Bone Cancer Treatment Regimens

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated. uSystemic Therapy for MSI-H/dMMR Tumors1 REGIMEN DOSING Preferred Regimens Pembrolizumab2-6,a Day 1: Pembrolizumab 200mg IV over 30 minutes. Repeat cycle every 3 weeks for up to 2 years. OR Day 1: Pembrolizumab 400mg IV over 30 minutes. Repeat cycle every 6 weeks for up to 2 years. uSystemic Therapy for TMB-H (≥10 mutations/megabase) Tumors1 Useful in Certain Circumstances Pembrolizumab2-6,b Day 1: Pembrolizumab 200mg IV over 30 minutes. Repeat cycle every 3 weeks for up to 2 years. OR Day 1: Pembrolizumab 400mg IV over 30 minutes. Repeat cycle every 6 weeks for up to 2 years. uSystemic Therapy for Chondrosarcoma: Metastatic and Widespread Disease Other Recommended Regimens Dasatinib7-9,c Days 1-28: Dasatinib 70mg-100mg orally twice daily. Repeat cycle every 4 weeks. Pazopanib10,11,c Days 1-28: Pazopanib 800mg orally daily. Repeat cycle every 4 weeks. uSystemic Therapy for Chondrosarcoma Conventional (Grades 1-3)1 Preferred Regimens No known standard chemotherapy options1 Useful in Certain Circumstances Ivosidenib Days 1-28: Ivosidenib 500mg orally daily. (for susceptible IDH1 mutations)12,13,c Repeat cycle every 4 weeks. uSystemic Therapy for Chondrosarcoma Dedifferentiated1 Preferred Regimens Follow osteosarcoma regimens (Category 2B)1 Useful in Certain Circumstances Ivosidenib Days 1-28: Ivosidenib 500mg orally daily. (for susceptible IDH1 mutations)12-13,c Repeat cycle every 4 weeks. uSystemic Therapy for Chondrosarcoma Mesenchymal1 Preferred Regimens Follow Ewing Sarcoma Regimens (category 2B)1

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1 CancerTherapyAdvisor.com Bone Cancer Treatment Regimens uSystemic Therapy for Chordoma1 REGIMEN DOSING Other Recommended Regimens Dasatinib7-9,c Days 1-28: Dasatinib 70mg-100mg orally twice daily. Repeat cycle every 4 weeks. Imatinib14,c Days 1-28 : Imatinib 400mg orally twice daily. Repeat cycle every 4 weeks. Sunitinib17,18,c,e Days 1-28: Sunitinib 37.5mg orally daily. Repeat cycle every 4 weeks. Useful in Certain Circumstances Erlotinib19,20,c Days 1-28: Erlotinib 150mg orally once daily. Repeat cycle every 4 weeks. Imatinib + Cisplatin14,19,21,22,c,d Day 1: Cisplatin 25mg/m2 IV over 60 minutes. Days 1-7: Imatinibc 400mg orally daily. Repeat cycle every week. Imatinib + Sirolimus14,23,24,c Days 1-28: Imatinib 400mg orally once daily Days 1-28: Sirolimus 2mg orally once daily (dose is adjusted to keep concentration within therapeutic range of 15-20 ng/mL). Repeat cycle every 4 weeks. Lapatinib (for EGFR mutation-positive Days 1-28: Lapatinib 1500mg orally once daily. chordomas)25,26,c Repeat cycle every 4 weeks. Sorafenib27-30,c,e Days 1-28: Sorafenib 400mg orally twice daily. Repeat cycle every 4 weeks. uEwing Sarcoma First-line Therapy (Primary/Neoadjuvant/Adjuvant Therapy)1

Preferred Regimens VDC/IE Day 1: Vincristine 2mg/m2 (maximum 2mg) IV over 5-10 minutes (Vincristine + Doxorubicin/Dactinomycin Day 1: Doxorubicin 75mg/m2 IV push + Cyclophosphamide Alternate with OR Ifosfamide and Etoposide) Day 1: Dactinomycin 1,250mcg/m2 IV push (Category 1)31-36,f-i Day 1: Cyclophosphamide 1,200mg/m2 IV over 60 minutes Day 1: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before cyclophosphamide, then at 4 and 8 hours from the start of each cyclophosphamide dose) Repeat cycle every 3 weeks for cycles 1 and 3 (neoadjuvant) and cycles 5, 7, 9, 11, 13, 15, and 17 (adjuvant), or cycles 1, 3, 5, 7, 9, 11, 13, 15, and 17 (metastatic), alternating with: Days 1-5: Ifosfamide 1,800mg/m2 IV over 3 hours daily Days 1-5: Mesna 360mg/m2 IV over 15 minutes three times daily (one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose) Days 1-5: Etoposide 100mg/m2 IV over 60 minutes daily. Repeat cycle every 3 weeks for cycles 2 and 4 (neoadjuvant) and cycles 6, 8, 10, 12, 14, and 16 (adjuvant) or cycles 2, 4, 6, 8, 10, 12, 14, and 16 (metastatic), alternating with: VDC regimen (shown above). VDC/IE Day 1: Vincristine 2mg/m2 IV (maximum 2mg) IV over 5-10 minutes (as neoadjuvant/adjuvant therapy for Days 1-2: Doxorubicin 37.5mg/m2 IV over 5-10 minutes OR patients aged <50 years) Day 1: Doxorubicin 75mg/m2 IV push OR (Category 1)31-37,f-i Day 1: Dactinomycin 1,250mcg/m2 IV push Day 1: Cyclophosphamide 1,200mg/m2 IV over 60 minutes Day 1: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before cyclophosphamide, then at 4 and 8 hours from the start of each cyclophosphamide dose). Repeat cycle every 2 weeks for cycles 1, 3, and 5 (neoadjuvant) and cycles 7, 9, 11, and 13 (adjuvant), alternating with: Days 1-5: Ifosfamide 1,800mg/m2 IV over 3 hours daily Days 1-5: Mesna 360mg/m2 IV over 15 minutes three times daily (one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose). Days 1-5: Etoposide 100mg/m2 IV over 60 minutes daily. Repeat cycle every 2 weeks for cycles 2, 4, and 6 (neoadjuvant) and cycles 8, 10, 12, and 14 (adjuvant), alternating with: VDC regimen (shown above).

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2 CancerTherapyAdvisor.com Bone Cancer Treatment Regimens uEwing Sarcoma First-line Therapy (Primary/Neoadjuvant/Adjuvant Therapy)1 (continued) REGIMEN DOSING Other Recommended Regimens

VAI Day 1: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes (Vincristine + Doxorubicin/Dactinomycin Days 1-2: Doxorubicin (even numbered cycles) 30mg/m2 IV push once daily + Ifosfamide)31,32,34,38,39,f,g,i Days 1-3: Dactinomycin (odd-numbered cycles) 500mcg/m2 IV push once daily Days 1-3: Ifosfamide 2,000mg/m2 IV over 3 hours once daily Days 1-3: Mesna 400mg/m2 IV over 15 minutes three times daily (once prior to ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose). Repeat cycle every 3 weeks for 4-8 cycles (neoadjuvant) and 5-12 cycles (adjuvant) or 14 cycles (metastatic).

VIDE Day 1: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes (Vincristine + Ifosfamide + Doxorubicin/ Days 1-3: Ifosfamide 3,000mg/m2 IV over 3 hours daily Dactinomycin + Etoposide)31,32,34,35,40,41,f,g,i Days 1-3: Mesna 600mg/m2 IV over 15 minutes 3 times daily (once prior to ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose) Days 1-3: Doxorubicin 20mg/m2 IV push daily OR Days 1-3: Dactinomycin 500mcg/m2 IV push daily Days 1-3: Etoposide 150mg/m2 IV over 60 minutes daily. Repeat cycle every 3 weeks for 4-8 cycles (neoadjuvant) and 5-12 cycles (adjuvant) for total of 9-16 cycles or 14 cycles total (metastatic). uEwing Sarcoma Primary Therapy for Metastatic Disease at Initial Presentation1

Preferred Regimens

VDC/IE Day 1: Vincristine 2mg/m2 (maximum 2mg) IV over 5-10 minutes (Vincristine + Doxorubicin/Dactinomycin Day 1: Doxorubicin 75mg/m2 IV push OR + Cyclophosphamide Day 1: Dactinomycin 1,250mcg/m2 IV push Alternate with Ifosfamide and Day 1: Cyclophosphamide 1,200mg/m2 IV over 60 minutes Etoposide)31-37,f,g,i Day 1: Mesna 240mg/m2 IV over 15 minutes three times daily (one dose before cyclophosphamide, then at 4 and 8 hours from the start of each cyclophosphamide dose) Repeat cycle every 3 weeks for cycles 1, 3, 5, 7, 9, 11, 13, 15, and 17 (metastatic), alternating with: Days 1-5: Ifosfamide 1,800mg/m2 IV over 3 hours daily Days 1-5: Mesna 360mg/m2 IV over 15 minutes three times daily (one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose) Days 1-5: Etoposide 100mg/m2 IV over 60 minutes daily. Repeat cycle every 3 weeks for cycles 2, 4, 6, 8, 10, 12, 14, and 16 (metastatic), alternating with: VDC regimen (shown above).

VDC Day 1: Vincristine 2mg/m2 (maximum 2mg) IV over 5-10 minutes (Vincristine + Doxorubicin/Dactinomycin Day 1: Doxorubicin 75mg/m2 IV push OR + Cyclophosphamide)31-33,42,f,i Day 1: Dactinomycin 1,250mcg/m2 IV push Day 1: Cyclophosphamide 1,200mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks for 17 cycles.

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3 CancerTherapyAdvisor.com Bone Cancer Treatment Regimens uEwing Sarcoma Second-Line Therapy (Relapsed/Refractory or Metastatic Disease)1 REGIMEN DOSING Preferred Regimens Cyclophosphamide + Topotecan33,43-46,i,j Days 1-5: Cyclophosphamide 250mg/m2 IV over 30 minutes Days 1-5: Topotecan 0.75mg/m2 IV over 30 minutes. Repeat cycle every 3 weeks. Irinotecan + Temozolomide47-50,j Days 1-5,8-12: Irinotecan 10-20mg/m2 IV over 90 minutes daily Days 1-5: Temozolomide 100mg/m2 orally once daily. Repeat cycle every 3 weeks. Irinotecan + Temozolomide + Days 1-5, 8-12: Irinotecan 10-20mg/m2 IV over 90 minutes daily Vincristine47-52 Days 1-5: Temozolomide 100mg/m2 orally daily Day 1: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes OR Days 1,8: Vincristine 1.5mg/m2 (maximum 2mg) IV over 5-10 minutes. Repeat cycle every 3 weeks. Other Recommended Regimens Cabozantinib53,54,c,l Days 1-28: Cabozantinib 60mg orally once daily. Repeat cycle every 4 weeks. Docetaxel + Gemcitabine55-57,i,j Days 1,8: Gemcitabine 675mg/m2 IV at a rate of 10mg/m2 per minute, followed by: Day 8: Docetaxel 75-100mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks. Useful in Certain Circumstances Ifosfamide + Carboplatin + Days 1-5: Ifosfamide 1,800mg/m2 IV daily Etoposide34,35,58,59,g,i-k Days 1-5: Mesna 360mg/m2 IV over 15 minutes three times daily — one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose) Days 1,2: Carboplatin 400mg/m2 IV daily Days 1-5: Etoposide 100mg/m2 IV daily. Repeat cycle every 3 weeks for up to 12 cycles. uGiant Cell Tumor of Bone Preferred Regimen Denosumab60-62 Days 1,8,15: Denosumab 120mg subcutaneous Administer for one 4-week cycle, followed by: Day 1: Denosumab 120mg subcutaneous. Repeat cycle every 4 weeks. Useful in Certain Circumstances Interferon Alfa 2B63-65 Days 1-28: Interferon alfa 2B 3million units/m2 subcutaneous daily (starting 48-72 hours post-surgery if involved). Repeat cycle every 4 weeks. uOsteosarcoma First-line Therapy (Primary/Neoadjuvant/Adjuvant Therapy or Metastatic Disease)1 Preferred Regimens Cisplatin + Doxorubicin (Category 1)21,32,66,d,i Day 1: Cisplatin 100mg/m2 IV continuous infusion over 24 hours Days 1-3: Doxorubicin 25mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 3 weeks for 2 cycles (neoadjuvant) and 4 cycles (adjuvant) for a total of 6 cycles, or 6 cycles total (metastatic). MAP Days 1-2: Doxorubicin 37.5mg/m2 IV continuous infusion over 24 hours daily High-Dose Methotrexate + Cisplatin + Days 1-2: Cisplatin 60mg/m2 IV over 60 minutes daily. Doxorubicin (Category 1)21,32,67-69,d,i,m Repeat weekly cycle on weeks 1 and 6 (neoadjuvant), followed by on weeks 12 and 17 (adjuvant), or on weeks 1, 6, 12, and 17 (metastatic). Days 1-2: Doxorubicin 37.5mg/m2 IV continuous infusion over 24 hours daily OR Day 1: Doxorubicin 75mg/m2 IV push. Repeat weekly cycle on weeks 22 and 26 (adjuvant or metastatic), with: Day 1: Methotrexate 12g/m2 (maximum 20g) IV over 4 hours Day 2: Leucovorin 15mg IV over 15 minutes starting 24 hours from initiation of methotrexate infusion and continuing every 6 hours until methotrexate level is less than 0.05 micromoles/L and at least total 8 doses. Repeat weekly cycle on weeks 4, 5, 9, and 10 (neoadjuvant), followed by: on weeks 15, 16, 20, 21, 24, 25, and 29 (adjuvant), or on weeks 4, 5, 9, 10, 15, 16, 20, 21, 24, 25, 28 and 29 (metastatic). continued

4 CancerTherapyAdvisor.com Bone Cancer Treatment Regimens uOsteosarcoma First-line Therapy (Primary/Neoadjuvant/Adjuvant Therapy or Metastatic Disease)1 (continued)

REGIMEN DOSING Other Recommended Regimens Doxorubicin + Cisplatin + Ifosfamide + See NCCN Bone Cancer Guidelines1 High-Dose Methotrexate21,32,34,67,70,d,g,m uOsteosarcoma Second-line Therapy (Relapsed/Refractory or Metastatic Disease)1

Preferred Regimens Ifosfamide (High-Dose)34,71,72,g,i Days 1-5: Ifosfamide 2,000-2,800mg/m2 IV over 3 hours daily Days 1-5: Mesna 300-500mg/m2 IV over 15 minutes three times daily (one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose). Repeat cycle every 3 weeks. Ifosfamide (High-Dose) + Days 1-5: Etoposide 100mg/m2 IV over 60 minutes daily Etoposide34,35,71-73,g,i Days 1-5: Ifosfamide 1,800mg/m2 IV over 3 hours daily Days 1-5: Mesna 360mg/m2 IV over 15 minutes 3 times daily (one dose before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose). Repeat cycle every 3 weeks. Regorafenib (Category 1)74,75,c Days 1-21: Regorafenib 160mg orally once daily. Repeat cycle every 4 weeks. Sorafenib27-30,c,e Days 1-28: Sorafenib 400mg orally twice daily. Repeat cycle every 4 weeks. Other Recommended Regimens Cabozantinib53,54,c,l Days 1-28: Cabozantinib 60mg orally once daily. Repeat cycle every 4 weeks. Cyclophosphamide + Topotecan33,43-46,i,j Days 1-5: Cyclophosphamide 250mg/m2 IV over 30 minutes Days 1-5: Topotecan 0.75mg/m2 IV over 30 minutes. Repeat cycle every 3 weeks. Docetaxel + Gemcitabine55-57,i,j Days 1,8: Gemcitabine 675mg/m2 IV at a rate of 10mg/m2 per minute, followed by: Day 8: Docetaxel 75-100mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks. Gemcitabine56,76 Days 1,8: Gemcitabine 1,200mg/m2 IV at rate of 10mg/m2/minute. Repeat cycle every 3 weeks. Sorafenib + Everolimus Days 1-28: Everolimus 5mg orally once daily (Category 2B)27,77,78,c,e Days 1-28: Sorafenib 400mg orally twice daily. Repeat cycle every 4 weeks. Useful in Certain Circumstances Cyclophosphamide + Etoposide33,35,79,i,n Day 1: Cyclophosphamide 4000mg/m2 IV over 3 hours daily Day 1: Mesna 1400mg/m2 IV before and after 4 hours and 8 hours from cyclophosphamide Days 2-4: Etoposide 100mg/m2 IV over 1 hour twice daily (total dose 600mg/m2). Repeat cycle every 3-4 weeks. High-Dose Methotrexate67,68,80,m Day 1: Methotrexate 12g/m2 (maximum 20g) IV over 4 hours Day 2: Leucovorin 15mg IV over 15 minutes starting 24 hours from initiation of methotrexate infusion and continuing every 6 hours until methotrexate level is less than 0.05micromoles/L and at least total 8 doses. Repeat weekly cycle on weeks 1, 2, 3, 7, 8, 9, 13, 14, 15, 19, 20, and 21. High-Dose Methotrexate + Etoposide + Day 1: Methotrexate 12g/m2 (maximum 20g) IV over 4 hours Ifosfamide34,35,67,80,g,i,m Day 2: Leucovorin 15mg IV over 15 minutes starting 24 hours from initiation of methotrexate infusion and continuing every 6 hours until methotrexate level <0.05micromoles/L and at least 8 total doses. Repeat cycle weekly on weeks 1, 2, 3, 7, 8, 9, 13, 14, 15, 19, 20, and 21. Days 1-4: Ifosfamide 3,000mg/m2 IV over 3 hours daily Days 1-4: Mesna 600mg/m2 IV over 15 minutes three times daily (one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose). Days 1-4: Etoposide 75mg/m2 IV over 60 minutes. Repeat cycle weekly on weeks 4, 10, 16, and 22.

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5 CancerTherapyAdvisor.com Bone Cancer Treatment Regimens uOsteosarcoma Second-line Therapy (Relapsed/Refractory or Metastatic Disease)1 (continued) REGIMEN DOSING Useful in Certain Circumstances Ifosfamide + Carboplatin + Days 1-5: Ifosfamide 1,800mg/m2 IV daily Etoposide34,35,58,59,g,i,k Days 1-5: Mesna 360mg/m2 IV over 15 minutes three times daily — one dose before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose) Days 1,2: Carboplatin 400mg/m2 IV daily Days 1-5: Etoposide 100mg/m2 IV daily. Repeat cycle every 3 weeks for up to 12 cycles. Samarium-152 ethylene diamine See NCCN Bone Cancer Guidelines1 tetramethylene phosphonate (for relapsed or refractory disease beyond second-line therapy)81,82

a Pembrolizumab is a systemic treatment option for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Additional dosing recommendations follow: 200mg IV Day 1, repeat every 3 weeks or 400mg IV Day 1, repeat every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months for treatment of patients with MSI-H bone cancer. Not for Giant Cell Tumor of Bone or Chordoma. b TMB-H for patients unresectable or metastatic tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options. Not for Giant Cell Tumor of Bone. c This agent has multiple potential drug-drug and/or drug-food interactions. Review patient medical profile and drug package insert for specific drug and food interactions and recommendations. d Hydration is required with supplemental electrolytes pre- and post-administration of cisplatin. e Sorafenib may cause cutaneous squamous cell carcinoma. Monitor for signs and symptoms of cutaneous squamous cell carcinoma prior to initiation of therapy and as clinically indicated. f Dactinomycin can be substituted for doxorubicin for concerns regarding cardiotoxicity. g Hydration is required pre- and post-administration of ifosfamide. h In patients younger than 18 years, evidence supports 2-week compressed treatment. i Administration with myeloid growth factor therapy is recommended. j Vincristine could be added to these regimens. k ICE regimen evaluated in patients 22.5 years of age or younger. l Cabozantinib (Cabometyx) tablets and cabozantinib (Cometriq) capsules are not interchangeable products. The dosage strengths of each product and dosing recommendations for specific indications differ. m In the event a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly recommended. n Together with mesna all patients had hyperhydration (3000 mL/m2/day) during chemotherapy administration.

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