Combined therapies with calcitonin and corticosteroids, or bisphosphonate, for treatment of hypercalcemia of malignancy

Design

Three (3) randomized, controlled trials

N= 34

Objective

To determine the advantages of combining calcitonin with corticosteroids or pamidronate for hypercalcemia of malignancy and to identify any specific groups of patients who may benefit from such therapy

Study Groups

Study 1 (N= 10)

Calcitonin alone (n= 5)

Calcitonin plus oral corticosteroids (n=5)

Study 2 (N= 10)

Calcitonin alone (n= 5)

Calcitonin plus oral corticosteroids (n=5)

Study 3 (N= 14)

Pamidronate alone (n= 7)

Pamidronate plus calcitonin (n= 7)

Inclusion Criteria

Patients with hypercalcemia of malignancy; solid tumors (study 1 and study 3); hematological malignancies (study 2)

Exclusion Criteria

Methods

In study 1, 10 patients with hypercalcemia caused by solid tumors (5 patients in each group) were allocated randomly to receive either calcitonin alone or calcitonin with oral corticosteroids.

In study 2, 10 patients with hypercalcemia caused by myeloma with at least one lytic lesion were also randomized to receive either calcitonin alone or in combination with corticosteroids (5 in each group).

In study 3, an additional 14 patients with hypercalcemia of malignancy caused by solid tumors were randomly allocated to receive either pamidronate alone or in combination with calcitonin (7 in each group).

The drugs were administered as follows: salmon calcitonin subcutaneously (200 units q8h for 7 days in studies 1 and 2, and for 3 days in study 3); oral prednisolone 40 mg/day; or a single infusion of 60 mg of pamidronate infusion over 6 h in 11 of normal saline.

Duration

Outcome Measures

Baseline Characteristics

Results

Study 1: The calcium-lowering effect of calcitonin was rapid and a significant decrease in plasma calcium concentration was seen within 24 h after commencing calcitonin therapy. However, there were no significant differences between the two groups at any time point. The calcium-lowering effect was only seen for 3-4 days despite continued calcitonin administration; adding steroids did not prolong the normocalcemic effect.

Study 2: Patients in both groups experienced rapid and significant decreases in plasma calcium levels, but the duration of normocalcemia was significantly longer in the combined therapy group (p< 0.01). By day 5, serum calcium levels were significantly higher in patients who received calcitonin alone (p< 0.01). By day 7, all five patients treated with calcitonin alone had relapses of hypercalcemia, whereas 4/5 (80%) patients in the combined therapy group remained normocalcemic.

Study 3: Serum calcium was lowered significantly by day 3 in both groups, but the combined pamidronate plus calcitonin group decreased calcium levels significantly faster by 24 hours (p< 0.05). The addition of calcitonin to pamidronate therapy had no effect on the duration of normocalcemia (14 vs 13 days).

Adverse Events

Study Author Conclusions

Except in patients with hypercalcemia caused by hematological malignancies, the calcium-lowering effect was not enhanced by adding steroids to calcitonin therapy. In patients with moderate to severe symptomatic hypercalcemia, infusions of pamidronate every 2 weeks and calcitonin therapy for the first 2-3 days rapidly reduced serum calcium levels and sustained normocalcemia.

InpharmD Researcher Critique

Potentiation of Calcitonin by Corticosteroids During the Treatment of the Hypercalcaemia of Malignancy

Design

Single-arm Prospective Pre-Post Study

N= 15

Objective

We have studied a group of patients with hypercalcemia of malignancy in whom the renal and
skeletal responses to calcitonin were incomplete and in whom corticosteroids were added. The aim was to investigate whether corticosteroids are of benefit under these circumstances and, if so, to identify their mode of action.

Study Groups

N/A

Inclusion Criteria

Patients with solid tumors associated with severe hypercalcemia

Exclusion Criteria

Myeloma or lymphoma

Methods

First, patients were rehydrated with intravenous saline (3L per 24 hours, equivalent to 450 mmol sodium per 24 hours). Once a stable but still elevated serum calcium was achieved for ≥48 hours, subcutaneously injected Salmon Calcitonin (25 units every 6 hours) was added. If hypercalcemia remained uncontrolled after at least another 72 hours, oral Prednisolone (10 mg every 6 hours) was added.

Serum calcium was corrected to a reference albumin concentration of 40 grams/L. 

Duration

Intervention: up to 12 days total (≤5 days of calcitonin monotherapy, followed by addition of concomitant corticosteroid for ≤7 days)

Outcome Measures

Response (measured by fasting serum [calcium, creatinine, albumin] and urine [calcium, creatinine, sodium]), net bone resorption (measured by fasting urine calcium:creatinine ratio [mmol/mmol])

Baseline Characteristics

Female Patients (n= 8)

Male Patients (n= 7)

Age, years, mean

Tumor Type:

Breast

Bronchus

Bladder

Renal

Unknown

75%

12.5%

0%

0%

12.5%

0%

57.1%

14.3%

28.6%

0%

Presence of Bone Metastases:

87.5%

42.9%

Presence of Soft Tissue Metastases:

Lymph Node Only

Liver and Lymph Node

Brain Only

Brain and Liver

Liver Only

Pelvic Only

None

50%

0%

12.5%

12.5%

0%

0%

25%

14.3%

14.3%

14.3%

0%

14.3%

28.6%

14.3%

Medication on Admission:

None

Megestrol Acetate

Tamoxifen

Stilboestrol

25%

25%

37.5%

0%

85.7%

0%

0%

14.3%

Results

Endpoint

Baseline (before the first ≥72 hours of Calcitonin monotherapy)

n= 12-13*

After the first ≥72 hours of Calcitonin Monotherapy

n= 12-13*

Immediately before adding corticosteroid therapy

n= 12-13*

After ≥72 hours of added corticosteroid therapy

n= 12-13*

p-Value

Serum Calcium (within the first 72 hours of Calcitonin monotherapy), mmol/L

Renal tubular calcium reabsorption, TmCa/GFR

*Results presented reflect the complete data available from 12 patients and partial data from 1 patient; the specific subjects that were excluded from the reported results was not disclosed.

The difference in the net bone resorption outcome before addition of corticosteroid vs. after addition of corticosteroid was reported by the study authors to be insignificant. However, the details were otherwise only described via a graph.

There were protocol deviations in subjects 6-10, who received Dexamethasone (12-16 mg daily) instead of the planned prednisolone; the study authors reported this was due to the preference of their physicians, and was beyond their control. However, although the numerical data was not described, the authors reported that there were no systematic differences between any of the results of patients treated with dexamethasone vs. prednisolone.

Adverse Events

Common Adverse Events: Not disclosed

Study Author Conclusions

Patients in the present study were selected either because their hypercalcemia was only partially controlled by calcitonin alone, or because after an initially good response there was evidence that treatment was becoming less effective. Addition of corticosteroids at this stage of declining calcition responsiveness gives a much clearer picture of their mode of action by comparison with previous studies where the combination has been given from the outset. Moreover individual responses to treatment of hypercalcemia vary considerably and the intention of the present study was to make within patient comparisons of the effect of adding corticosteroids to established calcitonin therapy. The present study shows that the decline in the suppressant effect of calcitonin in hypercalcemia associated with malignancy is most consistently due to a reduction in its calciuretic rather than boney effect. This is not unexpected since previous studies have shown that the predominant response to calcitonin in this situation is mediated by kidney rather than bone.

InpharmD Researcher Critique

As this is an older study, the dose of calcitonin used was a flat 25 units q6h, which may be lower for some patients than the currently accepted dose of 4-8 units/kg q6-12h. The body weights of the subjects were not disclosed.

Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia

Design

Randomized study

N= 39

Objective

To compare the effects of aminohydroxypropylidene diphosphonate (APD, pamidronate), mithramycin (plicamycin), and the combination of corticosteroids and calcitonin in the treatment of cancer-associated hypercalcemia

Study Groups

APD (n= 13)

Mithramycin (n= 13)

Corticosteroid/calcitonin (n= 13)

Inclusion Criteria

Patients with cancer-associated hypercalcemia (serum calcium > 2.80 mmol/L) for whom antihypercalcemic therapy was considered an appropriate treatment option

Exclusion Criteria

None reported

Methods

Patients were randomized into one of 3 treatment groups. All patients were rehydrated with intravenous saline (0.9%) 500 mL every 4 hours for ≥48 hours, then 500 mL every 6 hours for 12 hours before being administered their group's specific antihypercalcemic treatment:

APD group patients were given an infusion of 15 mg in 250 mL saline daily until serum calcium was normal (2.60 mmol/L) or nadir was reached.

Mithramycin group patients were administered mithramycin as an infusion of 25 mcg/kg in 500 mL dextrose, repeated after 2 days if serum calcium remained > 2.90 mmol/L.

Corticosteroid group patients received prednisone 40 mg/day orally in divided doses combined with salmon calcitonin 400 IU every 8 hours by subcutaneous injection, continued for 9 days. 

Duration

Intervention: 9 days

Outcome Measures

Baseline Characteristics

Limited patient baseline data was reported. The most common types of cancer were lung (48% of study group) and breast (17% of study group). There was no significant difference between groups regarding types of tumors. Overall serum albumin levels were low, at 30.4 ± 5.8 g/L, and these did not differ between the groups. 

Results

Serum calcium decrease fell significantly on day 1 of corticosteroid/calcitonin and mithramycin groups, and on day 2 in the APD group. The most rapid decrease in serum calcium was reported in the corticosteroid/calcitonin group, with a median decrease on 0.35 mmol/L occurring in 24 hours vs. 48 hours in the mithramycin group and 72 hours in the APD group. APD was observed to have the slowest onset of action, but the most sustained duration of effect; serum calcium levels in the APD group were significantly lower at both 6 and 9 days when compared to corticosteroid/calcitonin patients, and significantly lower at 9 days compared to mithramycin-treated patients. Continued corticosteroid/calcitonin therapy over 9 days did not successfully suppress accelerated bone resorption. 

Symptomatic improvement was reported in 55% (34 of 61) of cases of specific symptoms and 16% (7 of 42) of non-specific symptoms (e.g., malaise, fatigue, bone pain, visceral pain). No significant difference in symptomatic improvement rate was observed between the 3 groups.  

No significant difference was noted between groups for median overall survival time, which was short overall (39 days, range 3-420 days). Only 6 patients survived > 6 months, 3 with APD, 2 with mithramycin, and one with corticosteroids/calcitonin. Each of these patients were administered an additional anticancer therapy that resulted in primary tumor remission. 

Adverse Events

Mithramycin: Two patients reported with nausea, vomiting, and malaise. One patient experienced mild thrombocytopenia. Increased serum aminotransferases and gamma-glutamyl transpeptidase were observed in 11 patients. 

APD: Transient pyrexia was reported in 4 patients. Local thrombophlebitis at the injection site was reported in two patients.

Corticosteroid/calcitonin: No patients reported nausea or vasomotor symptoms; however, many patients did report discomfort with frequent calcitonin injections.  

Study Author Conclusions

APD was most effective in the medium-term control of malignancy-associated hypercalcemia. For rapid control of severe hypercalcemia, however, APD was less suitable because of its slow onset of action. In this situation, calcitonin, mithramycin, or intravenous phosphate may be more appropriate.

InpharmD Researcher Critique

The APD doses compared in this study may be lower than recommended in current clinical practice, and mithramycin has been discontinued in the USA. [2]