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Treatment Protocols
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Treatment Protocols

Overview

Osteosarcoma is the most common primary malignancy of bone in children and adolescents, characterized by the production of immature bone. Some cases may be related to syndromes such as the following:

Hereditary retinoblastoma
Li-Fraumeni syndrome
Rothmund-Thomson syndrome
Bloom and Werner syndrome

In adults, osteosarcomas are often considered secondary neoplasms, resulting from one of the following:

Irradiation
Sarcomatous transformation of Paget disease
Bone infarcts
Transformation of benign bone lesions.

Patients present with bone pain, which typically has been ongoing for weeks to months, and the development of an expansile mass that is tender to palpation. Laboratory evaluation usually shows elevation in alkaline phosphatase, lactate dehydrogenase (LDH), and erythrocyte sedimentation rate. Those values do not correlate with disease extent, although a very high LDH level is associated with a poor clinical outcome.

Plain radiographs show show destruction of the normal trabecular bone pattern, indistinct margins, characterized by a mixture of radiodense and radiolucent areas, destruction of the cortex, and periosteal new bone formation, with the formation of a Codman triangle. For definitive diagnosis a biopsy is required, which shows malignant sarcomatous stroma with osteoid.

The staging workup should include magnetic resonance imaging of the entire length of the involved bone, computed tomography (CT) of the chest, and technetium radionuclide bone scanning. Positron emission tomography (PET) or a PET/CT scan can be considered in special circumstances.

Chemotherapy has dramatically improved survival in these patients. Prior to the use of chemotherapy, the majority of patients developed metastasis after surgery.

Treatment protocols for osteogenic sarcoma are provided below, including general and first-line treatment recommendations and recommendations for second-line therapy for relapsed or refractory disease.

General treatment

General treatment recommendations for patients with osteosarcoma are listed below.^[1]

Stages IA-IB (low grade):

Primary treatment for patients with low-grade osteogenic sarcoma includes wide excision only.
Chemotherapy, either prior to excision or postoperatively, is not typically recommended.
Periosteal lesions are one exception where adjuvant chemotherapy may be indicated postoperatively.

Stages IIA-IVB (high grade):

Chemotherapy is warranted for all stages of high-grade osteogenic sarcoma.
For nonmetastatic osteosarcoma, two to three cycles of chemotherapy are typically given preoperatively (neoadjuvant); three to four cycles of chemotherapy are given postoperatively (adjuvant).

First-line treatment

Primary, neoadjuvant, or adjuvant therapy for metastatic disease:

Doxorubicin and cisplatin or
High-dose methotrexate, doxorubicin (Adriamycin), and cisplatin (MAP) or
MAP + ifosfamide (MAP-I) or
Ifosfamide, cisplatin, and epirubicin (ICE)

Neoadjuvant doxorubicin and cisplatin^{[2, 3, 4]}:

Doxorubicin 25 mg/m ² IV bolus once daily on days 1 to 3 (total dose 75 mg/m ²)
Cisplatin 100 mg/m ² IV continuous 24-hour infusion on day 1

Supportive treatment is as follows:

Prehydration: normal saline (NS) 400 mL/m ² and 5% dextrose in water (D5W) 400 mL/m ² over 2 hours
The volume of fluid for cisplatin continuous infusion is 2400 mL/m ² NS, with potassium chloride (KCl) 80 mEq/L and mannitol 32 g/m ²
Posthydration: D5W 600 mL/m ² over 6 hours, with KCl 20 mEq/L and mannitol 8 g/m ²; and NS 600 mL/m ² over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L. Then D5W 600 mL/m ² over 12 hours, with KCl 20 mEq/L and mannitol 8 g/m ².
Furosemide 20-40 mg IV if urine output is < 400 mL/m ² over 6 hours

An alternative regimen is as follows:

Cisplatin 100 mg/m ² IV continuous 24-hour infusion on day 1 plus
Doxorubicin 25 mg/m ² IV bolus once per day on days 1 to 3 (total dose 75 mg/m ²) plus
Growth factor support with filgrastim 5 mcg/kg SC once daily on days 4 to 13 or lenograstim (not available in the United States) 5 mcg/kg SC once daily on days 4 to 13
Supportive treatment: 4 hours of prehydration prior to cisplatin, 24 hours of posthydration plus mannitol after cisplatin; recommended fluid is NS with KCl and mannitol

Protocols consist of the following:

Three 21-day cycles followed by definitive surgery on week 9, then adjuvant cisplatin and doxorubicin (same dosage and length of treatment), starting 14 to 28 days after surgery
Three 14-day cycles followed by definitive surgery in a 14-day window between cycles three and four, then adjuvant cisplatin and doxorubicin (same dosage and length of treatment)

Neoadjuvant MAP therapy^[2]:

Methotrexate (MTX) 12,000 mg/m ² IV over 6 hours once on day 1 plus
Doxorubicin 37.5 mg/m ² IV on day 1 and 2 (total dose: 75 mg/m ²) plus
Cisplatin 60 mg/m ²/day intra-arterial continuous on days 1 and 2 (total dose: 120 mg/m ²)

Supportive treatment is as follows:

Leucovorin 15 mg IV or PO Q6H x 10 doses starting 24 hours after the start of MTX infusion
Hydration during and after MTX infusion

The recommended protocol is as follows:

Two 27-day cycles followed by definitive surgery on week 11
Patients treated with amputation restart chemotherapy 3 to 5 days after surgery; patients who undergo limb salvage or rotation plasty restart chemotherapy 10 to 21 days after surgery.
If the surgically removed specimen has ≥90% tumor necrosis, adjuvant therapy is with MAP (same dosage and length of treatment).
If the surgically removed specimen has < 90% tumor necrosis, adjuvant therapy is with MAP-IE.

Neoadjuvant MAP-I^[5]

Methotrexate 12,000 mg/m ² IV over 4 hours once on day 1; if 4-hour MTX level is < 1000 µM/L, the next cycle's dose is increased by 2000 mg/m ² plus
Cisplatin 60 mg/m ²/day IV continuous 48-hour infusion on days 8 & 9 (total dose: 120 mg/m ²) plus
Doxorubicin 75 mg/m ² IV continuous 24-hour infusion on day 10 plus
Ifosfamide 3000 mg/m ²/day IV continuous 120-hour (5-day) infusion on days 29 to 33, given together with mesna (total dose: 15,000 mg/m ²)

Supportive treatment is as follows:

Leucovorin 15 mg IV or PO Q6H x 10 doses on days starting 24 hours after the start of MTX infusion
Hydration during and after MTX
Mesna 3000 mg/m ²/day IV continuous 120-hour (5-day) infusion on days 29 to 33, given together with ifosfamide (total dose: 15,000 mg/m ²)

The recommended protocol is as follows:

Two 42-day cycles followed by surgery then
Adjuvant MAP-I

Adjuvant MAP-I

Three 9-week cycles of the following:

MTX 12,000 mg/m ² IV over 4 hours once on day 36; if 4-hour methotrexate level is < 1000 µM/L, the next cycle's dose is increased by 2000 mg/m ² plus
Doxorubicin 90 mg/m ² IV continuous 24-hour infusion on day 1 plus
Cisplatin 60 mg/m ²/day IV continuous 48-hour infusion on days 43 & 44 (total dose: 120 mg/m ²) plus
Ifosfamide 3000 mg/m ²/day IV continuous 120-hour (5-day) infusion on days 22 to 26, given together with mesna (total dose: 15,000 mg/m ²)

Supportive treatment is as follows:

Mesna 3000 mg/m ²/day IV continuous 120-hour (5-day) infusion on days 22 to 26, given together with ifosfamide (total dose: 15,000 mg/m ²)
Leucovorin 15 mg IV or PO Q6H x 10 doses, starting day 36, 24 hours after the start of MTX
Hydration during and after MTX infusion

Ifosfamide, cisplatin, and epirubicin^[6]:

ICE is given as follows:

Cisplatin 100 mg/m ² IV over 2 hours once on day 1 plus
Ifosfamide 2000 mg/m ²/day IV over 4 hours once per day on days 2 to 4, given with mesna (total dose: 6000 mg/m ²) plus
Epirubicin 90 mg/m ² IV over 15 minutes once on day 1

Supportive treatment is as follows:

Mesna 2000 mg/m ²/day IV over 4 hours once per day on days 2 to 4, given together with Ifosfamide (total dose: 6000 mg/m ²)
Prehydration and posthydration with mannitol diuresis for cisplatin

Recommended protocols are as follows:

Neoadjuvant ICE: three 21-day cycles, then surgery followed by adjuvant ICE
Adjuvant ICE: Three 28-day cycles

Second-line therapy for relapsed or refractory disease

Patients with localized and metastatic osteosarcoma may experience relapse. Treatment recommendations for patients with relapsed or refractory disease consist of any one of the following regimens:

Docetaxel and gemcitabine
Cyclophosphamide and etoposide
Cyclophosphamide and topotecan
Gemcitabine
Ifosfamide (high-dose) +/- etoposide
Ifosfamide, carboplatin, and etoposide
High-dose methotrexate, etoposide, and ifosfamide
Samarium-153–ethylene diamine tetramethylene phosphonate for relapsed or refractory disease beyond second line therapy
Sorafenib
Sorafenib + everolimus
Ra223

Docetaxel and gemcitabine^[7]:

Gemcitabine 675 mg/m ² on days 1 and 8 of a 21-day cycle plus
Docetaxel 100 mg/m ² on day 8 of every 21-d cycle given after gemcitabine

Cyclophosphamide and etoposide

Two 21-day cycles as follows, then restaging^[8]:

Cyclophosphamide 4000 mg/m ² IV over 3 hours once on day 1 plus
Etoposide 100 mg/m ² IV over 1 hour BID on days 2 to 4 (total dose: 600 mg/m ²)
Supportive medication: mesna 1400 mg/m ² IV TID on day 1: before, 4 hours after, and 8 hours after cyclophosphamide

Cyclophosphamide and topotecan^[9]:

Twelve to fourteen 21-day cycles of the following:

Cyclophosphamide 250 mg/m ² IV over 30 minutes once daily on days 1 to 5, given first
Topotecan 0.75 mg/m ² IV over 30 minutes once daily on days 1 to 5, given second

Supportive treatment is as folllows:

500 mL/m/ ² fluids PO/IV 2-4 hours before chemotherapy
Antiemetics as premedication before chemotherapy
3 L/m ² fluids PO/IV over 24 hours after chemotherapy
Filgrastim 5 mcg/kg SC once daily starting on day 6, to continue until absolute neutrophil count (ANC) is at least 1500/μL after the nadir period

Gemcitabine^[10]:

Gemcitabine 1000 mg/m ² IV once daily on days 1, 8, 15, 22, 29, 36, 43
8-week course, thenmaintenance therapy if patient does not have progressive disease:

Ifosfamide and etoposide^{[11, 12]}:

Ifosfamide (Ifex) 3000 mg/m ² IV over 3 hours, in D5W 250 to 500 mL, once daily on days 1 to 4
Etoposide 75 mg/m ² IV over 1 hour, in D5W 250 to 500 mL, daily on days 1 to 4

Supportive treatment is as follows:

Mesna 3600 mg/m ²/day IV continuous infusion on days 1 to 4 (total dose: 14,400 mg/m ²)
At least 2000 mL/m ²/day of hydration with chemotherapy

The recommended protocol is two 21- to 28-day cycles, with the second cycle starting when ANC >1500/μL and platelet count >100,000/μL

Ifosfamide, carboplatin, and etoposide^[13]:

Ifosfamide 1800 mg/m ² IV once per day on days 1 to 5
Carboplatin 400 mg/m ² IV "for 2 days"
Etoposide 100 mg/m ² IV once per day on days 1 to 5

Supportive treatment includes the following:

Filgrastim 5 or 10 mcg/kg/day SC once per day, starting 24 hours after completing ICE, and continuing until day 18 if ANC is at least 1000/μL, or until ANC is at least 1000/μL post nadir, whichever comes later
Interleukin-6 (IL-6) at 2.5, 3.75, or 5.0 mcg/kg SC BID, starting 24 hours after completing ICE; continued until platelet count is at least 100,000/μL for 2 consecutive days or until day 35, whichever comes sooner.

The recommended protocol is as follows:

21-day cycles, with next cycle starting as soon as ANC is at least 1000/μL and the platelet count is at least 100,000/μL
Resection of disease allowed after 4 cycles, based on patient's response to ICE.

High-dose methotrexate, etoposide, and ifosfamide^{[2, 14]}

In the neoadjuvant setting, treatment is as follows:

MTX 12,000 mg/m ² IV over 4 hours, in D5W 1L with sodium bicarbonate 1 mEq/kg, on weeks 1, 2, 3, 7, 8, 12, 13 plus
Ifosfamide 3000 mg/m ²/day (total dose: 12,000 mg/m ²) IV over 3 hours, in NS 250 to 500 mL, once daily on days 22 to 25 (week 4) and days 57 to 60 (week 9), given together with mesna plus
Etoposide 75 mg/m ² IV over 1 hour, in NS 250 to 500 mL, once daily on days 22 to 25 (week 4) and days 57 to 60 (week 9)

Supportive treatment includes the following:

Leucovorin) 15 mg PO Q6H x up to 10 doses on weeks 1, 2, 3, 7, 8, 12, 13, starting 20 hours after the completion of MTX infusion
Mesna 3600 mg/m ²/day (total dose: 14,400 mg/m ²) IV continuous 96-hour (4-day) infusion on days 22 to 25 (week 4) and days 57 to 60 (week 9), given together with ifosfamide
Up to 2 L/day hydration with ifosfamide and mesna

The recommended protocol is as follows:

Surgery occurs during week 14, with further treatment based on pathologic response
Patients with good response receive adjuvant methotrexate, ifosfamide, etoposide, whereas patients with poor response receive adjuvant cisplatin and doxorubicin.

In the adjuvant setting, treatment is as follows:

MTX 12,000 mg/m ² IV over 4 hours, in D5W 1L with sodium bicarbonate 1 mEq/kg, on weeks 1, 2, 3, 7, 8, 12, 13 plus
Ifosfamide 3000 mg/m ²/day (total dose: 12,000 mg/m ²) IV over 3 hours, in NS 250 to 500 mL, once daily on days 22 to 25 (week 4), 57 to 60 (week 9), given together with mesna plus
Etoposide 75 mg/m ² IV over 1 hour , in NS 250 to 500 mL, once daily on days 22 to 25 (week 4) and days 57 to 60 (week 9)

Supportive treatment includes the following:

Leucovorin 15 mg PO Q6H x up to 11 doses on weeks 1, 2, 3, starting 20 hours after the completion of MTX infusion
For MTX, provide hydration and urine alkalinization by PO and IV routes to maintain urine output at 1.6 L/m ² over the first 24 hours and 2 L/m ² on days 2-3, with urine pH >7
Daily monitoring of methotrexate levels and creatinine
Mesna 3600 mg/m ²/day IV continuous 96-hour (4-day) infusion on days 22 to 25 (week 4), given together with Ifosfamide (total dose: 14,400 mg/m ²)
Up to 2 L/day hydration with ifosfamide & mesna

The recommended protocol is as follows:

Three 28-day cycles, then
MTX 12,000 mg/m ² IV over 4 hours, in D5W 1L with sodium bicarbonate 1 mEq/kg, once daily on days 1, 8, 15

Samarium-153-ethylene diamine tetramethylene phosphonate (¹⁵³Sm-EDTMP)^{[15, 16]}:

Samarium-153 (Quadramet) 30 mCi/kg IV once on day 1
Growth factor support, started when ANC < 1000/μL, with filgrastim or sargramostim
On day 14, infuse peripheral blood progenetor cell (PBPC) or bone marrow cells
Complete blood cell count (CBC) measured twice weekly until engraftment/hematologic recovery
Transfuse patients for hemoglobin < 8 mg/dL, platelet count < 20,000/μL

Sorafenib^[17]:

Sorafenib 400 mg PO BID given 1 hour before or 2 hours after food
Treatment course continued until progression of disease or toxic side effects

Sorafenib + everolimus^[18]:

Sorafinib 800 mg PO daily given 1 hour before or 2 hours after food
Everolimus 5 mg PO daily
Treatment course continued until progression of disease or toxic side effects

Ra223^{[19, 20]}:

²²³RaCl ₂, 75 kBq/kg, at 4-week intervals
Response to treatment monitored via CT/MRI

Radiation therapy

Treatment of primary tumor^{[21, 22, 23]}:

Radiation therapy (RT) should be considered for patients with positive margins of resection, subtotal resections, or unresectable disease
Postoperative RT (R1 and R2 resections):1 55 Gy with 9–13 Gy boost to microscopic or gross disease (total dose to high-risk sites 64–68 Gy)
Unresectable disease: 60–70 Gy (total dose will depend on normal tissue tolerance)

Treatment of metastatic disease^[15]:

Consider use of 153Sm-EDTMP and radium 223
Consider use of stereotactic radiosurgery, especially for oligometastases

Surveillance

Follow-up should include the following^[1]:

Physical exam, including primary site of disease
Imaging of chest
CBC and other laboratory studies as clinically indicated
Reassess function every visit

The recommended orthopedic and oncologic follow-up schedule is as follows:

Years 1 and 2: Every 3 months
Year 3: Every 4-6 months
Years 4 and 5: Every 6 months
Thereafter: Every 12 months

Imaging follow-up is as follows:

Chest imaging every 6 months for 2 years then annually thereafter for low grade tumors
Chest imaging every 3-6 months for 5 years then annually thereafter for high grade tumors
Consider PET/CT and/or bone scan (category 2B) at baseline and then as clinically indicated

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Author

Mohammad Muhsin Chisti, MD, FACP Associate Professor of Medicine (Hematology and Oncology), Oakland University William Beaumont School of Medicine; Medical Director of Research, Karmanos Cancer Institute

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Coauthor(s)

Maher Osman Dakroub, DO Clinical Instructor, Michigan State University College of Osteopathic Medicine; Resident Physician, Department of Internal Medicine, McLaren Oakland

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Edwin Choy, MD, PhD Associate Professor of Medicine, Harvard Medical School; Director of Sarcoma Oncology, Department of Medicine, Division of Hematology/Oncology, Dana Farber/Harvard Cancer Center, Massachusetts General Hospital

Edwin Choy, MD, PhD is a member of the following medical societies: American Society of Clinical Oncology, Children's Oncology Group, Connective Tissue Oncology Society, Radiation Therapy Oncology Group, Sarcoma Alliance for Research through Collaboration

Disclosure: Received research grant from: Amgen, Mirati, Novartis, Eli Lilly, Exelexis, Astra Zeneca, Iterion, and IMDZ.

Additional Contributors