Bone Cancer: Pharmacologic Management

Primary bone cancers are rare cancers that arise from primitive mesenchymal cells from which all connective tissues are derived. Bone cancer accounts for 0.2% of all cancers.¹ The National Cancer Institute estimates 3970 new cases of bone cancer and 2140 deaths attributed to the disease in 2023.¹ Secondary bone metastases, which originate from other organs and spread to the bone, are much more common (30% to 75%).²

Multiple bone cancer subtypes exist based on their origin, with varying demographic and clinical features: chondrosarcoma (40%), osteosarcoma (28%), chordoma (10%), Ewing sarcoma (8%), undifferentiated pleomorphic sarcoma/fibrosarcoma (4%), and giant cell tumor of bone (GCTB; 4%-10%).³ Chondrosarcoma is the most common primary bone cancer in adults, and osteosarcoma (56%) and Ewing sarcoma (34%) are more common in children and adolescents.⁴ Primary bone cancer has a higher prevalence in male vs female individuals at a ratio of 1.43 to 1.⁵

Most bone cancers are idiopathic; however, there are some risk factors associated with different subtypes: 

• Previous cancer treatment with radiation therapy, particularly at a young age⁴

• Osteosarcoma
  • TP53 mutation⁶ 
  • Rb1 mutation⁶  
  • Paget disease⁴
  • Werner syndrome and Rothmund-Thomson syndrome⁶ 
• Chondrosarcoma
  • Older age⁷
  • History of benign bone tumors⁷
  • Multiple exostoses⁷
• Chordoma
  • TBXT mutation⁷
  • Tuberous sclerosis (TSC1 or TSC2 mutation)⁷

Bone cancer is aggressive in many cases and requires early diagnosis and treatment. The 5-year survival rate for patients with bone cancer is 68.9%.¹ With improvements in survival largely due to the introduction of adjuvant chemotherapy, the cure rate for patients with nonmetastatic osteosarcoma is up to 70%.⁸ Survival rates for patients with Ewing sarcoma approach 70%.⁹ 

Bone Cancer Types

Chondrosarcoma 

Chondrosarcomas arise from cartilage-producing cells.¹⁰ They are the second most common sarcoma of bone after osteosarcoma. Chondrosarcomas occur more frequently in older adults, with more than 70% of patients with chondrosarcoma older than 40 years at the time of diagnosis.^11,12 The 5-year survival rate for patients with localized chondrosarcoma is 91%, while the 5-year survival rate for patients with distant spread of chondrosarcoma is 17%.¹³ Chondrosarcomas most commonly affect the axial skeleton (pelvis, scapula, sternum, and ribs), proximal femur, and proximal humerus.¹⁴ Mutations in genes IDH1, IDH2, and COL2A1; retinoblastoma pathway alterations; and chromosome translocations are implicated in the development of chondrosarcomas.¹⁵  

Treatment of Chondrosarcoma

National Comprehensive Cancer Network (NCCN) recommendations for treatment of resectable, low-grade chondrosarcoma confined within the cortex of the bone include wide excision (or intralesional excision) with or without adjuvant chemotherapy.¹⁶ For low-grade chondrosarcoma of the pelvis, wide excision is preferred. Wide excision with negative margins is recommended for high-grade, clear cell, or extracompartmental tumors. Limb-sparing surgery or amputation is used for local control. Wide resection with negative margins is the preferred primary treatment for large tumors and pelvic localization.¹⁶  

For inoperable high-grade and low-grade tumors, radiation therapy with a proton and/or photon beam is recommended. Postoperative radiation therapy can be used for tumors in locations not ideal for surgery, such as in the skull base and axial skeleton.¹⁶ 

Chemotherapy is generally not effective in the treatment of chondrosarcoma. The targeted therapy agents listed below can be used for select cases of dedifferentiated chondrosarcoma¹⁶: 

• Dasatinib¹⁷  
• Pazopanib¹⁸  
• Ivosidenib¹⁹ 

Metastatic chondrosarcoma. Oligometastatic chondrosarcomas are treated with resection (for resectable disease) or radiation therapy (unresectable) that may include ablative therapy.¹⁶ For widespread chondrosarcoma, radiation therapy, surgery, and/or ablative therapies are recommended. Comprehensive genomic profiling is recommended for patients with metastatic chondrosarcoma to identify candidates for targeted therapy.¹⁶ 

Relapsed chondrosarcoma. Wide excision is recommended for local recurrent tumors that are operable, with radiotherapy or re-resection to achieve negative surgical margins. Radiation therapy is used for treatment of unresectable recurrent tumors.¹⁶  

Osteosarcoma  

Osteosarcoma is the most common primary bone cancer in children and adolescents, with 75% of cases diagnosed in patients between 15 and 25 years of age.²⁰ Osteosarcomas in older patients often develop secondary to Paget disease or radiation.²⁰ In approximately 50% of cases, osteosarcoma arises from the long bones around the knee.²¹ Due to the development of aggressive multiagent chemotherapy regimens, the 5-year survival rate for patients with osteosarcoma has improved greatly. With resistance to chemotherapy, however, survival of patients who experience relapse remains low at 20%.²²

The etiology of osteosarcoma is not clear; however, multiple genetic changes have been linked to primary osteosarcoma, including⁶:

• RB1 gene mutation, which causes hereditary retinoblastoma (associated with an increased risk of osteosarcoma later in life)⁶
• TP53 mutation found in Li-Fraumeni syndrome, which predisposes patients to several types of cancer⁶
• RECQL4 mutation found in Rothmund-Thompson syndrome and is associated with predisposition to osteosarcoma⁶
• BLM mutation found in Bloom syndrome, which predisposes patients to osteosarcoma and other cancers⁶
• WRN mutation found in Werner syndrome⁶ 
• LOH18CR1 found in Paget disease²¹

The NCCN recommends genetic testing and consultation for patients with chondrosarcoma or osteosarcoma. Because osteosarcoma predominantly affects children and adolescents, the NCCN recommends discussion of fertility preservation in patients diagnosed with osteosarcoma.¹⁶ 

Treatment of Osteosarcoma

The main treatment modality for osteosarcoma is limb-sparing or amputation surgery. There is no significant difference in survival and local recurrence between the two; however, limb-sparing surgery may be preferred for preservation of function. For patients with high-grade osteosarcomas with good response to neoadjuvant/preoperative chemotherapy, limb-sparing surgery with wide surgical margins is the preferred treatment. Amputation is the treatment option for tumors that cannot be resected with limb-sparing surgery with adequate surgical margins.¹⁶ To ensure that the biopsy is performed correctly, it is strongly recommended that an initial evaluation of proven or suspected osteosarcoma is made by a qualified orthopedic oncologist.²¹  

The preferred first-line chemotherapy treatment for primary osteosarcoma includes¹⁶:

• Cisplatin and doxorubicin
• High-dose methotrexate, cisplatin, and doxorubicin (MAP)²³

Postoperative chemotherapy is recommended for patients with a good response. For patients with positive surgical margins, surgical re-resection with or without radiation therapy is considered. In patients with inoperable osteosarcoma or incomplete resection, radiation therapy with combined proton/photon or proton beam radiotherapy has been shown to be effective for local control. If there is a poor response, a different regimen of chemotherapy can be considered; however, this approach but has generally been unsuccessful. Growth factor support should be a component of chemotherapy.¹⁶ 

Metastatic Osteosarcoma at Presentation. Chemotherapy with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide in patients with metastatic osteosarcoma at presentation did not result in significant survival improvement. Combining aggressive chemotherapy and resection of primary and metastatic tumors improved survival in patients with osteosarcoma of the extremity with lung metastases at presentation.¹⁶ Therefore, the NCCN recommends neoadjuvant chemotherapy followed by wide excision of the primary tumor. For management of resectable metastatic disease, chemotherapy, metastasectomy, and stereotactic radiation therapy are suggested treatment options. Ablation may be considered if lung metastasectomy is not possible.¹⁶

Relapsed or Refractory Osteosarcoma. Second-line therapy for relapsed, refractory, or metastatic osteosarcoma includes¹⁶: 

• Regorafenib (preferred)²⁴
• High-dose ifosfamide and etoposide (preferred)
• Sorafenib (preferred)²⁵
• Cabozantinib (other)²⁶
• Cyclophosphamide and topotecan (other)
• Gemcitabine (other)
• Docetaxel and gemcitabine (other)
• Sorafenib and everolimus (other)

Chordoma

Chordomas arise from the tissues of the notochord and most commonly affect the axial skeleton, including the sacrum, skull base, and spine. Chordomas are found more commonly in male patients and older adults, with the median age at presentation being approximately 60 years.^27,28 Chordomas consist of 3 histologic subtypes: conventional, chondroid, and dedifferentiated. 

Treatment of Chordoma

Wide excision with or without radiotherapy is recommended for patients with resectable conventional or chondroid chordomas of the sacrum and mobile spine.¹⁶ For resectable skull base tumors, intralesional excision with or without radiation therapy is the preferred treatment. Postoperative radiotherapy has been associated with improved local control and survival. Radiation therapy is the primary treatment option for unresectable chordomas. Systemic therapy (alone or with surgery or radiotherapy) is recommended for recurrent tumors. Although chemotherapy is not generally effective in chordomas, multiple targeted therapy agents have demonstrated efficacy in their treatment¹⁶:

• Imatinib²⁹ 
• Dasatinib²⁷ 
• Sunitinib 
• Erlotinib
• Lapatinib 
• Sorafenib

Relapsed Chordoma. Treatment for recurrent disease may involve surgery, radiotherapy, and/or systemic therapy. Various systemic therapies — including imatinib (with or without cisplatin or sirolimus), dasatinib, sunitinib, erlotinib, lapatinib (for patients with epidermal growth factor receptor [EGFR]-positive disease), and sorafenib — may be considered for patients with recurrent tumors, and targeted therapies can be considered for recurrent chordomas. Comprehensive genomic profiling can help identify molecules that are candidates for targeted therapy.¹⁶

Ewing Sarcoma  

Ewing sarcoma is the second most common primary malignant bone tumor.³⁰ It largely affects adolescents and is highly metastatic.³¹ The 5-year relative survival rate for localized Ewing sarcoma is 82%, and that of distant disease is 39%.³² Ewing sarcoma originates from a primordial bone marrow-derived mesenchymal stem cell and primarily affects the pelvis, femur, and the bones of the chest wall.³⁰

Genetic alterations play an important role in the etiology of Ewing sarcoma. The EWS/FLI-1 fusion gene resulting from the t(11;22) chromosomal translocation in the EWS and ETS family of genes is found in 85% of cases of Ewing sarcoma.³⁰

Treatment of Ewing Sarcoma

The preferred primary treatment for Ewing sarcoma is multiagent chemotherapy with:

• VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide)³³

Patients with Ewing sarcoma that responds to primary treatment are treated with local control therapy (wide excision, definitive radiation therapy with chemotherapy, or amputation in selected cases) followed by adjuvant chemotherapy. Multiagent chemotherapy for at least 9 weeks is recommended prior to surgery to downstage the tumor and increase the probability of achieving a complete resection with microscopically negative margins. Surgical resection with or without radiation therapy is used for local control following chemotherapy.¹⁶ 

Adjuvant chemotherapy following surgery improves survival in a majority of patients and is recommended for all patients with Ewing sarcoma. Chemotherapy with or without radiotherapy or surgery is recommended for patients who experience relapse after adjuvant chemotherapy. Progressive disease is managed with adjuvant chemotherapy after radiation with or without surgery.¹⁶ 

Local control with wide excision, radiation therapy with chemotherapy, and amputation are treatment options for stable disease showing improvement following primary treatment for Ewing sarcoma. Treatment decisions are made based on tumor location, size, response to chemotherapy, and the patient’s age and health status.¹⁶ 

Adjuvant chemotherapy for a duration of 28 to 49 weeks is recommended after wide excision or amputation for Ewing sarcoma, regardless of surgical margins. Resection or radiation therapy is recommended for oligometastatic disease. The preferred chemotherapy regimens for patients with relapsed or refractory Ewing sarcoma include combination therapies such as¹⁶:

• Cyclophosphamide and topotecan 
• Vincristine, irinotecan, and temozolomide

Undifferentiated Pleomorphic Sarcoma

Undifferentiated pleomorphic sarcoma is a high-grade, aggressive, soft-tissue sarcoma associated with a high rate of local recurrence and local nodal and distal metastases.³⁴ It most commonly affects the shoulder girdle and pelvis (appendicular skeleton). Mutations in TP53, CDKN2A, RB1, and ATRX genes, and radiation have been shown to be associated with undifferentiated pleomorphic sarcoma.³⁵ 

Chemotherapy (adjuvant and neoadjuvant) with doxorubicin and cisplatin has led to improvements in survival in patients with nonmetastatic undifferentiated pleomorphic sarcoma. The NCCN recommendations for the treatment of osteosarcoma are also appropriate for the treatment of high-grade undifferentiated pleomorphic sarcoma.¹⁶

Giant Cell Tumor of Bone 

A rare benign primary tumor of the bone, GCTB affects young adults between 20 and 40 years of age.³⁶ It occurs most commonly in the meta-epiphyseal regions of the distal femur and proximal tibia. Although generally benign, GCTB can be aggressive and lead to destruction of bone architecture. 

Treatment of GCTB

The primary treatment for localized, resectable GCTB involves intralesional excision with adjuvant chemotherapy. Serial arterial embolization can be effective for the treatment of giant cell tumors of the extremities.¹⁶ 

Denosumab, a RANK ligand inhibitor, and/or serial embolization are recommended for localized, unresectable axial lesions.³⁷ Long-term use of denosumab, however, may lead to an increase in local recurrence. Radiation therapy is an option. 

Resectable, metastatic GCTB is managed as described for localized disease. Intralesional excision is another option. For unresectable metastatic disease, denosumab, observation, and radiotherapy are recommended. Management of recurrent disease follows the same recommendations indicated for localized or metastatic-at-presentation diseases. For resectable, locally recurring GCTB, radiographic imaging of the chest and denosumab can be considered prior to surgery.¹⁶

Pharmacologic Treatment of Bone Cancer 

Systemic treatment of bone cancer largely consists of chemotherapy, targeted therapy, and bisphosphonates. Chemotherapy is used in adjuvant and neoadjuvant settings in the treatment of osteosarcoma and Ewing sarcoma. In chondrosarcoma, chordoma, and GCTBs, chemotherapy has not been effective. Instead, multiple targeted therapy agents have been shown to improve outcomes. 

Chemotherapy

The survival rates of patients with osteosarcoma or Ewing sarcoma have improved dramatically, largely due to advances in chemotherapy protocols. Multiagent regimens have been shown to be effective in the treatment of localized disease. 

Dactinomycin. Dactinomycin is an actinomycin used as a cytotoxic agent for the treatment of bone cancer.³⁸ It binds to DNA and inhibits RNA synthesis, leading to cell death in cancer cells. Dactinomycin is indicated for the treatment of Ewing sarcoma, in combination with vincristine, doxorubicin, cyclophosphamide, and radiation therapy. The recommended dosage of dactinomycin for the treatment of Ewing sarcoma is 15 µg/kg administered intravenously daily for 5 days in combination with other chemotherapy agents. The dosage should be adjusted according to the surface area, not to exceed 15 µg/kg/d or 400 to 600 µg/m²/d.

The following adverse reactions were reported with the use of dactinomycin in combination with radiation therapy³⁸:

• Bone marrow suppression
• Secondary primary tumors (including leukemia)
• Gastrointestinal toxicity 

Other side effects associated with dactinomycin include³⁸:

• Nausea and vomiting
• Fatigue
• Liver toxicity
• Anemia
• Low leukocyte count
• Low platelet count
• Kidney toxicity
• Lung toxicity

Due to the risk of harm to the fetus, use of dactinomycin during pregnancy should be avoided. Breastfeeding mothers should be warned of the risk of dactinomycin being transmitted to the infant.³⁸ 

Dactinomycin use in patients of advanced age may be associated with an increased risk for bone marrow suppression than that seen in younger patients. Dose adjustment may be needed for elderly patients based on a higher incidence of decreased hepatic, renal, or cardiac function and on comorbidities or use of other medications.³⁸

Doxorubicin Hydrochloride. Doxorubicin, an inhibitor of topoisomerase II, is indicated for the treatment of metastatic bone sarcomas.³⁹ It is used in combination with other chemotherapeutic agents as first-line treatment of osteosarcoma and Ewing sarcoma.¹⁶ The recommended dosage and administration of doxorubicin as a single agent is 60 to 75 mg/m² as an intravenous (IV) injection every 21 days. In combination therapies, doxorubicin is given as 40 to 75 mg/m² IV every 21 to 28 days.³⁹  

Adverse reactions reported with doxorubicin include³⁹:

• Cardiomyopathy
• Secondary malignancies
• Bone marrow suppression
• Lung toxicity
• Extravasation
• Tumor lysis syndrome
• Increased susceptibility to radiation toxicity
• Alopecia
• Nausea and vomiting

Use of doxorubicin with the following medications should be avoided³⁹:

• Verapamil
• Phenobarbital
• Phenytoin
• St John’s wort
• Trastuzumab
• Paclitaxel 
• Dexrazoxane 
• 6-Mercaptopurine

Pregnant patients should be warned of the risk of harm to the fetus with doxorubicin, and birth control should be used by female and male patients during and for 6 months after treatment to avoid pregnancy. Nursing mothers should discontinue breastfeeding during treatment. Use of doxorubicin puts pediatric patients at risk of developing late cardiovascular dysfunction, prepubertal growth failure, and temporary gonadal impairment.³⁹ 

Methotrexate Sodium. Methotrexate sodium is an antifolate antimetabolite that impairs DNA synthesis and replication in cancer cells.⁴⁰ It is used for the treatment of nonmetastatic osteosarcoma in high doses, followed by leucovorin rescue. Methotrexate at high doses has been shown to improve survival in patients with nonmetastatic osteosarcoma when used in combination with leucovorin and other chemotherapeutic agents after surgical resection of the primary tumor. 

For treatment of osteosarcoma, high-dose methotrexate with leucovorin rescue is administered with additional chemotherapeutic agents, including doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) at the following doses and schedules⁴⁰:

• Methotrexate 12 g/m² IV as a 4-hour infusion (starting dose) at weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery
• Leucovorin 15 mg orally every 6 hours for 10 doses starting 24 hours after start of the methotrexate infusion at weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery
• Doxorubicin (as single agent) 30 mg/m²/d IV for 3 days at weeks 8 and 17 after surgery
• Doxorubicin 50 mg/m² and cisplatin 100 mg/m² IV at weeks 20, 23, 33, and 36 after surgery
• BCD: Bleomycin 15 units/m², cyclophosphamide 600 mg/m², and dactinomycin 0.6 mg/m² IV for 2 days at weeks 2, 13, 26, 39, and 42 after surgery

Prior to administration of methotrexate, baseline assessment including complete blood count, hepatic enzymes, and kidney function should be conducted, and the patient should be monitored closely for impairment of kidney function, hematologic toxicity, and sufficient hydration according to the guideline indicated.⁴⁰ 

Serious adverse reactions reported with methotrexate include⁴⁰:

• Severe bone marrow suppression
• Liver, lung, and kidney toxicities
• Gastrointestinal toxicity
• Malignant lymphomas
• Severe skin reactions
• Tumor lysis syndrome

The most common side effects associated with methotrexate include⁴⁰:

• Ulcerative stomatitis
• Low white blood cell count
• Nausea
• Abdominal pain
• Fatigue
• Fever

Concomitant use of methotrexate with the following medications has been shown to increase toxicity and should be avoided or closely monitored⁴⁰: 

• Nonsteroidal anti-inflammatory drugs (NSAIDs) 
• NSAIDs and salicylates 
• Probenecid
• Phenylbutazone
• Phenytoin
• Oral antibiotics (tetracycline, chloramphenicol)
• Sulfonamides
• Mercaptopurine
• Penicillins
• Hepatotoxic agents (azathioprine, retinoids, sulfasalazine)
• Theophylline
• Trimethoprim/sulfamethoxazole

Methotrexate should not be administered to pregnant patients due to the risk of fetal harm. Pregnancy should be avoided during and for at least 1 ovulatory cycle following treatment for female patients and during and for 3 months after treatment for male patients. Breastfeeding should be discontinued during treatment. Patients of advanced age should be monitored closely for signs of lung, bone marrow, and kidney toxicity while undergoing treatment with methotrexate. Dosage adjustment may be necessary for elderly patients.⁴⁰  

Combination Chemotherapy Regimens

Outcomes of osteosarcoma and Ewing sarcoma improve dramatically with the use of aggressive and effective combination chemotherapy regimens.²⁰ 

VDC/IE. VDC/IE is a multiagent chemotherapy regimen used in the treatment of localized Ewing sarcoma. It consists of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide. 

MAP. MAP is a multiagent chemotherapy regimen recommended for the treatment of localized osteosarcoma. It consists of high-dose methotrexate, cisplatin, and doxorubicin. 

Targeted Therapy 

Although traditional chemotherapy is not effective in the treatment of some types of bone cancer, there are multiple targeted therapy agents that have been shown to be effective. Although they are not FDA approved, the NCCN recommends the use of the following targeted therapy agents based on their efficacy in clinical trials.

Sorafenib. Sorafenib is a kinase inhibitor that prevents tumor growth by inhibiting multiple kinases involved in cell growth and angiogenesis.⁴¹ It is used in treatment of locally advanced and metastatic chordomas.⁴² It is taken orally at a starting dosage of 400 mg twice daily for 9 months or until unacceptable toxicity. 

Adverse reactions reported with sorafenib include⁴¹:

• Diarrhea
• Fatigue
• Infection
• Alopecia
• Nausea
• Gastrointestinal and abdominal pain
• Hypertension

Concomitant use of sorafenib with the following medications should be avoided⁴¹:

• Strong CYP3A4 inducers (carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St John’s wort)
• Strong CYP3A4 inhibitors (ketoconazole)
• Neomycin

Pregnant patients should be warned of the risk of fetal harm, and birth control should be used by female patients with reproductive potential and male partners of female patients with reproductive potential during treatment and for 6 months and 3 months after treatment, respectively. Breastfeeding should be discontinued during treatment and for 2 weeks after treatment.⁴¹

Regorafenib. Regorafenib is an inhibitor of multiple kinases involved in growth of cancer cells.⁴³ It is recommended for the treatment of relapsed, refractory, or metastatic osteosarcomas.¹⁶ It is given orally at an initial dose of 160 mg (four 40-mg tablets) on days 1 to 21 of each 28-day cycle.⁴⁴ 

Adverse reactions associated with regorafenib include⁴³:

• Severe liver toxicity
• Hemorrhage
• Skin toxicity
• Hypertension
• Cardiac ischemia and infarction
• Fatigue
• Hand-foot skin reaction

Concomitant use of regorafenib with the following medications should be avoided⁴³ :

• Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine, phenobarbital, and St John’s wort)
• Strong CYP3A4 inhibitors (clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole)

Pregnant patients should be warned of the risk of fetal harm, and nursing mothers should be advised of the risk of passing regorafenib to the infant. Safe and effective use of regorafenib in patients younger than 18 has not been established.⁴³  

Imatinib. Imatinib is a tyrosine kinase inhibitor that prevents proliferation of cancer cells.⁴⁵ It is recommended as a single agent or with cisplatin or sirolimus for the treatment of chordoma. As a single agent, it is taken orally at 400 mg twice daily continuously for 24 months.⁴⁶ In combination regimens, it is taken orally at 400 mg once daily with cisplatin (25 mg/m²/wk)⁴⁷ or sirolimus (2 mg/d).⁴⁸

Adverse reactions reported with imatinib include⁴⁵: 

• Lung toxicity
• Low blood cell counts
• Edema
• Congestive heart failure
• Kidney toxicity
• Nausea and vomiting
• Musculoskeletal pain
• Fatigue

Concomitant use of imatinib with the following medications should be avoided⁴⁵:

• CYP3A inducers and inhibitors
• Drugs metabolized by CYP3A4 (triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, warfarin)
• Drugs metabolized by CYP2D6

Pregnant patients should be advised of the risk of fetal harm with imatinib, and nursing mothers should discontinue breastfeeding during treatment and for 1 month after treatment.⁴⁵ 

Denosumab. Denosumab is a human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL).⁴⁹ By blocking the activation of osteoclasts by RANKL, denosumab prevents bone metastasis.⁵⁰ It is approved for treatment of osteoporosis and prevention of skeletal-related events in patients with bone metastasis and GCTB.⁵¹ Denosumab has been shown to reduce bone resorption and increase/improve bone mass and/or strength in bone metastasis. However, it should be noted that long-term denosumab use may be associated with increased risk of local recurrence.⁴⁹

Denosumab is administered subcutaneously at 120 mg every 4 weeks in the upper arm, thigh, or abdomen. Additional 120-mg doses are given on days 8 and 15 of the first month of treatment.⁴⁹ 

Adverse reactions associated with denosumab include⁴⁹:

• Joint pain
• Back pain
• Headache
• Nausea
• Fatigue

The pregnancy status of female patients should be verified before treatment. Pregnant patients should be advised of the risk of harm to the fetus, and birth control should be used to avoid pregnancy during treatment and for 5 months after treatment. Nursing mothers should be warned of the risk of passing denosumab to the infant in breast milk.⁴⁹

Dasatinib. Dasatinib is a multikinase inhibitor that prevents growth and proliferation of cancer cells.⁵² It is recommended for treatment of chondrosarcoma and chordoma.¹⁶ It is given orally at 70 mg twice daily in a 28-day cycle.⁵³  

Adverse reactions reported with dasatinib include⁵²:

• Bone marrow suppression
• Hemorrhage
• Edema
• Congestive heart failure
• Diarrhea
• Headache

Use of the following medications with dasatinib should be avoided⁵²:

• CYP3A4 inhibitors and inducers
• CYP3A4 substrates (alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergotamine, dihydroergotamine)
• Antacids
• H2 antagonists/proton pump inhibitors (famotidine, omeprazole)

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Author Bio

Bora Lee, PhD, earned a Bachelor of Science in biology from Boston College and a PhD in Molecular and Cellular Biology from the University of Massachusetts Amherst. She has more than 10 years of translational research experience in reproductive medicine and women’s health, with a focus on fertility and placental health. She is passionate about improving people’s lives by helping them to make informed health decisions.