, or thigh. No necrosis or sloughing of skin was observed throughout the 45 infusions. All infusions were completed, none required discontinuation due to discomfort. No difference was evident between the gravity and pump infusions. Nursing strategies reported to decrease local irritation included decreasing the infusion rate, changing the location of the sc site, and applying local heat. Toxicity of pain, swelling, redness or bruising developed in 17 of 31 infusions with hyaluronidase (55%, 95% confidence interval (CI) 37%—72%) versus 5 of 14 infusions without hyaluronidase (36%, 95% CI 11%-61%, P - 0.23). Eighteen of 33 infusions for hypercalcemia were excluded from the evaluation of efficacy. Reasons for exclusion were: seven with only one calcium value for days 2-10; two with no follow-up calcium determinations due to death; two with concurrent calcitonin; two where calcium was not determined following prehydration and
916 Table 1. Patient and infusion characteristics.
Demographics Median age in years (range) Male/female Patients (n) Infusions (n) Primary tumor site Lung Breast Prostate Bladder Unknown Renal Rectal Melanoma Lymphoma Total Indication Hypercalcemia of malignancy (n) Bone pain (n) Total Site preparation Hyaluronidase 300 units (n) Hyaluronidase 150 units (n) Without hyaluronidase (n) Total Delivery Infusions via gravity (n) Infusions via pump (n) Total Duration of infusion Median hours (range) Parenteral prehydration Median duration in days (range) Median volume in litres per day (range)
Evaluable for local toxicity
Evaluable for efficacy in hypercalcemia
66 (46-87) 24/13 37" 45
70 (46-87) 9/4 13 b 15
16.
t
4 1
s
3
2 2 2 1 1 1 37
,2"1 0 1 i 0 13
33 12 45
15 0
7 24 14" 45
3 9 3 15
25 20 45
9 6 15
9 (4-30.5)
15
8 (6-30.5) 3(1-7) 1.9(1.3-2.4)
' Eight patients received two infusions each. b Two patients received two infusions each.
prior to clodronate; two where prehydration was unknown; one with inadequate prehydration (< 1 1/d); one where a normal corrected calcium value was obtained prior to administration of clodronate; and one where the corrected serum calcium determination was < 2.7 mmol/1. All evaluable patients achieved normocalcemia (^2.6 mmol/1). Mean normocalcemia occurred on day 4 following clodronate and was maintained until day 9, when sufficient data was no longer available (Figure 1). Discussion Our results suggest that sc clodronate is an effective treatment for hypercalcemia of malignancy and associated with minimal local toxicity. Hyaluronidase, used in hypodermoclysis to improve absorption of fluid [6], did
Time(Days) Figure 1. Corrected serum calcium (mean+/-se) before and after 15 subcutaneous infusions of clodronate in 13 patients.
not appear to confer a reduction in sc site toxicity, and may not be necessary. This technique may be helpful in the care of the terminally ill at home as sc administration can be easily accomplished in the domiciliary setting, sparing the patient the discomfort and costs associated with transportation and hospital intravenous administration. Alternatively sc administration can be advantageous in the hospital setting in patients for whom an i.v. site may be problematic.
References 1. Purohit OP, Radstone CR, Anthony C et al. A randomised doubleblind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995; 72: 1289-93. 2. Ernst DS, MacDonald RN, Paterson HG et al. A double-blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992; 7(1). 4-11. 3. Ernst DS, Brasher P, Hagen N et al. A randomized, controlled trial of intravenous clodronate in patiens with metastatic bone disease and pain. J Pain Symptom Manage 1997; 13 (6): 319-26. 4. Walker P, Watanabe S, Lawlor P, Bruera E. Letter to the editor subcutaneous clodronate. Lancet 1996; 348: 345. 5. SAS Software Release Gil. SAS Institute Inc. Cory, NC, USA. 6. Bruera E, de Stoutz ND, Fainsinger RL et al. Comparison of two different concentrations of hyaluronidase in patients receiving 1-hour infusions of hypodermoclysis. J Pain Symptom Manage 1995; 10(7): 505-9. Received 23 April 1997; accepted 6 August 1997.
Correspondence to: Dr. Paul Walker Palliative Care Program Grey Nuns Community Hospital & Health Centre 1100 Youville Drive West Edmonton, Alberta
Canada T6L 5X8
Short report Subcutaneous clodronate: A study evaluating efficacy in hypercalcemia of malignancy and local toxicity P. Walker, S. Watanabe, P. Lawlor, J. Hanson, J. Pereira & E. Bruera Palliative Care Program, Grey Nuns Community Hospital & Health Centre, Cross Cancer Institute, Edmonton, Canada
Summary
The logistics of administering intravenous bisphosphonates may be problematic in the care of advanced cancer patients, especially in the home setting. Hypodermoclysis is a convenient method of administering fluid via subcutaneous infu-
Introduction Bisphosphonates have extremely poor oral bioavailability resulting in recommendations for intravenous administration for the treatment of hypercalcemia of malignancy [1] and bone pain [2, 3]. We have published our initial experience with subcutaneous (sc) clodronate as a proposed alternative [4].
Patients and methods Thirty-seven inpatients underwent 45 clodronate infusions (Table 1). All were diagnosed with terminal cancer, defined as locally recurrent or metastatic cancer showing no response to antineoplastic therapy. Clodronate 1500 mg in 1 litre of normal saline was administered via a # 2 3 gauge x 3/4 inch butterfly needle placed in the sc tissue. Initial infusions utilized 300 units of hyaluronidase injected into the sc site prior to infusion. This was later followed by infusions utilizing 150 units, and then infusions without hyaluronidase. Standard, non-portable hospital infusion pumps were initially used, followed by infusions utilizing gravity alone. Progressively, the infusions were requested to be given over 24 hours, 12 hours, and then 6 hours duration. The actual duration of infusion could vary from that requested, at the nurse's discretion. Evaluation of the sc sites was obtained from the parenteral fluid record, in which nurses prospectively recorded their assessment of the site at a minimum frequency of every eight hours. Any additional information describing site toxicity was also included. Data was collected for three days following infusion of clodronate. The volume of hydration with parenteral fluids was recorded for the week prior to clodronate administration. Normal saline or 2/3 D 5 W 1/3 N.S. were administered via hypodermoclysis or intravenously. Criteria for evaluating the efficacy of sc clodronate included: parenteral fluid hydration of a minimum volume of 1 litre/day for a duration of at least 1 day, corrected serum calcium values following hydration ^2.7 mmol/1 (day - 1 to 0), and a minimum of two serum calcium determinations between day 2 to day 10 post clodronate. Patients receiving antineoplastic or other medications that may reduce serum calcium levels were eliminated from the efficacy evaluation. Corrected
sion, presently used in the domiciliary setting. Results of the administration of clodronate via this route are reported. Key words: biphosphonates, clodronate, hypercalcemia, hypodermoclysis
serum calcium values were obtained from the following formula: Ca (corrected) mmol/1 = (40-albumin g/1) 0.02 + Ca (measured) mmol/1. The efficacy of sc clodronate on pain intensity was not assessed because of the open uncontrolled nature of the study. Chi-square test was used for the comparison of proportions. Descriptive statistics and data analysis were performed using the SAS system [5],
Results The observed site toxicity was as follows: none in 32 infusions (71%), local pain in eight (18%), swelling in six (13%), redness in five (11%), bruising in three (7%) and allergic reaction in one (2%). All pain, swelling and redness resolved within a few hours. The three cases of nontender bruising resolved spontaneously in two to three days. The majority of the sc sites were in the anterior chest, abdomen, or thigh. No necrosis or sloughing of skin was observed throughout the 45 infusions. All infusions were completed, none required discontinuation due to discomfort. No difference was evident between the gravity and pump infusions. Nursing strategies reported to decrease local irritation included decreasing the infusion rate, changing the location of the sc site, and applying local heat. Toxicity of pain, swelling, redness or bruising developed in 17 of 31 infusions with hyaluronidase (55%, 95% confidence interval (CI) 37%—72%) versus 5 of 14 infusions without hyaluronidase (36%, 95% CI 11%-61%, P - 0.23). Eighteen of 33 infusions for hypercalcemia were excluded from the evaluation of efficacy. Reasons for exclusion were: seven with only one calcium value for days 2-10; two with no follow-up calcium determinations due to death; two with concurrent calcitonin; two where calcium was not determined following prehydration and
916 Table 1. Patient and infusion characteristics.
Demographics Median age in years (range) Male/female Patients (n) Infusions (n) Primary tumor site Lung Breast Prostate Bladder Unknown Renal Rectal Melanoma Lymphoma Total Indication Hypercalcemia of malignancy (n) Bone pain (n) Total Site preparation Hyaluronidase 300 units (n) Hyaluronidase 150 units (n) Without hyaluronidase (n) Total Delivery Infusions via gravity (n) Infusions via pump (n) Total Duration of infusion Median hours (range) Parenteral prehydration Median duration in days (range) Median volume in litres per day (range)
Evaluable for local toxicity
Evaluable for efficacy in hypercalcemia
66 (46-87) 24/13 37" 45
70 (46-87) 9/4 13 b 15
16.
t
4 1
s
3
2 2 2 1 1 1 37
,2"1 0 1 i 0 13
33 12 45
15 0
7 24 14" 45
3 9 3 15
25 20 45
9 6 15
9 (4-30.5)
15
8 (6-30.5) 3(1-7) 1.9(1.3-2.4)
' Eight patients received two infusions each. b Two patients received two infusions each.
prior to clodronate; two where prehydration was unknown; one with inadequate prehydration (< 1 1/d); one where a normal corrected calcium value was obtained prior to administration of clodronate; and one where the corrected serum calcium determination was < 2.7 mmol/1. All evaluable patients achieved normocalcemia (^2.6 mmol/1). Mean normocalcemia occurred on day 4 following clodronate and was maintained until day 9, when sufficient data was no longer available (Figure 1). Discussion Our results suggest that sc clodronate is an effective treatment for hypercalcemia of malignancy and associated with minimal local toxicity. Hyaluronidase, used in hypodermoclysis to improve absorption of fluid [6], did
Time(Days) Figure 1. Corrected serum calcium (mean+/-se) before and after 15 subcutaneous infusions of clodronate in 13 patients.
not appear to confer a reduction in sc site toxicity, and may not be necessary. This technique may be helpful in the care of the terminally ill at home as sc administration can be easily accomplished in the domiciliary setting, sparing the patient the discomfort and costs associated with transportation and hospital intravenous administration. Alternatively sc administration can be advantageous in the hospital setting in patients for whom an i.v. site may be problematic.
References 1. Purohit OP, Radstone CR, Anthony C et al. A randomised doubleblind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995; 72: 1289-93. 2. Ernst DS, MacDonald RN, Paterson HG et al. A double-blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992; 7(1). 4-11. 3. Ernst DS, Brasher P, Hagen N et al. A randomized, controlled trial of intravenous clodronate in patiens with metastatic bone disease and pain. J Pain Symptom Manage 1997; 13 (6): 319-26. 4. Walker P, Watanabe S, Lawlor P, Bruera E. Letter to the editor subcutaneous clodronate. Lancet 1996; 348: 345. 5. SAS Software Release Gil. SAS Institute Inc. Cory, NC, USA. 6. Bruera E, de Stoutz ND, Fainsinger RL et al. Comparison of two different concentrations of hyaluronidase in patients receiving 1-hour infusions of hypodermoclysis. J Pain Symptom Manage 1995; 10(7): 505-9. Received 23 April 1997; accepted 6 August 1997.
Correspondence to: Dr. Paul Walker Palliative Care Program Grey Nuns Community Hospital & Health Centre 1100 Youville Drive West Edmonton, Alberta
Canada T6L 5X8