Evidence Based Clinical Guidelines

Warr, Johnston & Breast Cancer Disease Site Group . Use of bisphosphonates in women with breast cancer: practice guideline report #1–11 (Version 2.2002). 2004. Cancer Care Ontario Program. Program in Evidence-based Care (A Cancer Care Ontario Program).
Design: Guideline (prognosis),
Grade :1++
Country: Canada (federal state, Commonwealth Realm)
Inclusion criteria:
Included studies:
Women with bone metastases due to breast cancer (it was not apparent whether or not patients may have had other metastatic disease or if any had solitary bone metastasis).
Exclusion criteria:
None stated
Population:
Women with bone metastases due to breast cancer
Interventions:
Any bisphosphonate compared with other bisphosphonate, placebo or no treatment. Different doses or routes of administration of any bisphosphonate.

Clodronate (iv or oral), pamidronate (iv or oral), ibandronate (iv or oral) and iv zoledronate were used in the included studies.
Outcomes:
Included studies reported on at least one of the following:
survival, quality of life, adverse events, bone pain (measured by pain scales and/or analgesia use) and skeletal related events (excluding hypercalcaemia).
Results:
See Use of Bisphosphonates in Women with Breast Cancer. Practice Guideline Report #1–11 (Version 2.2002)
D Warr, M Johnston, and members of the Breast Cancer Disease Site Group:
http://www​.cancercare​.on.ca/pdf/pebc1-11f.pdf
General comments:
This guideline was originally written in 1998 and was updated in 2002 and 2004. Three patient groups were reviewed of which only the evidence for women with MBC and bone metastases is included here.

The 2002 literature search found the following relevant articles and abstracts, which are summarized in the practice-guideline report: 2 evidence-based practice guidelines from other guideline-development groups (ASCO and SIGN), 1 Cochrane systematic review with meta- analysis, published in 2002 (Pavlakis et al. 2002) and 28 RCTs, only 9 of which were not included in the Cochrane review.

The 2004 search found 1 update to the ASCO guideline, 1 RCT updating an abstract included in the Cochrane review, 1 RCT updating an abstract in the original guideline and the results from a study, presented in two abstracts at the 2003 San Antonio Breast Cancer Symposium, which pooled data from three RCTs to compare IV and oral ibandronate with placebo.
Evidence summary:
Oral clodronate and intravenous (iv) pamidronate significantly reduced skeletal events and pain in women with breast cancer metastatic to bone. The review of the evidence did not specify in detail results about preventing MSCC, although an outcome in at least 2 individual studies, it was not reported as an individual result. The closest result was the rate of SREs.

Direct comparisons found 4mg zoledronate equivalent to 90mg pamidronate given iv every 3 to 4 weeks.

Bisphosphonates did not improve survival but did reduce skeletal events and pain in women with breast cancer metastatic to bone. There was no significant difference in adverse effects between those receiving bisphosphonates and controls.

This guideline was appraised using the AGREE tool and found to be of high standard.

UPDATE NOTE
In 2005 the Cochrane Review (Pavlakis 2002) was updated; additional studies to both this Warr 2004 Review and Pavlakis 2002 are: Body et al 2004 and Kohno 2005.

Findings from Body 2004:
When 50mg oral ibandrontate was compared to placebo in women with advanced breast cancer the mean bone-pain scores at study endpoint showed a significant reduction in favour of 50 mg oral ibandronate.

A significant improvement in global quality of life was reported in patients 50 mg oral ibandronate (P = 0.032).

The incidence of renal adverse events was low and comparable between treatment and placebo arms. The proportion of patients reporting and adverse event was generally low (and included dyspepsia, nausea, oesophagitis and hypocalcamia)

Findings from Kohno 2005:
This study evaluated zolendronate versus placebo in Japanese women with stage IV breast cancer.

This study provides the only available data on the effect of stage IV disease zolendronate on incidence of skeletal events compared with placebo. Results showed that zolendronate statistcally reduces the risk of a skeletal event compared to placebo (RR = 0.59, 95% CI 0.42 to 0.82). The study also showed that the median time to first skeletal event was not reached in the zolendronate arm, versus 364 days in the placebo arm; p = 0.007.

From a Brief Pain Inventory, there was a statistically significant reduction with zolendronate.

There was a higher incidence of grade I hypocalcaemia with zolendronate. There was no evidence of decreased renal function in the zolendronate treated patients.

References included in this Guideline:

Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE, Morley W, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001;91:1191-200

Body J-J, Diel IJ, Lichinitser MR, Kreuser ED, Dornoff W, Gorbunova VA, et al. Intravenous ibandronate reduces the incidence of skeletal complications in paients with breast cancer and bone metastases. Ann Oncol;14:1399-1405.

Body JJ, Lichinitser MR, Diehl I, Schlosser K, Pfarr E, Cavalli F, et al. Double-blind placebocontrolled trial of intravenous ibandronate in breast cancer metastatic to bone (abstract). Proc Am Soc Clin Oncol 1999;18:575a.

Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, et al.Oral ibandronate reduces the risk of skeletal complications in breat cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. British Journal of Cancer 2004;90:1133–1137.

Coleman RE, Purohit OP, Vinholes JJ, Zerki J. High-dose pamidronate. Clinical and biochemical effects in metastatic bone disease. Cancer 1997;80:1686-90.

Conte PF, Latreille J, Mauriac L, Calabresi F, Santos R, Campos D, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: Results from a multinational randomized controlled trial. J Clin Oncol 1996;14:2552-9.

Diel, IJ, Marschner, N, Kindler, M, Lange, O, Untch, M, Hurtz, et al. Continual oral versus intravenous therapy with bisphosphonates in patients with breast cancer and bone metastases (abstract). Proc Am Soc Clin Oncol 1999;18:128a.

Elomaa I, Blomqvist C, Porkka L, Holmstrom T, Taube T, Lamberg-Allardt C, et al. Clodronate for osteolytic metastases due to breast cancer. Biomed & Pharmacother 1988;42:111-6.

Ernst DS, MacDonald RN, Paterson AHG, Jensen J, Brasher P, Bruera E. A double blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992;7:4-11.

Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16:2038-44.

Hultborn R, Gundersen S, Ryden S, Holmberg E, Carstensen J, Wallgren UB, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebocontrolled multicenter study. Anticancer Res 1999;19:3383-92.

Kohno N, Aogi K, Minami H, Nakamura S, Asaga T, Iino Y, Watanabe T, Goessl C, Ohashi Y, Takashima S. Zolendronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, Placebo-controlled Trial. Journal of ClinicalOncology 2005; 23(15):3314–21.

Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H, Mouridsen HT. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999;246:67-74.

Martoni A, Guaraldi M, Camera P, Biagi R, Marri S, Beghe F, et al. Controlled clinical study on the use of dichloromethylene diphosphate in patients with breast carcinoma metastasizing to the skeleton. Oncology 1991;48:97-101.

O’Rourke N, McCloskey E, Houghton F, Huss H, Kanis JA. Double-blind, placebo-controlled, dose-response trial of oral clodronate in patients with bone metastases. J Clin Oncol 1995;13:929-34.

Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59-65.

Pavlakis N, Schmidt RL, Stockler M. Bisphosphonates for breast cancer. Cochrane Database of Systematic Reviews 2002 (Issue 1) and 2005, Issue 3. Art. No.: CD003474. DOI: 10.1002/14651858.CD003474.pub2.

Robertson AG, Reed NS, Ralston SH. Effect of oral clodronate on metastatic bone pain: A double-blind, placebo-controlled study. J Clin Oncol 1995;13:2427-30.

Rosen L, Gordon D, Dugan W, Major P, Eisenberg P, Provencher L, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43.

Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377-87.

Rosen LS, Gordon D, Kaminsky M, Howell A, Belch A, Mackey J, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735-44.

Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846-54.

Tripathy D, Lazarev A, Lichinitser MR, Decker D, McLachlan SA, Budde M. Oral ibandronate lowers the incidence of skeletal complications in breast cancer patients with bone metastases (abstract). Proc Am Soc Clin Oncol 2002;21:Abstract #176.

Tubiana-Hulin M, Beuzeboc P, Mauriac L, Barbet N, Frenay M, Monnier A, et al. Doubleblinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bull Cancer 2001;88:701-7.

van Holten-Verzantvoort AT, Kroon HM, Bijvoet OL, Cleton FJ, Beex LV, Blijham G, et al. Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:491-8.
Saad F, Gleason DM, Murray R. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 94: 1458–68 2002;94(No 19):1458–1468.
This paper was included in the Yuen et al Cochrane Review and the summary of findings have been lifted from this review and copied below:
AIM: To evaluate the effectiveness and safety of zoledronic acid (ZA) in terms of reducing skeletal-related events associated with metastatic bone disease men with hormone- refractory prostate cancer.
METHODS:
  • Randomized double blind placebo-controlled study.
  • 3 arm study: 2 active arms, 1 placebo arm.
  • Quality score (2/2/1) – means high methodological quality: randomisation; blinding and attrition rate. Allocation concealment was not used
  • Primary outcome: skeletal-related event (pathologic fracture, spinal cord compression, change in anti-neoplastic
  • therapy for bone pain, bone surgery or radiotherapy).
  • Secondary outcomes: time to first skeletal-related event, skeletal morbidity rate, proportion of patients with skeletal-related events, time to disease progression, bone lesion response, bone biochemical markers, quality of life parameters.
  • Pain assessment: Brief Pain Inventory pain score
  • Analgesic assessment: analgesic score 0–4
  • Pain assessment schedule: 3,6,9,12,15 months
PARTICIPANTS: INTERVENTIONS:
Active arm 1: zoledronic acid 4mg, 214 patients
Active arm 2: zoledronic acid 8mg, 221 patients
Control arm: placebo q3w × 20 cycles (15 months), 208 patients..
Ca supplement and vit D.
OUTCOMES:
  • Pain score, mean change (95%
  • control 0.42 (0.22)
  • Analgesic score: No statistically significant difference (scores not included).
  • Patients having skeletal-related events: active1 71/214, active2 85/221, control 92/208, pathologic fractures 28/214 33/221 46/208, vertebral fractures 8/214, 8/221, 17/208, non- vertebral fractures 22/214, 22/221, 33/208, bone radiotherapy 49/214 53/221 61/208, bone surgery 5/214 6/221 7/208, spinal cord compression 9/214, 11/221, 14/208.
Saad 2002 definition of “skeletal related events” and this included pathologic fracture, spinal cord compression, surgery to bone, radiation therapy to bone or a change of antineoplastic therapy to treat bone pain.
  • Time to first skeletal-related event: active1 but not active2 is significantly longer than control.
  • Patients with radiological bone response: active1 56/214 (CR0,PR9,SD47), active2 52/221
  • (CR0,PR6,SD46), control 43/208 (CR0,PR8,SD35)
  • Patients with adverse events: bone pain (active1 108/214, active2 133/218, placebo 127/208), nausea (active1
  • 77/214, active2 115/218, placebo 77/208), constipation, fatigue, anaemia (active1 57/214, active2 60/218,
  • placebo 37/208), myalgia, vomiting (active1 46/214, active2 115/218 placebo 43/208), weakness, anorexia,
  • fever, lower limb oedema, dizziness, diarrhoea, weight increase.
  • ECOG performance scores, FACT-G QoL and EURO-QOL scores: No statistically significant difference.
  • Median time to cancer progression = 84 days in all treatment groups.
  • PSA, percent change from baseline, no statistically significant difference.
  • Median survival (days) (active1, active2, placebo): 546, 407, 464 p = 0.091 (active1 vs placebo), p = 0.386 (active2 vs placebo).
RESULTS: see Yuen review plus below
Skeletal-Related Events
  • At least one skeletal-related event occurred in:
    92 (44.2%) patients who received placebo and
    71 (33.2%) patients who received zoledronic acid at 4 mg (difference= −11.0%, 95% CI − 20.3% to −1.8%; P=0.021)
  • At least one skeletal-related event occurred in:
    85 (38.5%) patients who received zoledronic acid at 8/4 mg (difference= −5.8%, 95% CI − 15.1% to 3.6%, P=0.222 versus placebo).
  • Compared with patients who received the placebo, fewer patients who received zoledronic acid at 8/4 mg (22.1% versus 14.9%, P=0.054 – not significant) and statistically significantly fewer patients who received zoledronic acid at 4 mg experienced a fracture (22.1% versus 13.1%, P=0.015).
  • Compared with patients who received the placebo, fewer patients who received Zoledronic acid at 8/4 mg (29.9% versus 34.6%, P=0.300 – not significant) and statistically significantly fewer patients who received 4 mg ZA (25.7%, P=0.048 versus placebo) experienced any skeletal-related event other than fracture.
  • Individual non-fracture skeletal-related events (radiation therapy to bone, surgery to bone, and spinal cord compression) occurred less frequently in patients who received either dose of zoledronic acid than in those who received placebo. This was not the case for changes in antineoplastic treatment
  • Two additional efficacy variables associated with skeletal related events were assessed: The difference in the time to the first occurrence of any skeletal-related event between patients who received zoledronic acid at 4 mg and those who received placebo was statistically significant (P = 0.011).
Kaplan–Meier estimates of event rates for time to the first on-study skeletal-related event for all intent-to-treat patients with metastatic prostate cancer randomly assigned to receive zoledronic acid at 4 mg, zoledronic acid at 8/4 mg, or placebo.
Percentage of patients (95% confidence interval [CI]) without a skeletal-related event: At 90 days: zoledronic acid at 4 mg, 90.9% (95% CI 86.8% to 94.9%); zoledronic acid at 8/4 mg, 83.3% (95% CI78.2% to 88.4%); placebo, 83.5% (95% CI78.4% to 88.7%); at 270 days: Zoledronic acid at 4 mg, 70.0% (95% CI 63.0% to 76.9%); zoledronic acid at 8/4 mg, 58.0% (95% CI 50.5% to 65.6%); placebo, 57.3% (95% CI 49.7% to 64.8%); at 450 days: zoledronic acid at 4 mg, 55.1% (95% CI 46.9% to 63.4%); zoledronic acid at 8/4 mg, 46.8% (95% CI 38.2% to 55.4%); placebo, 42.8% (95% CI 34.4% to 51.2%). At the last study evaluation (450 days), P=0.011 for ZA at 4 mg versus placebo (indicating a significant finding) and P=0.491 (not significant) for zoledronic acid at 8/4 mg versus placebo.
  • The time to the first skeletal-related event was not reached for patients who received 4 mg ZA and therefore, considered as at least 420 days (based on the fact that the estimated event rate was <50% at day 420, the end of treatment), whereas the median time to the first skeletal-related event was 321 days for patients who received placebo.
  • The median time to the first skeletal-related event for patients who received 8mg ZA = 363 days, not statistically significantly different from that of patients who received placebo (P = 0.491).
  • The mean skeletal morbidity rates for all skeletal-related events combined and for each individual type of skeletal-related event were lower for patients who received 4 mg ZA or at 8/4 mg than for those who received the placebo, with the exception of changes in antineoplastic therapy, which occurred more frequently for those who received 8/4 mg ZA at than for those in the other groups. (no significant difference observed)
Pain:
  • Mean pain scores (range 0–10) increased from baseline in all three groups at every 3- month interval, with one exception at 3 months where the ZA groups had a slight decrease from baseline.
    The mean increase from baseline in pain score at 15 months was:
    0.88 (95% CI .61 to 1.15) for patients who received the placebo compared with 0.58 (95% CI 0.29 to 0.87) for patients who received zoledronic acid at 4 mg (P=0.134 versus placebo) and 0.43 (95% CI 0.16 to 0.70) for patients who received zoledronic acid at 8/4 mg (P=0.026 versus placebo).
  • Analgesic scores (range 0–4) were also increased slightly more from baseline at every time point for patients who received the placebo than for patients who received either dose of ZA.
    The differences in analgesic scores were not statistically significant.
QoL: The mean ECOG performance scores increased from baseline to the last measurement, with no statistically significant difference among the three groups. The total FACT-G quality-of-life and the EURO-QOL scores decreased from baseline to the last measurement, with no statistically significant differences among the three groups.
Adverse events: The most common adverse events that occurred during the trial were Fatigue, anemia, myalgia, fever, and lower-limb edema which occurred in at least 5% more patients in both of the ZA groups than in the placebo group.
Rosen et al. (2003) Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumours. JCO; 21 No 16 p.3150–3157.
Design: RCT, Evidence level 1+
Country: International

Aim: To investigate the effectiveness of zoledronic acid (ZA) in the treatment of patients with bone metastases secondary to solid tumors other than breast or prostate cancer.
Inclusion criteria
Exclusion criteria
Population
773 patients with osteolytic, osteoblastic, or mixed bone metastases from solid tumors other than breast or prostate cancer were enrolled in the study.

257 patients received 4 mg zoledronic acid – 68 patients completed study
266 patients to received 8/4 mg zoledronic acid – 65 patients completed study
250 patients to received placebo – 63 patients completed study

The main reason for discontinuation was death followed by adverse event and patient withdrawing consent. Discontinuation rates were similar between the treatment groups
Interventions
Patients were randomly assigned in a double-blind method to receive:
zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months.
  • Initially, patients received zoledronic acid via 5-minute infusion in 50 mL of infusate; however, due to concerns over renal safety, a protocol amendment changed the infusion time to 15 minutes and increased the volume of the infusion to 100 mL (195 patients were accrued before this amendment).
  • A subsequent amendment to the protocol was implemented because of concerns over decreased renal tolerability at the higher dose level, required patients originally randomly assigned to receive 8 mg zoledronic acid to instead receive 4 mg zoledronic acid; this arm is referred to as the 8/4-mg arm.
  • All patients were accrued before this amendment, and 198 patients (75%) in the 8/4-mg group had completed or discontinued study treatment and received only the 8-mg dose; however, 67 patients (25%) were still receiving treatment and were switched to the lower dose.
Outcomes
For all efficacy variables analyzed, comparisons of 4 mg zoledronic acid versus placebo were used to assess the effectiveness of zoledronic acid.
The proportion of patients with at least one SRE during the 9 months on study. (Skeletal-related events included pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone.)

Secondary efficacy analyses of SREs included time to first SRE, the skeletal morbidity rate (defined as the number of SREs per year), and a multiple event analysis.

Other secondary outcomes included:
change from baseline in BPI composite pain score,
analgesic use,
ECOG performance status,
best bone lesion response,
time to progression of bone lesions,
changes from baseline in biochemical markers of bone resorption,
time to progression of overall disease,
survival.
Quality of life (using the Function Assessment of Cancer Therapy – General (FACT-G) instrument

Note on reported results:
  • Andersen-Gill multiple event analysis accounts for all complications and for the timing of complications to provide a sensitive and comprehensive assessment of cumulative skeletal morbidity.
  • The hazard ratio represents the risk of experiencing a skeletal complication relative to a comparator or placebo; a hazard ratio < 1 indicates decreased risk.
Results
SREs
  • There was no statistically significant difference in SREs (which excluded hypercalcemia of malignancy - HCM), between 4 mg zoledronic acid versus placebo (38% v 44%; P =0.127)
  • There was statistically significant for the comparison of 8/4 mg zoledronic acid versus placebo (35% v 44%; P=0 .023).
  • In the analysis of all skeletal events (including HCM), 4 mg ZA significantly reduced the proportion of patients with an event as compared with the placebo group (38% v 47%; P=0.039).
  • 35% of patients treated with 8/4 mg ZA had an event (P=0.006 compared with the placebo group).
  • The most common SREs were radiation to bone and pathologic fracture.
  • A treatment benefit was observed across all event types; in particular, no patients treated with 4 mg ZA developed HCM compared with 8 patients (3%) in the placebo group (P=0.004).
  • Compared with the placebo group, patients in the 8/4-mg group experienced significant decreases in HCM (P=0.044), pathologic fracture (P=0.003), and vertebral fracture (P=0.004).
  • WRT spinal cord compression event: 3% in 4 mg ZA; 3% in 8/4 mg ZA; 4% in the placebo group. (No stats provided –see table 3 from paper)
  • ZA significantly extended the median time to first SRE by more than 2 months compared with placebo
  • Median time to first SRE (excluding HCM) was statistically significant different: 230 days for 4 mg zoledronic acid versus 163 days for placebo (P =0.023);
  • Median time to first SRE (including HCM) was calculated but I have not reported it here as HCM was thought not to be relevant to MSCC.
  • A multivariate analysis adjusting for previous SRE experience showed that this comparison remained statistically significant (P=0.028).
  • The median time to first event was not reached for individual SREs. However, the time to first pathologic fracture was significantly longer in patients treated with 4 mg zoledronic acid compared with the placebo group (first quartile, 238 v 161 days; P=0.031).
  • The time to first vertebral fracture and the time to first radiation therapy were significantly longer (P=0.05) in the 4-mg group.
  • Patient survival in this study was short (approximately 6 months), time to first SRE was also reported including death as an event. Results were similar as reported earlier: for patients treated with 4 mg zoledronic acid, the median time to first event (excluding HCM, including death) was 136 days versus 93 days for the placebo group (P=0.039).
  • For each analysis, event rates were similar in the 4-mg and 8/4-mg groups.
  • The skeletal morbidity rate for all events (SREs excluding HCM) was lower among patients treated with either 4 mg zoledronic acid (mean ± SD, 2.24 ± 9.12; P=0.069) or 8/4 mg zoledronic acid (mean ± SD, 1.55 ± 3.8; P=0.005) compared with the placebo group (mean SD, 2.52 ± 5.11).
  • The skeletal morbidity rate (the number of events per year; including HCM) was significantly lower among patients treated with either 4 mg zoledronic acid (mean ± SD, 2.24 ± 9.12; P=0.017) or 8/4 mg zoledronic acid (mean ± SD, 1.59 ± 3.8; P=0.001) compared with the placebo group (mean ± SD, 2.73 ± 5.29).
  • The skeletal morbidity rate for each type of SRE was lower in the Zoledronic acid treatment groups compared with the placebo group except for surgery to bone and spinal cord compression.
  • A multiple event analysis (using the Andersen-Gill approach) showed a significant 27% risk reduction for multiple skeletal events, in favour of 4 mg zoledronic acid (hazard ratio =0.732; P=0.017), among patients in both the NSCLC cancer and other solid tumour group, versus the placebo group
  • The results were similar when HCM was included in the analysis.
Sub-group analysis:
NOTE: This trial was powered for the primary end point, and so subset analyses were not expected to detect statistically significant differences. The authors however did go onto conduct subgroup analyses for the NSCLC and other solid tumour patient groups.
  • The proportion of patients with an SRE was not significantly different for patients in the NSCLC group treated with 4 mg zoledronic acid versus placebo (42% v 45%; P=0.557);
  • There was no significance for time to first event (median 171 v 151 days; P=0.188) for patients treated with 4 mg zoledronic acid.
  • In the other solid tumour group: 4 mg zoledronic acid reduced the proportion of patients with an SRE (33% v 43%; P=0.110, not significantly different) and extended the time to first event (median, 314 v 168 days; P=0.051, not significant) compared with placebo.
Bone Lesion Response and Time to Progression of Bone Lesions
  • Analysis of best radiographic bone lesion response at month 9 showed a partial response in 8% of patients treated with 4 mg ZA versus 4% of placebo-treated patients.
  • Bone lesions progressed in 33% with 4 mg ZA and 36% of patients treated with placebo.
  • The time to progression of bone lesions was longer in patients treated with 4 mg ZA (median, 145 days; P=0.340) and in patients treated with 8/4 mg zoledronic acid (median, 238 days; P=0.009) compared with the placebo group (median, 109 days).
Other Outcomes:
Pain:
  • The mean BPI composite pain score increased slightly from baseline to month 9 for all three treatment groups,
  • indicating increases in pain.
  • The mean composite pain score decreased among patients in the 4-mg zoledronic acid group who had pain at baseline.
Analgesic use: ECOG performance status:
  • Mean analgesic score and ECOG performance status increased from baseline to month 9 for all three treatment groups, indicating increases in analgesic use and decreases in functional capacity due to progressive disease.
QoL:
  • There were no statistically significant differences between zoledronic acid and placebo with respect to any of these global quality-of-life outcomes.
  • Changes in FACT-G scores were also comparable between treatment groups.
Time to Disease Progression and Overall Survival:
  • The median time to overall disease progression was 89 days in patients treated with 4 mg zoledronic acid, compared with 84 days in patients treated with placebo (P=0.117, no significant difference).
  • The median time to death was the same in both treatment groups: median of 203 days for ZA treated patients, compared with 183 days for the placebo group (P=0.623).
Safety:
  • The most commonly reported adverse events (all grades) in all treatment groups were bone pain, nausea, anemia, vomiting, constipation, dyspnea, and fatigue
  • The proportion of patients having nausea (46%), vomiting (36%), and dyspnea (33%) was higher in the 4-mg zoledronic acid treatment group compared with the placebo group (34%, 29% and 26% respectively).
  • The proportion of patients experiencing bone pain, was higher in the placebo group (59%) compared with either ZA treatment group (51% 4 mg ZA and 49% 8mg ZA group).
  • Serious adverse events affected similar proportions of patients in all treatment groups.
  • The most frequently reported serious adverse events, regardless of drug group, were anemia, dehydration, aggravated malignant neoplasm, and dyspnea, and these were similar across the treatment groups.
  • Before the implementation of the 15-minute infusion amendment, the proportion of patients with decreased renal function was substantially higher in the zoledronic acid treatment groups compared with the placebo group (hazard ratio = 3.8). After the implementation of the 15-minute infusion-time amendment, the proportion of patients with decreased renal function was no significant difference between the 4-mg zoledronic acid and placebo groups (10.9% v 6.7%).
General comments
  • Randomisation, blinding and power calculations were conducted which reduced the level of bias that could influence the result.
  • Intention to treat analysis is mentioned
  • No Follow up reported.
  • QUESTION: Is HCM relevant to MSCC?
Rosen et al. (2004) Long-term efficacy and safety of zoledronic acid for the treatment of skeletal metastases in patients with Non small cell Lung carcinoma and other solid tumours. Cancer; p.2613–2621.
Design: RCT, Evidence level 1+

Aim: To report the long-term efficacy and safety results of the above trial (Rosen et al 2003) trial after 21 months of continued therapy in patients with advanced carcinoma of the lung and other solid tumors.
Inclusion criteria
See above
Exclusion criteria
See above
Population
  • Of the 773 patients enrolled, 196 patients completed the 9-month core phase (see Rosen 2003 above) and 101 patients elected to continue in the extension phase of treatment.
  • Approximately 25% of these patients in the extension phase (n=26) completed 21 months of treatment
  • Discontinuation rates were similar between the treatment groups; death and adverse events were the most commonly reported reasons for discontinuation of therapy.
Interventions
See above
Outcomes
  • The primary efficacy analysis was the percentage of patients with ≥1 SRE at 21 months. [SREs included pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone.]
  • Secondary outcomes:
    Time to first SRE, the annual incidence of SREs (also known as the skeletal morbidity rate), and multiple-event analysis.
    [The multiple event analysis is a comprehensive analysis that considers not only the number of events but also the time it takes to develop the first and subsequent events, thereby providing an overall estimate of the clinical impact of the skeletal complications.]
    Time to first SRE, time to progression of bone metastases, time to overall disease progression, and overall survival were compared between treatment groups using the Kaplan-Meier method and the logrank test.
  • QoL
  • Safety
Results
SREs:
Efficacy analyses are based on a comparison of a dose of 4 mg of zoledronic acid versus placebo.
  • No statistical significant difference between 4 mg of ZA versus placebo when HCM (hypercalcemia of malignancy) was excluded (39% vs. 46%; P=0.127) in terms of the proportion of patients with an SRE at 21 months (as reported, after 9 months of treatment, Rosen 2003)
  • 4% of patients in the placebo group developed HCM, compared with no patients in the 4-mg zoledronic acid group. Consequently, when HCM was counted as an SRE, the 4-mg zoledronic acid dose was found to significantly reduce the proportion of patients with an SRE compared with placebo (39% vs.48%; P=0.039).
  • Treatment with ZA consistently reduced all types of skeletal complications.
  • Radiation to bone was the most common type of SRE in all treatment groups, followed by pathologic fractures
  • Spinal cord compression was reported: 3% of patients given 4 mg ZA; 3% in 8/4 mg ZA and 4% in placebo group (see table 2 from paper)
  • Treatment with 4 mg of zoledronic acid delayed the onset of skeletal complications, significantly extending the median time to first SRE (including HCM) by >2 months (median, 236 days for 4 mg of zoledronic acid vs. 155 days for placebo; P=0.009).
  • ZA (4 mg) significantly extended the time to first pathologic fracture compared with placebo (25% quartile =294 days for the 4-mg zoledronic acid dose vs. 161 days for placebo; P=0.020)
  • The annual incidence of skeletal complications is expressed as the number of SREs divided by time on study. Patients in 4 mg ZA group were reported to have a 36% lower annual incidence of SREs (including HCM) compared with patients treated with placebo (mean of 1.74 SREs per year for the 4-mg ZA dose vs. mean of 2.71 SREs per year for placebo; P=0.012).
  • Patients treated with the 8/4-mg ZA dose had a mean of 1.56 SREs per year (P=0.001 vs. placebo).
NOTE:
Multiple-event analysis accounts both for the absolute number of SREs and for the timing between them to provide a more sensitive assessment of the risk of skeletal complications between the two treatment groups.
  • The hazard ratio for the 4-mg ZA dose versus placebo = 0.693 (95% CI, 0.542–0.886; P=0.003), indicating a 31% reduction in the risk of developing an SRE (including HCM) for a patient treated with 4 mg of ZA compared with placebo. (These results were consistent with Rosen 2003).
Other outcomes:
QoL:
  • Mean ECOG scores increased from baseline in all treatment groups (in which an increased ECOG score indicates worsening performance status); however a “trend” toward a smaller increase in ECOG scores at the end of the study for the 4-mg dose of ZA versus placebo was reported by authors.
  • At 21 months, the mean increase in the ECOG performance status was 0.99 ± 1.20 for the 4-mg ZA dose and 1.20 ± 1.22 for placebo (P= 0.080 not significantly different).
Safety:
ZA at dose of 4 mg was found to be safe and well tolerated with long-term administration. The most commonly reported adverse events in all treatment groups were bone pain, nausea, anaemia, emesis, constipation, and dyspnoea.
General comments

From: Chapter 6, Treatment Selection and Strategies

Cover of Metastatic Spinal Cord Compression
Metastatic Spinal Cord Compression: Diagnosis and Management of Patients at Risk of or with Metastatic Spinal Cord Compression.
NICE Clinical Guidelines, No. 75.
National Collaborating Centre for Cancer (UK).
Copyright © 2008, National Collaborating Centre for Cancer.

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