1. Addition of pamidronate to chemotherapy for treatment of osteosarcoma is feasible Meyers PA, Healey JH, Athanasian E, Boland P, Morris C, Laquaglia MP, Antonescu C, Wexler L, Merchant M, Merola P, Chou A, Abramson S, Kellick M Memorial Sloan-Kettering Cancer Center Meyers PA, Healey JH, Athanasian E, Boland P, Morris C, Laquaglia MP, Antonescu C, Wexler L, Merchant M, Merola P, Chou A, Abramson S, Kellick M Memorial Sloan-Kettering Cancer Center

2. Need for new agents in osteosarcoma Population based data suggests little improvement in outcome in two decades Addition of ifosfamide to cisplatin, doxorubicin and HDTMX did not improve survival Population based data suggests little improvement in outcome in two decades Addition of ifosfamide to cisplatin, doxorubicin and HDTMX did not improve survival

3. 3 Osteosarcoma 5-Year Survival Data Surgery Only (Historical) 1975- 1980 1981- 1986 1987- 1992 % Surviving 1993- 2000 SEER <15 years 15-29 years

4. 4

5. Bisphosphonates and breast cancer Clodronate reduced the risk of bone metastases But also Reduced the risk of visceral metastases Clodronate reduced the risk of bone metastases But also Reduced the risk of visceral metastases Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M, Bastert G. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998;339:357-63.

6. Bisphosphonates and osteosarcoma AuthorYearBisphosphonateModel system Cheng2004aledronatehuman lines in vitro Farese2004aledronatedog lines in vitro Molinuevo2007aledronaterat cell line in vitro Heikkila2003clodronatehuman lines in vitro Kubo2006minodronatehuman in vitro/xenograft Mackie2001pamidronaterat cell line in vitro Sonnemann2001pamidronatehuman lines in vitro Ashton2005pamidronatedog lines in vitro Murayama2008Risedronate*human lines in vitro *synergy with chemotherapy

7. Bisphosphonates and osteosarcoma AuthorYearBisphosphonateModel system Evdokiou2003zoledronatehuman lines in vitro Heymann2005Zoledronate*rat cell line in vivo Ory2005Zoledronatemouse cell line in vivo Horie2006zoledronatemouse cell line in vitro Kubista2006zoledronatehuman lines in vitro Benassi2007Zoledronate*human lines in vitro Dass2007zoledronatehuman lines in xenograft Horie2007Zoledronate*mouse cell line in vitro Iguchi2007zoledronatehuman lines in vitro Ory2007zoledronatehuman/rat lines in vitro Ory2008zoledronatehuman/rat lines in vitro *synergy with chemotherapy

8. Choice of pamidronate ReferenceIndicationAge RangeDoseSchedule Kutluk, 1997Hypercalcemia4 Young, 1998Hypercalcemia2 – 151 mg/kg Schmid, 2001Hypercalcemia51 mg/kg Lala, 2000Fibrous dysplasia0.5-1 mg/kg qd x3 days q6months Farran, 2001Langerhans cell Histiocytosis 142 mg/kg qd x 3 days q1month Rauch, 2002Osteogenesis imperfecta 1 – 160.25-1 mg/kg qd x 3 days q2-4months Barr, 2001ALL3 – 161 mg/kg qd x 3 daysq3months

9. Study Aims 1. Determine safety and feasibility of concurrent pamidronate and chemo 2. Estimate prosthesis survival for patients who receive pamidronate and chemotherapy 3. Estimate EFS and survival for patients who receive pamidronate and chemotherapy 1. Determine safety and feasibility of concurrent pamidronate and chemo 2. Estimate prosthesis survival for patients who receive pamidronate and chemotherapy 3. Estimate EFS and survival for patients who receive pamidronate and chemotherapy

10. Patient population Newly diagnosed, untreated osteosarcoma 29 patients with localized disease 11 patients with metastasis at initial presentation Newly diagnosed, untreated osteosarcoma 29 patients with localized disease 11 patients with metastasis at initial presentation

11. Induction treatment regimen WeekChemotherapy 0Cisplatin 120 mg/m2 Doxorubicin 75 mg/m2 3,4HD MTX 12 g/m2 5Cisplatin 120 mg/m2 Doxorubicin 75 mg/m2 8,9HD MTX 12 g/m2 Surgery primary and metastases week 10 Pamidronate 2 mg/kg (max dose 90 mg) qmonth

12. Maintenance treatment regimen WeekChemotherapy 0Cisplatin 120 mg/m2 Doxorubicin 75 mg/m2 3,4HD MTX 12 g/m2 5Cisplatin 120 mg/m2 Doxorubicin 75 mg/m2 8,9HD MTX 12 g/m2 10Doxorubicin 75 mg/m2 13,14HD MTX 12 g/m2 15Doxorubicin 75 mg/m2 18,19HD MTX 12 g/m2 Pamidronate 2 mg/kg (max dose 90 mg) qmonth

13. Pamidronate dose schedule Pamidronate 2 mg/kg (max dose 90 mg) qmonth for one year (12 doses) Separate pamidronate from cisplatin or HDMTX by at least 48 hours Pamidronate 2 mg/kg (max dose 90 mg) qmonth for one year (12 doses) Separate pamidronate from cisplatin or HDMTX by at least 48 hours

14. Toxicity Usual and expected toxicity with cisplatin, doxorubicin, HDMTX No increase in nephrotoxicity or ototoxicity No osteonecrosis of the jaw Usual and expected toxicity with cisplatin, doxorubicin, HDMTX No increase in nephrotoxicity or ototoxicity No osteonecrosis of the jaw

17. Orthopedic reconstruction 21 endoprosthetic reconstructions 13/14 uncemented implants osteointegrated 12 allograft reconstructions 2 failures, 4 delayed unions and 6 successful grafts 5 of 33 reconstructions failed No stress fractures, no growth disturbance Results better than historical norm 21 endoprosthetic reconstructions 13/14 uncemented implants osteointegrated 12 allograft reconstructions 2 failures, 4 delayed unions and 6 successful grafts 5 of 33 reconstructions failed No stress fractures, no growth disturbance Results better than historical norm

18. Conclusions We can safely administer pamidronate and chemotherapy to young patients with osteosarcoma EFS and survival are comparable to our historical institutional experience Prosthesis survival is at least as good as our historical institutional experience We can safely administer pamidronate and chemotherapy to young patients with osteosarcoma EFS and survival are comparable to our historical institutional experience Prosthesis survival is at least as good as our historical institutional experience

19. Future Directions Consider a prospective randomized trial of chemotherapy +/- bisphosphonate Consider use of zoledronate rather than pamidronate Zoledronate is more potent than pamidronate: increased risk for toxicity as well as increased potential for benefit Will this require pilot data? Consider a prospective randomized trial of chemotherapy +/- bisphosphonate Consider use of zoledronate rather than pamidronate Zoledronate is more potent than pamidronate: increased risk for toxicity as well as increased potential for benefit Will this require pilot data?