Adding metronomic chemo provides no benefit to MAP for osteosarcoma

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.