Preoperative chemotherapy

A meta-analysis of protocols for the treatment of osteosarcoma concluded the following:[27]

A meta-analysis of protocols for the treatment of osteosarcoma concluded the following:[27]

Regimens containing three active chemotherapy agents were superior to regimens containing two active agents.

A meta-analysis of protocols for the treatment of osteosarcoma concluded the following:[27]

Regimens with four active agents were not superior to regimens with three active agents.

A meta-analysis of protocols for the treatment of osteosarcoma concluded the following:[27]

Three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.

An Italian study that used regimens containing fewer courses of high-dose methotrexate observed the following results:[28][Level of evidence B4]

An Italian study that used regimens containing fewer courses of high-dose methotrexate observed the following results:[28][Level of evidence B4]

There was a lower probability for EFS than found in earlier studies that used regimens containing more courses of high-dose methotrexate.

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Results showed that:[29][Level of evidence A1]

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Results showed that:[29][Level of evidence A1]

The addition of ifosfamide did not improve outcome.

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Results showed that:[29][Level of evidence A1]

The addition of L-MTP-PE produced improvement in the EFS rate, which did not meet the conventional test for statistical significance (P = .08), and a significant improvement in the OS rate (78% vs. 70%; P = .03).

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Results showed that:[29][Level of evidence A1]

There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion.[30]

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

In pilot study 1, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2.

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

In pilot study 2, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2.

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

In pilot study 3, all patients received the same four-drug initial chemotherapy as pilot study 2. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

Outcomes for all three pilot studies were similar to each other and to historical controls.

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or EFS.

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry.

The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4] The results of these pilot studies were as follows:

There was no evidence for an increased risk of secondary leukemia.

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

At a median follow-up of 54 months for all registered patients (N = 2,260), the 3-year EFS rate was 59% (95% confidence interval [CI], 57%–61%), and the 5-year EFS rate was 54% (95% CI, 52%–56%).

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

The 3-year OS rate was 79% (95% CI, 77%–81%), and the 5-year OS rate was 71% (95% CI, 68%–73%).

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

Patients with localized disease at diagnosis (M0) who underwent complete surgical resection (n = 1,549) had 3-year EFS and OS rates from surgery of 70% and 88%, respectively; the 5-year EFS and OS rates from surgery were 64% and 79%, respectively.

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

Forty percent of patients/families who participated in the study declined randomization after definitive surgical resection, making interpretation of the outcome of the randomized study questions more difficult and challenging the generalizability of the results.

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

Of patients with more than 90% necrosis, 716 were randomly assigned to continue the same chemotherapy after surgery with or without the addition of interferon alpha-2B. The 3-year EFS rates were 74% (95% CI, 69%–79%) for patients who received MAP and 77% (95% CI, 72%–81%) for patients who received MAP plus interferon alpha-2B. The HR was 0.83 (95% CI, 0.61–1.12; P = .2).[33]

The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]

Of patients with less than 90% necrosis, 618 were randomly assigned to continue MAP chemotherapy or to receive MAPIE chemotherapy. The 3-year EFS estimates for patients with localized disease were 60% (95% CI, 54%–66%) for the MAP group and 57% (95% CI, 51%–63%) for the MAPIE group. The HR was 1.03 (0.81–1.33, P = .80).[34]

In a French Sarcoma Group trial, high-dose methotrexate was omitted for adult patients with osteosarcoma. The cohort included 60 patients aged 16 to 63 years (median age, 27 years). Patients received initial therapy with ifosfamide and cisplatin. Doxorubicin was added after definitive surgery for patients who had less necrosis after initial chemotherapy.[35]

In a French Sarcoma Group trial, high-dose methotrexate was omitted for adult patients with osteosarcoma. The cohort included 60 patients aged 16 to 63 years (median age, 27 years). Patients received initial therapy with ifosfamide and cisplatin. Doxorubicin was added after definitive surgery for patients who had less necrosis after initial chemotherapy.[35]

With a median follow-up of 322 months, the 5-year disease-free survival (DFS) rate was 51.8%, and the 5-year OS rate was 64.4%.

In a French Sarcoma Group trial, high-dose methotrexate was omitted for adult patients with osteosarcoma. The cohort included 60 patients aged 16 to 63 years (median age, 27 years). Patients received initial therapy with ifosfamide and cisplatin. Doxorubicin was added after definitive surgery for patients who had less necrosis after initial chemotherapy.[35]

At 10 years, the DFS rate was 49.9%, and the OS rate was 64.4%.

In a French Sarcoma Group trial, high-dose methotrexate was omitted for adult patients with osteosarcoma. The cohort included 60 patients aged 16 to 63 years (median age, 27 years). Patients received initial therapy with ifosfamide and cisplatin. Doxorubicin was added after definitive surgery for patients who had less necrosis after initial chemotherapy.[35]

At 25 years, the DFS rate was 47.8%, and the OS rate was 55.9%.