Slide 1: Management of Metastatic Breast Cancer to Bone
“Management of Metastatic Breast Cancer to Bone” Adam Brufsky, MD, PhD Co-Director, Assistant Professor of Medicine Magee-Womens Cancer Program at UPMC Cancer Centers Pittsburgh, PA
Slide 2: A Typical Case
A Typical Case 48 year old woman In 2000, had a R MRM for a 5 cm IDC, ER/PR(-), Her 2 (-), 6/10 LN(+) Received AC x 4, T x 4 and XRT to R chest wall In March 2003, she complains of mild R hip pain Bone scan shows multiple mets in B ribs, T spine, R iliac bone Metastatic workup (-), repeat Her2 by FI
Slide 3: Management Options
Management Options Pain management (NSAIDs/opioids) Bisphosphonates Chemotherapy (capecitabine?) External beam radiation Orthopedic intervention (rods, etc) Radiopharmaceuticals
Slide 4: Skeletal-Related Complications in the Pamidronate Trials in Breast Cancer
Skeletal-Related Complications in the Pamidronate Trials in Breast Cancer Pamidronate Placebo Patients (%) Fractures Hypercalcemia P=0.054 P=0.014 P=0.036 P=0.010 P18 P19 P18 P19 Theriault et al. J Clin Oncol. 1999;17:846. Hortobagyi et al. J Clin Oncol. 1998;16:2038.
Slide 5: Incidence of Treatment for Skeletal-Related Complications in the Pamidronate Trials
Incidence of Treatment for Skeletal-Related Complications in the Pamidronate Trials in Breast Cancer Pamidronate Placebo Patients (%) Radiation Surgery P=0.058 P<0.001 P=0.245 P=0.01 P18 P19 P18 P19 Theriault et al. J Clin Oncol. 1999;17:846. Hortobagyi et al. J Clin Oncol. 1998;16:2038.
Slide 6: Zometa vs Pamidronate Percentage of Patients With Each SRE
Zometa® vs Pamidronate Percentage of Patients With Each SRE *HCM is excluded as a skeletal-related event 24 Months Extension Data Percent of patients All SREs* Fractures Radiation to bone Surgery to Bone Spinal cord comp HCM ZOMETA 4 mg (N = 581) Pam 90 mg (555) Coleman et al. SABCS 2002, Abstract 3
Slide 7: Zometa and Pain Palliation
Zometa and Pain Palliation Zoledronic acid 4 mg Zoledronic acid 8/4 mg Placebo LS mean change baseline in pain score Time, months 1.2 0.8 0.6 0.4 0.2 -0.2 -0.4 Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
Slide 8: Management Options
Management Options Pain management (NSAIDs/opioids) Bisphosphonates Chemotherapy (capecitabine?) External beam radiation Orthopedic intervention (rods, etc) Radiopharmaceuticals
Slide 9: Chemotherapy
Chemotherapy Taxanes, vinca alkaloids, capecitabine, anthracyclines All have potential toxicity Difficult to measure benefit in bone-only MBC Risk-benefit ratio in asymptomatic patient
Slide 10: Management Options
Management Options Pain management (NSAIDs/opioids) Bisphosphonates Chemotherapy (capecitabine?) External beam radiation Orthopedic intervention (rods, etc) Radiopharmaceuticals
Slide 11: External Beam Radiation: Local Field
External Beam Radiation: Local Field Pain relief efficacy Periods of complete pain relief in 50% of patients Partial pain relief in 40% of patients Onset of pain relief: few days to 4 weeks >50% of patients with some pain relief have reemergence of pretreatment pain levels Duration of pain relief: 3
Slide 12: Management Options
Management Options Pain management (NSAIDs/opioids) Bisphosphonates Chemotherapy (capecitabine?) External beam radiation Orthopedic intervention (rods, etc) Radiopharmaceuticals
Slide 13: Orthopedic intervention
Orthopedic intervention Elective internal fixation for weight-bearing long bone metastases Lesions involving 50% or more of the diaphysis Lesions destroying 50% or more of the cortex Lesions >2.5 cm in the femoral neck, subtrochanteric, or intertrochanteric region or in supracondylar regions of the
Slide 14: Management Options
Management Options Pain management (NSAIDs/opioids) Bisphosphonates Chemotherapy (capecitabine?) External beam radiation Orthopedic intervention (rods, etc) Radiopharmaceuticals
Slide 15: Radiopharmaceuticals in Management of Bone Metastases
Radiopharmaceuticals in Management of Bone Metastases Home to areas of increased osteoblastic activity Primary side effect: transient myelosuppression Three FDA approved agents Samarium-153 lexidronam injection (IV) Strontium-89 chloride injection (IV) Phosphorus-32 (IV or PO)
Slide 16: Sm-153-EDTMP Dose-Controlled Clinical Trial BA-108
Sm-153-EDTMP Dose-Controlled Clinical Trial BA-108 114 patients with metastatic bone pain from various primary sites Randomized 0.5 mCi/kg Sm-153-EDTMP n = 55 1.0 mCi/kg Sm-153-EDTMP n = 59 Week 4 Pain relief - 55% 22% reported “much better” or “completely improved” Pain relief - 70% 33% reported “m
Slide 17: Sm-153-EDTMP Dose-Controlled Clinical Trial BA-108 Toxicity
Sm-153-EDTMP Dose-Controlled Clinical Trial BA-108 Nadir as a % of Baseline With Sm-153-EDTMP 0.5 mCi/kg 1.0 mCi/kg 56% 43% Platelet 60% 49% WBC 8% 9% Grade Toxicity Resche et al. Eur J Cancer. 1997;33:1583–1591.
Slide 18: Study BA-108 Patient Subgroups: Change in AUPC
Study BA-108 Patient Subgroups: Change in AUPC at Week 4 All Patients n=103 Breast Cancer n=35 Prostate Cancer n=58 -4 Change in AUPC -8 0.5 mCi/kg -12 1.0 mCi/kg
Slide 19: Study BA-106 Patient Subgroups: Change in AUPC
Study BA-106 Patient Subgroups: Change in AUPC at Week 4 Breast Cancer (n=21) Prostate Cancer (n=78) All Patients (n=116) Lung & Other Cancers (n=19) Change in AUPC -4 -8 -12 Placebo 0.5 mCi/kg -16 -20 1.0 mCi/kg *Note palliative response in breast cancer
Slide 20: Survival of Patients with Breast Cancer After Sm-153-EDTMP
Survival of Patients with Breast Cancer After Sm-153-EDTMP in Study BA-108 0.5 mCi/kg (n=15) 1.0 1.0 mCi/kg (n=20) 0.9 0.8 0.7 0.6 Surviving 0.5 0.4 0.3 0.2 0.1 Months Resche et al. Eur J Cancer. 1997;33:1583–1591.
Slide 21: What about an antineoplastic effect
What about an antineoplastic effect – aren’t we radiating the tumor? Should we use radiopharmaceuticals earlier in the course of MBC?
Slide 22: Barriers to Early Radiopharmaceutical Use
Barriers to Early Radiopharmaceutical Use 1. Are there negative interactions with bisphosphonates? 2. Are there negative interactions with EBXRT? 3. Can we dose multiple times? 4. Are there negative interactions with chemotherapy? 5. Are there negative interactions with concurrent chemotherapy?
Slide 23: Pilot Study to Assess Tolerance Sm-153-EDTMP With Pamidronate
Pilot Study to Assess Tolerance Sm-153-EDTMP With Pamidronate in Metastatic Breast Cancer 20 patients with painful metastatic breast cancer received pamidronate 90 mg every 4 weeks and Sm-153-EDTMP 1.0 or 0.5 mCi/kg Results 1-month follow up: 18/20 reported good response to treatment Mean time to WB
Slide 24: Pamidronate Does Not Interfere With Samarium-153 Uptake
Pamidronate Does Not Interfere With Samarium-153 Uptake in Metatastic Breast Cancer Patients 3 patients with metastatic breast cancer evaluated for Sm-153-EDTMP uptake before and after 1-4 days of pamidronate Sm-153-EDTMP 1 mCi/kg was divided into 6 equal portions and given before pamidronate, short
Slide 25: Skeletal Images
Skeletal Images Six Hours After Sm-153-EDTMP Injection Both sets of images are similar; note the bone metastases. Baseline Day After Pamidronate Marcus et al. Clin Nucl Med. 2002;27:427-430.
Slide 26: Barriers to Early Radiopharmaceutical Use
Barriers to Early Radiopharmaceutical Use 1. Are there negative interactions with bisphosphonates? (no) 2. Are there negative interactions with EBXRT? 3. Can we dose multiple times? 4. Are there negative interactions with chemotherapy? 5. Are there negative interactions with concurrent chemotherapy?
Slide 27: Effect of External Beam Radiation on Sm-153-EDTMP Uptake and Distribution
Effect of External Beam Radiation on Sm-153-EDTMP Uptake and Distribution 14 patients with metastatic breast or prostate cancer Split-dose technique Sm-153 EDTMP 0.5 mCi/kg ð palliative external beam 3000-4000 cGy over 2-4 weeks ð Sm-153-EDTMP 0.5 mCi/kg At 3 hours and 24 hours post Sm-153-EDTMP inj
Slide 28: Barriers to Early Radiopharmaceutical Use
Barriers to Early Radiopharmaceutical Use 1. Are there negative interactions with bisphosphonates? (no) 2. Are there negative interactions with EBXRT? (no) 3. Can we dose multiple times? 4. Are there negative interactions with chemotherapy? 5. Are there negative interactions with concurrent chemothe
Slide 29: Safety and Efficacy of Repeated Doses of Sm-153-EDTMP
Safety and Efficacy of Repeated Doses of Sm-153-EDTMP Additional Quadramet® doses administered based on recurrence of pain in study 424Sm12 48 prostate cancer, 5 breast cancer, 1 unknown primary 132 doses administered to 54 patients (2 to 11 doses per patient) 54 patients: 2 doses 11 patients: 3 dos
Slide 30: WBC and Platelet Nadirs
WBC and Platelet Nadirs Dose 1 Dose 2 Doses >3 3.6±1.1 [54%] 3.6±1.1 [49%] WBC Nadir [% of baseline] 3.5±0.9 [57%] 105±49 [48%] 129±37 [50%] Platelet Nadir [% of baseline] 93±38 [50%] Sartor et al. 2005 ASCO Annual Meeting Abstract No: 4635
Slide 31: Barriers to Early Radiopharmaceutical Use
Barriers to Early Radiopharmaceutical Use 1. Are there negative interactions with bisphosphonates? (no) 2. Are there negative interactions with EBXRT? (no) 3. Can we dose multiple times? (yes) 4. Are there negative interactions with chemotherapy? 5. Are there negative interactions with concurrent ch
Slide 32: Chemotherapy and EXBRT with Samarium-153 in Breast Cancer
Chemotherapy and EXBRT with Samarium-153 in Breast Cancer 48 patients receiving 79 courses of 153Sm-EDTMP Pre- and post treatment data for Entire co-hort 28 patients with prior CT 20 patients with prior CT and RT Lowest nadir values observed: WBC: 1,200/uL PLT: 29,000/uL Median time to nadir: 28 day
Slide 33: % Decreases From Baseline in WBCs and Platelets
% Decreases From Baseline in WBCs and Platelets All Pts CT + RT CT WBC PLT Heron, et. al., ASCO 2004
Slide 34: Barriers to Early Radiopharmaceutical Use
Barriers to Early Radiopharmaceutical Use 1. Are there negative interactions with bisphosphonates? (no) 2. Are there negative interactions with EBXRT? (no) 3. Can we dose multiple times? (yes) 4. Are there negative interactions with chemotherapy? (no) 5. Are there negative interactions with concurre
Slide 35: Bevacizumab is part of the new standard of care for MBC
Bevacizumab is part of the new standard of care for MBC Bevacizumab is a humanized monoclonal antibody directed against VEGF Recognizes all VEGF-A isoforms Active in metastatic colon cancer and NSCLC Toxicity manageable A randomized phase III trial of paclitaxel +/- bevaciumab as first line MBC ther
Slide 36: E2100: Paclitaxel Versus Paclitaxel/Bevacizumab Interim Analysis
E2100 Paclitaxel Versus Paclitaxel/ Bevacizumab For Previously-Untreated Metastatic Breast Cancer Interim Analysis RANDOMIZATION Paclitaxel 90 mg/m2 D1, 8, 15 Bevacizumab 10 mg/kg D1 and 15 28 Day Cycle Paclitaxel 90 mg/m2 D1, 8, 15 28 Day Cycle
Slide 37: E2100: Paclitaxel Versus Paclitaxel/Bevacizumab Interim Analysis Results
E2100 Paclitaxel Versus Paclitaxel/ Bevacizumab For Previously-Untreated Metastatic Breast Cancer Interim Analysis Pac Pac + Bev HR P-Value Overall Response Rate All patients 14% 28% - <.0001 Measurable Disease 16% 34% - <.0001 Progression-free survival 6.1 mo 11 mo 0.498 <.001 Overall survival - -
Slide 38: Proposed Phase II Pilot Clinical Trial of Samarium, Paclitaxel, and Bevacizumab
Proposed Phase II Pilot Clinical Trial of Samarium, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer 25-30 women with MBC Bone disease +/- other sites, ER/PR (+/-), Her 2(-) No prior chemotherapy (bisphosphonates allowed) All receive paclitaxel 80 mg/2 weekly weeks 1-3 with week 4 off and bev
Slide 39: Phase III Trial Design
Phase III Trial Design MBC, bone-only, ER/PR (+/-), Her2 (-) Randomize to Paclitaxel 80 mg/m2 IV weekly, 3 on, 1 off x 4-6 cycles with bevacizumab 10 mg/kg wks 1 and 3 of each cycle Paclitaxel 80 mg/m2 IV weekly, 3 on, 1 off x 4-6 cycles with bevacizumab 10 mg/kg wks 1 and 3 of each cycle with Sm153
Slide 40: Summary
Summary Radiopharmaceuticals can provide meaningful palliation of painful bone metastases in women with MBC Transient myelosuppression is the major side effect Issue of when to use these compounds is currently under investigation Early vs late in MBC course With/without chemotherapy Asymptomatic vs