Clinical Practice Guidelines for the management of locally advanced ...

with bone pain at study entry. At nine weeks the mean decrease in worst pain score on a 0–10 pain
scale was 0.86 in the pamidronate arm and 0.69 in the placebo group (p=0.58). No significant
difference was seen in the use of radiation for bone pain relief (p=0.88). However a pre-planned
subgroup analysis of men with stable or falling analgesia showed at nine weeks (n=121) a 2.13 unit
decrease in mean worst pain score on a 0–10 scale in the pamidronate group, which was significantly
(p=0.008) larger than the 0.79 unit decrease in the placebo group. Retrospective subgroup analysis for
men with moderate rather than mild baseline pain was reported to show a significant reduction in pain
(p=0.004) at nine weeks.
Ernst et al 2003 35 using a randomised double blind design (n=227) compared clodronate (1500 mg iv
every three weeks) combined with mitoxantrone and prednisone with placebo and mitroxantrone and
prednisone. Similar levels of pain control were noted in both arms; 43% experiencing pain
improvement in the clodronate arm and 38% experiencing pain improvement in the placebo group
(p=0.52). In this study analgesia was considered in determining the pain response. Similar proportions
of men required local radiotherapy with over 12 months follow-up; 16% of men in the clodronate arm
and 14% of the men in the placebo arm (p=0.85). However, in a subgroup analysis of men with
moderate rather than mild baseline pain (n=49), 58% of men receiving clodronate treatment
experienced pain palliation whereas only 26% of men receiving placebo experienced pain palliation
(odds ratio=4.6, 95% CI=1.3 to 15.5, p=0.04).
For completeness and to appreciate the limitations of the remaining studies, a brief outline follows.
Smith 1989 37 examined the effect of sodium etidronate on the control of bone pain in a small (n=28)
double-blind RCT. Men received either sodium etidronate (iv) 7.5 mg/kg/day for three days then
orally 2x200mg/day for one month, or placebo. No significant differences were observed between the
two groups (p=1.00).
Adami and Mian 1989 38 randomised 13 men with radiographic evidence of bone metastases to
treatment with either 300mg of sodium clodronate (iv) daily or placebo for 14 days. It was reported
that pain scores measured using a visual analogue scale and analgesic consumption fell in the treated
group, but the statistical significance of the difference compared with the placebo group was not
reported. In a multi-centre double-blind RCT without any documented chemotherapy, Strang et al
1997 39 treated 55 men with either sodium clodronate 300mg (iv) for three days followed by oral
sodium clodronate at a dose of 3200mg daily or placebo for four weeks. They did not find a
significant improvement in pain scores between groups at 32 days follow up, however their data
suggested that patients with higher initial pain scores (n=20) may have a better response than those
with lower scores. This trial was terminated prematurely because of recruitment difficulties and as a
result numbers may not have been sufficient to show any statistically significant differences in men
with high pain scores.
Elomaa et al 1992 33 and Kylmala et al 1993 40 reported a randomised trial of sodium clodronate
3.2g/day for one month followed by 1.6g/day for a further five months. At one month there was a
reduction in pain from baseline in both the control and the clodronate arms. Although the reduction
was greater in the treated group, with 28% of men no longer experiencing pain compared with 15% of
men in the control arm, the difference was not statistically significant (p=0.26). The probable
explanation for this finding (ie pain relief without clodronate in the control group) was that both
groups were started on estramustine phosphate 2x280mg per day at the same time as the clodronate.
The symptomatic improvement in the control group was almost certainly due to the effect of the
extramustine, thus rendering it difficult to determine the true effect of clodronate.
Kylmala et al 1997 34 reported the results of a similar double-blind placebo controlled trial. Fifty-seven
men, most of whom had painful bone metastases, began estramustine therapy and were randomised to
either clodronate (iv) 300mg a day for five days and then oral clodronate 1.6g/day for 12 months, or
placebo. Again, no significant difference was found between the groups, with mean pain scores in the
treatment group not significantly improved from those in the control group over the 12 months.
81
Castration-resistant prostate cancer