Presentation on theme: "Bisphosphonates in Cancer Management. “A Story of Success” Mohamed Abdulla M.D. Professor of Clinical Oncology Cairo University W: www.oncologyclinic.org."— Presentation transcript:
Bisphosphonates in Cancer Management. “A Story of Success” Mohamed Abdulla M.D. Professor of Clinical Oncology Cairo University W: E: Khartoum 04/12/2010
Agenda: Magnitude of The Problem; Skeletal Related Events. Patho-physiology of Bone Metastases. Bone Directed Therapy & Improvements in Quality of Life. Anti-Tumor Effect. Focus on Breast Cancer.
1. Parkin DM, et al. Int J Cancer. 2001;94(2): ; 2. Coleman RE. Cancer Treat Rev. 2001;27(3): ; 3. Coleman RE. Cancer. 1997;80(8): ; 4. Zekri J, et al. Int J Oncol. 2001;19(2): year world prevalence, thousands 1 Incidence of bone metastases in cancers 2 Median survival, months 2-4 Myeloma Renal Melanoma Bladder 1, Thyroid Lung 1, Breast 3, Prostate 1, More lytic More blastic Prevalence of Skeletal Affection in Cancer Patients:
Bone Complications and Quality of Life: 1. Groot MT, et al. Eur Urol. 2003;43: Weinfurt KP, et al. ESMO Abstract 662P. 3. Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: Riggs BL, et al. Bone. 1995;17:505S-511S. Skeletal complications Negative impact on survival  Increased medical costs  Impaired mobility  Diminished quality of life [2-4]
Pathologic Fractures Negatively Affect Survival: Data from Saad F, et al. Cancer. 2007;110(8): Hazard ratio Decreased mortality Increased mortality.04 P value 29% Risk increase 1.29 <.01 52% 1.52 Prostate cancer Breast cancer
FDA Accepts Composite Endpoints to Evaluate Therapy Benefit: Composite endpoints based on occurrence of skeletal- related events (SREs) defined as –Radiation to bone for bone pain or to treat or prevent pathologic fractures or spinal cord compression –Pathologic fracture –Spinal cord compression –Surgery to bone Johnson JR, et al. J Clin Oncol. 2003;21:
Patients With Bone Metastases Are at High Risk for Developing Skeletal-Related Events: SRE, skeletal-related event. 1. Lipton A, et al. Cancer. 2000;88(5): ; 2. Saad F, et al. Eur Urol Suppl. 2007;6(11): Breast 1 24 Months Prostate 2 24 Months Cancer Type Placebo arms of large randomized studies Patients With SRE, % Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression SREs Any
Bone as a Dynamic Structure: Normal Turnover:
The annual turnover rate is 25% in cancellous bones & 2 – 3% in cortical bones. The Process takes about 4 – 6 months. 1 osteoclast resorbs what 100 osteoblasts build.
Osteoblastic Prostate and breast Bone formation mediated by osteoblasts Types of Cancer Bone Disease: Osteolytic Breast and myeloma Bone destruction mediated by osteoclasts
Normal interplay between Osteoclasts and Osteoblasts: RANK RANK Ligand Osteoprotegerin Destruction Formation
The Vicious Cycle of Bone Metastases: The Lytic Story: PTHrP released by tumor cells Tumor Cells PTHrP BMP PDGF FGFs IGFs TGF-β Osteoclast Mundy GR, Yoneda T. N Engl J Med.1998;339: Osteoclastic resorption stimulated Peptides (eg, TGF-β) released by bone resorption Tumor cell production of PTHrP increased More bone resorption Tumor cell proliferation Bone
Tumor Cells bFGFs EGF TGF-β Osteoclast Mundy GR, Yoneda T. N Engl J Med.1998;339: Bone Proteases ET-1, BMPs IGFs, OPG Osteoblasts Sclerotic metastasis RANKL The Vicious Cycle of Bone Metastases: The Sclerotic Story:
Management of Bone Metastases Ionizing Irradiation Chemo-Hormonal Therapy & Drug Therapy Orthopedic Procedures Radioactive Isotopes External Beam Radiation Therapy Principles of Management of Bone Metastases: Specific Drug Directed Therapy
Ionizing External Beam Rth: Used over a Century for Palliation of Bone Mets. Related Effects. Bone Relief in The Majority of Patients. Reducing The Rate of Bone Destruction Months of Pain Control. Disadvantages: 1.Myelosuppression. 2.Dose to Surrounding Critical Structures.
Radioactive Isotopes: Radio- nuclide Carrier Ligand Half Life (Days) ß Energy (MeV) Gamma Energy (MeV) Max. Range mm 89 StChloride SmEDTMP ReHEDP ReHEDP
Overall Structure of Bisphosphonates R 2 Chain R 1 Chain PO 3 H 2 C Osteoclast PO 3 H 2
PTHrP BMP PDGF FGFs IGFs TGF-β Effect of Bisphosphonates on Vicious Cycle of Bone Destruction: Mundy GR, Yoneda T. N Engl J Med. 1998;339: Tumor Cells PTHrP BMP PDGF FGFs IGFs TGF-β Decrease activity of osteoclasts –Reduction in release of peptides – Slowed tumor-cell growth – Reduced production of PTHrP – Decrease in bone resorption Osteoclast Bone
Different Classes of Bisphosphonates: pamidronate Zoledronic acid clodronate tiludronate alendronate ibandronate P P OH OH OH O OH OH O N risedronate etidronate Non-Nitrogen containing 1 Nitrogen containing 1 Nitrogen ring 2 Nitrogen ring Potency increases Bone affinity increases
Therapy options (preservation of function) Effects on cancer cells (alone or with chemotherapy) Anticancer effects in bone microenvironment Mortality associated with skeletal-related events Skeletal-related events * Anticancer effects Improved disease outcomes Delayed disease progression Prolonged survival * Zoledronic acid has demonstrated efficacy in preventing bone loss in women with hormone-sensitive early breast cancer receiving endocrine therapy. Bisphosphonate Therapy: Potential Mechanisms for Improved Outcomes: Bisphosphonates
Prostate Solid tumors Lung cancer RCC Relative Risk of SRE Breast Zoledronic Acid and Risk of SREs in Multiple Tumor Types: 36% % % % %.019 Risk ReductionP Value In favor of ZOL In favor of placebo Kohno N, et al. J Clin Oncol. 2005;23: Saad F, et al. J Natl Cancer Inst. 2004;96: Rosen LS, et al. Cancer. 2004;100: Lipton A, et al. Cancer. 2003;98:
Zoledronic Acid more than just an anti-osteoclast !! Main mode of action is inhibition of FPP synthase enzyme which plays a key role in cell mediated signal transduction
Preclinical Anticancer Activity With Bone-Targeted Therapies ZOL, zoledronic acid; IBN, ibandronate; PAM, pamidronate; CLO, clodronate; ALN, alendronate; RIS, risedronate; DEN, denosumab. ZOLIBNPAMCLOALNRISDEN Prevention Angiogenesis ( ) Apoptosis Proliferation Invasion Adherence Migration ( ) Activity Inhibition of tumor growth Synergy with chemotherapy Immunomodulation denotes activity; ( ) to be confirmed.
HOW? Adapted from Mundy GR, et al. Nature Reviews Cancer. 2002;2: InvasionAngiogenesisPrimary tumor MetastasesAdhesion & extravasation Arrest in distant capillary Micrometastases Inhibits angiogenesis Decreases adhesion to bone Synergy with anticancer drugs Induces tumor cell apoptosis Stimulates immune surveillance Decreases matrix invasion Direct antitumor effect Indirect antitumor effect
Bisphosphonate Indications: Indication HCM Breast cancer Multiple myeloma Prostate cancer Other solid tumors Clodronate Pamidronate Zoledronic acid Ibandronate = European registration. = Global registration.
Zoledronic Acid A focus on Breast Cancer
Oral clodronate 1,600 mg (Kristensen 1999)31% (Paterson 1993)17% (Tubiana-Hulin 2001)8% P value Risk reduction ZOL 4 mg 41%.001 (Kohno 2005) 0.59 PAM 90 mg23%<.001 (Aredia study 18 and 19) 0.77 Ibandronate 6 mg18%.04 (Body 2003) 0.82 Ibandronate 50 mg14%.08 (Body 2004) (pooled).03 (pooled) Cochrane database comparing placebo-controlled trials in breast cancer setting. ZOL, zoledronic acid; PAM, pamidronate. Adapted from Pavlakis N, et al. Cochrane Database Syst Rev. 2005:CDC SRE Risk Reduction in BC: Results From an Independent Meta-analysis:
Zoledronic Acid Reduced All Types of SREs at 1 Year in Patients With Bone Metastases From BC: SRE, skeletal-related event; BC, breast cancer; SCC, spinal cord compression; HCM, hypercalcemia of malignancy. Adapted from Kohno N, et al. J Clin Oncol. 2005;23(15): Zoledronic acid 4 mg (n = 114)Placebo (n = 113) P =.001
Breast Cancer—Benefits of ZOL Are Beyond Those of PAM and Continue After the Onset of SREs: Risk reduction Relative risk In favor of zoledronic acid In favor of pamidronate P value All SREs (n = 766) % % Excluding first SRE ZOL reduced the risk of experiencing any SRE on study or after the first SRE by ~30% vs PAM a in a large, double-blind, phase III trial a As determined by Andersen-Gill multiple event analysis. ZOL, zoledronic acid (4 mg q 3-4 wks); PAM, pamidronate (90 mg q 3-4 wks); SRE, skeletal-related event. Adapted from Zheng M, et al. Poster presented at: 9th International Conference on Primary Therapy of Early Breast Cancer; January 26-29, 2005; St. Gallen, Switzerland. Poster 104.
Zoledronic Acid Significantly Reduces Mean Composite Brief Pain Inventory (BPI) Score: Patients continued to receive chemotherapy or standard treatment for breast cancer. IV, intravenous. 1. Lipton A, et al. Cancer. 2000;88(5): ; 2. Body J-J, et al. Ann Oncol. 2003;14(9): Reprinted from Kohno N, et al. J Clin Oncol. 2005;23(15): BPI Mean Change From Baseline Time on Study, Weeks * * * * * * * * * * * 0 * * Decreased pain Increased pain *P <.05 ZOL 4 mg q 4 wk Placebo 20 20
* * * * ZOL Significantly Improves Most Quality-of-Life Measures in Patients With Bone Metastases From BC: Graph depicts overall mean change from baseline quality-of-life scores reported at final visit after 9 infusions. ZOL, zoledronic acid; BC, breast cancer; EORTC QLQ, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire. *P < 0.05 compared with baseline values. Reprinted from Wardley A, et al. Br J Cancer. 2005;92(10):
Adjuvant Zoledronic Acid in Breast Cancer.
Reduces the viability of human breast cancer cells in vitro 1 1. Senaratne SG, et al. Br J Cancer * These points have reached statistical significance. Cell viability (% control) after 4 days of treatment Bisphosphonate concentration (µM) zoledronic acid pamidronate clodronate Zoledronic Acid: An Anti-Tumor Potential:
Ovarian Suppression Plus TAM or ANA +/- ZA: ABCSG-12 Trial Design: Gnant M, et al. ASCO Abstract LBA4. Accrual 1,803 premenopausal breast cancer patients Endocrine-responsive (ER and/or PR positive) Stage I & II, <10 positive nodes No chemotherapy except neoadjuvant Treatment duration: 3 years Tamoxifen 20 mg/d Anastrozole 1 mg/d Tamoxifen 20 mg/d + Zoledronic acid 4 mg Q6Mos Anastrozole 1 mg/d + Zoledronic acid 4 mg Q6Mos Surgery (+RT) Randomize 1:1:1:1 Goserelin 3.6 mg Q28D
ABCSG-12: Zoledronic Acid Significantly Improves DFS vs Endocrine Therapy Alone: Death without prior recurrence Secondary malignancy Contralateral breast cancer Distant recurrence Locoregional recurrence Gnant M, et al. N Engl J Med. 2009;360(7): Median follow-up = 48 mo Zoledronic acid vs no zoledronic acid Time since randomization (mo) Disease-free survival, % ZOL No ZOL (n = 904) No ZOL (n = 899) ZOL First event per patient (n) HR = 0.64 P =.01
Letrozole + Zoledronic acid 4 mg every 6 mos Letrozole + delayed* zoledronic acid 4 mg every 6 mos *Zoledronic acid started when 1 of the following occurs: BMD T score < -2 SD, clinical fracture, or asymptomatic fracture at 36 mos Patients with stage I-IIIa breast cancer, who are: Postmenopausal or amenorrheic due to cancer treatment ER+ and/or PgR+ T-score ≥ -2 SD (N = 2195) Treatment duration 5 yrs Z-FAST, ZO-FAST, EZO-FAST: Zoledronic Acid + Letrozole Adjuvant Synergy Trials: Key endpoints Primary: bone mineral density Secondary: bone markers; fractures; and time to recurrence/relapse
ZO-FAST: Upfront Zoledronic Acid Significantly Decreased the Risk of DFS Events: a Multiple sites of metastases may be reported for the same patient. Sites of distant metastases include bone, brain, liver, lung, skin, and lymph node DFS (%) Time (mo) Upfront ZOL Delayed ZOL HR = P =.0314 Disease-Free Survival Adapted from Eidtmann H, et al. Presented at SABC Symposium, Dec 10-14, Abstract 44. (n = 532) Disease Recurrence a Patients (n) Delayed ZOLUpfront ZOL Lymph node Distant Local Risk of DFS events decreased by 41% at 36 mo
Safety Profiles of Adjuvant Zoledronic Acid + Endocrine Therapy: ZO-FAST / Z-FAST / E-ZO-FAST 1 48 / 61 / 36 mo ABCSG mo Patients, n (%) Upfront + LET (n = 1079) Delayed + LET (n = 1104) + TAM (n = 449) + ANA (n = 450) Arthralgia503(47)625(57)65(15)150(33) Myalgia157(15)146(13)None reported Pyrexia129(12)34(3)34(8)46(10) Bone pain162(15)104(9)132(29)185(41) Hot flashes332(31)372(34)27(6)25(6) Renal adverse events (grade 3 or above) 4(0.3)3(0.3)0(0) Atrial fibrillation2(0.2)6(0.5)None reported ONJ a 5(0.4)0(0) a Overall incidence of ONJ (osteonecrosis of the jaw) in the total population (N = 3082) = 0.16%. 1. Coleman R, et al. Presented at San Antonio Breast Cancer Symposium, Dec 13-16, Abstract Gnant M, et al. N Engl J Med 2009;360(7): Adjuvant ZOL in premenopausal and postmenopausal women
DTC = Disseminated tumor cells; BL = Baseline; ZOL = Zoledronic acid. 1. Rack BK, et al. Breast Cancer Res Treat. 2007;106:S40. Abstract 511; 2. Aft R, et al. Presented at: ASCO Abstract 1021; 3. Lin A, et al. Breast Cancer Res Treat. 2007;106:S40. Abstract 510; 4. Lin A, et al. Presented at: ASCO Abstract 559. P =.0018 P =.01 6 mo 3 mo 1 yr ZOL keeps patients DTC-freeZOL DTC clearanceZOL consistently DTCs over time Rack et al. 1 (N = 172) ZOL q 4 wk vs no ZOL for 6 mo Lin et al. 3,4 (N = 45) ZOL q 4 wk (vs BL) for 2 yr Aft et al. 2 (N = 120) ZOL q 3 wk vs no ZOL for 1 yr (w/Chx) ZOL Reduced Residual Cancer Burden in 3 Clinical Trials in Early Breast Cancer: Patients with persisting DTCs, % DCT-free at BL Overall Patients with persisting DTCs, % year2 years Patients with DTCs, %
Neoadjuvant AZURE: Exploratory Analysis of Residual Invasive Tumor Size (RITS) and pCR: Adjusted Median RITS (mm) P = Multivariate analysis N = 205. RITS, residual invasive tumor size; CT, chemotherapy; ZOL, zoledronic acid; pCR, pathologic complete response Coleman R, et al. British Journal of Cancer; 2010: March (e-pub: doi: /sj.bjc ) Patients achieving pCR (%) CT CT + ZOL 43% ~2 fold CT alone CT + ZOL
Zoledronic Acid Dosing Rationale in Breast Cancer: 1. Gnant M, et al. Presented at ASCO, May 30-Jun 3, Abstract LBA4.4. Rosen LS, et al. Cancer J. 2001;7(5): Brufsky A, et al. Oncologist. 2008;13(5): Kohno N, et al. J Clin Oncol. 2005;23(15): Coleman R, et al. Eur J Cancer Suppl. 2007;5(4). Abstract ADJUVANT Early Late METASTATIC DescriptionEarly stage (BC I–III) ABCSG-12 trial 1 E/Z/ZO-FAST trials 2 Later stage (BC II/III) AZURE trial 3 Metastatic BC Trial 010, ,5 Tumor burdenLowModerateVery high Key clinical issue with skeleton Potential site for harboring tumor cells and seeding metastatic disease Ongoing, active destruction of skeletal integrity through tumor cell–mediated, osteoclast bone resorption Treatment goal with zoledronic acid Prevent metastases, improve DFS / RFS Stop cycle of bone destruction. Significantly reduce the risk of skeletal-related events Dose ZOL needed4 mg IV q6mo4 mg IV up 8x/yr4 mg IV q3–4wk
Keep in Mind: Immediate use of zoledronic acid (4 mg IV q6mo) prevents bone loss in women with early stage BC receiving adjuvant letrozole Disease free survival was significantly improved with the use of zoledronic acid upfront The safety results were as expected and consistent with the known safety profiles of the drug. The growing body of evidence of zoledronic acid anti- tumor effect.