Bone Metastases In Renal Cell Carcinoma: What Can Be Done

1
Bone Metastases In Renal Cell Carcinoma What Can
Be Done?

• Fred Saad, MD, FRCS
• Director of Urologic Oncology
• Professor of Surgery/Urology
• U of M Chair in Prostate Cancer
• University of Montreal

2
Renal Cell Cancer Background

• More than 100,000 deaths per year worldwide
• Incidence steadily increasing over the past 3
  decades
• Many patients with renal cell cancer will develop
  bone metastases

Ries et al. SEER Cancer Statistics. At
http//seer.cancer.gov/csr/1973_1999/. Accessed
2002. Zekri et al. Int J Oncol. 200119379.
3
Bone Metastases in Renal Cell Cancer

• The skeletal morbidity rate among patients with
  renal cell cancer during the first year was
  similar to that observed in patients with breast
  cancer and multiple myeloma (2.5 - 4.0
  SREs/patient/year)
• Bone metastases rarely respond to immune based
  therapy
• Median survival of patients with bone mets 12
  months

Zekri et al. Int J Oncol. 200119379.
4
Renal Cell Cancer Radiologic Appearance of Bone
Lesions
Among patients with bone lesions, the majority
were osteolytic
Zekri et al. Int J Oncol. 200119379.
5
Renal Cell Cancer Distribution of Bone
Metastases
No. of Patients ()Site (n31)

• Pelvis 15 (48)
• Ribs 15 (48)
• Spine 13 (42)
• Femora 7 (23)
• Humeri 3 (10)
• Skull 3 (10)
• Clavicle 2 (6)
• Ulna 1 (3)
• Tibia 1 (3)

Zekri et al. Int J Oncol. 200119379.
6
Renal Cell Cancer Skeletal-Related Events

• No. of patients () No. of
• SRE (N31) events
• Radiotherapy 25 (81) 37
• Long-bone fractures 13 (42) 15
• Hypercalcemia 9 (29) 16
• Orthopedic surgery 9 (29) 12
• Spinal cord compression 4 (13) 4

An additional 32 patients developed
hypercalcemia without evidence of metastatic bone
disease on imaging tests. Criteria for
hypercalcemia not defined. Zekri et al. Int J
Oncol. 200119379.
7
Zoledronic Acid inPatients With Renal Cell
Carcinoma and Bone Metastases

• Long-Term Analysis (21 Months)

8
Zoledronic Acid in Solid Tumors Trial Design
R A N DO M I Z E D
n257
Zoledronic acid 4 mg q3wk
n250
Placebo q3wk
0
9 monthsCore analysis
21 months Final analysis
9
Efficacy Analysis

• Primary efficacy end point
• Proportion of patients experiencing 1 SRE
• Pathologic bone fracture
• Radiation therapy to bone
• Spinal cord compression
• Surgery to bone
• Secondary efficacy end points
• Time to first SRE
• Skeletal morbidity rate
• Time to progression of bone metastases

SRE skeletal-related event HCM hypercalcemia
of malignancy.
10
Tumor Types
Tumor Type No. of Patients ()

• NSCLC 378 (49)
• Renal cell carcinoma 74 (10)
• Small cell lung cancer 58 (8)
• Colon/rectal/intestinal 55 (7)
• Cancer unknown primary 51 (7)
• Bladder 32 (4)
• Esophagus/gastroesophageal 17 (2)
• Head and neck 17 (2)
• Melanoma 16 (2)
• Thyroid 11 (1)
• Other tumor types (n11) 57 (7)

Zoledronic acid 4-mg group and placebo
(n46). Rosen et al. J Clin Oncol. 2003213150.
11
Proportion of Patients With Any SRE
Zoledronic acid significantly reduces the
proportion of RCC patients with an SRE
P0.011
100
79
80
60
RCC patients with any SRE ()
41
40
20
0
Zol 4 mg
Placebo
(n27) (n19)
12
Time to First Skeletal-Related Event
Zoledronic acid significantly extends the time
to first SRE
Median No. of Days P Value Zol 4
mg 424 0.006 Placebo 72
Zol 4 mg 27 12 7 4 2 1 Placebo 19 4 1 1 0 0
After start of study drug.
13
Percent of Patients With Each SRE
Zoledronic acid consistently reduces all types of
SREs
14
Time to Progression of Bone Lesions
Zoledronic acid significantly extends the time to
disease progression
Median No. of Days P Value Zol 4
mg 586 0.014 Placebo 89
Zol 4 mg 27 13 7 3 2 0 Placebo 19 3 0 0 0 0
After start of study drug.
15
Time to First Pathologic Fracture
Zoledronic acid significantly extends time to
first pathologic fracture
100
Median No. of Days P Value Zol NR 0.003 Placeb
o 168
80
60
RCC patients without
pathologic fracture ()
40
20
0
0
120
240
360
480
600

Days
Zol 4 mg 27 17 9 5 4 2 Placebo 19 6 1 1 1 1
After start of study drug.
16
Survival
Median No. of days P Value Zol 4
mg 347 0.104 Placebo 216
Zol 4 mg 27 23 15 11 8 2 Placebo 19 14 8 5 2 1
After start of study drug.
17
Andersen-Gill Multiple Event Analysis
58 reduction in the risk of developing an SRE
for patients receiving zoledronic acid compared
with placebo
HazardRatio
RiskReduction
P Value
0.69
Lung and other solid tumors
0.003
31
0.42
Renal cell cancer
0.010
58
0.8
0
0.2
0.4
0.6
1
1.2
1.8
1.4
1.6
2
Relative risk
In favor of zoledronic acid
In favor of placebo
18
Most Frequent Renal-Related Adverse Events
No. of Patients ()
Zol 4 mg Placebo (n27) (n19)

• Hematuria 2 (11.1) 1
  (6.7)
• Blood creat increased 0 (0.0) 0 (0.0)
• Hyperuricemia 1 (5.6) 0 (0.0)
• Renal failure 1 (5.6) 0 (0.0)
• Difficulty in micturition 0 (0.0) 1 (6.7)
• Oliguria 0 (0.0) 1 (6.7)
• Total 4 (22.2)
  3 (20.0)

Post 15-minute infusion Safety-evaluable
population gt0.5 mg/dL if baseline lt1.4 mg/dL
gt1.0 mg/dL if baseline gt1.4 mg/dL.
19
Zoledronic Acid in Patients With Renal Cancer
Clinical Summary

• Significantly reduced the proportion of patients
  with an SRE
• Significantly decreased mean skeletal morbidity
  rate of all SREs
• Extended time to first SRE and time to first
  fracture
• Significantly increased median time to
  progression of bone lesions
• Was safe and well tolerated

20
Bone Metastatic Renal Cell Carcinoma Conclusions

• New treatment options now available for
  metastatic RCC increase survival and may increase
  the time patients are at risk for bone
  comlications
• Zoledronic acid can be considered a treatment
  option for patients with bone metastases from
  renal cell carcinoma