Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high‐grade, operable osteosarcomas of the extremities: A report from the Latin <scp>A</scp>merican Group of Osteosarcoma Treatment

Senerchia, Andreza Almeida; Macedo, Cristiane R; Ferman, Sima; Scopinaro, Marcelo; Cacciavillano, Walter; Boldrini, Érica; Moraes, Vera Lúcia; Rey, Guadalupe; Oliveira, Claudia; Castillo, Luis; Almeida, Maria Tereza Assis de; Borsato, Maria Luisa; Lima, Eduardo; Lustosa, Daniel; Barreto, José Henrique Silva; El‐Jaick, Tatiana; Aguiar, Simone S.; Brunetto, Algemir Lunardi; Greggiani, Lauro; Cogo‐Moreira, Hugo; Atallah, Álvaro Nagib; Petrilli, Antônio Sérgio

doi:10.1002/cncr.30411

Cited by 52 publications

(66 citation statements)

References 35 publications

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“…In addition, Pramanik et al compared MC and supportive care in progressive pediatric solid malignant tumors and found that median PFS and OS were similar in both groups with BS. Lastly, a recent study, investigating the efficacy of the addition of MC to standard chemotherapy versus standard chemotherapy alone in patients with nonmetastatic high‐grade operable osteosarcoma, demonstrated that the addition of MC with methotrexate and cyclophosphamide was not statistically superior to the standard treatment without MC (5‐year PFS = 61% vs 64%, P = 0.395; 5‐year OS = 76% vs 73%, P = 0.539). Our study is consistent with these findings, and we do not believe that this MC regimen should be used for refractory/relapsing osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

SFCE METRO‐01 four‐drug metronomic regimen phase II trial for pediatric extracranial tumor

Heng-Maillard

Verschuur

Aschero

et al. 2019

Pediatric Blood & Cancer

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Objective To investigate the antitumor activity of a four‐drug metronomic chemotherapy (MC) regimen in relapsed/progressing pediatric extracranial solid tumors (EST). The primary objective was clinical benefit (complete response /partial response/stable disease [SD]) after two cycles of therapy (four months). Methods Patients aged ≥4 to 25 years with progressing EST and adequate organ function were eligible. Treatment consisted of an eight‐week cycle of oral celecoxib b.i.d., weekly vinblastine, and oral cyclophosphamide for three weeks alternating with oral methotrexate for three weeks, with a two‐week rest. The Kepner–Chang two‐stage model was used with 10 patients in the first stage. If primary objective was reached in two or more patients, eight additional patients were included according to four groups: neuroblastoma (NBL), soft‐tissue sarcoma (STS), bone sarcoma (BS), and miscellaneous (Misc.). Results Forty‐four patients were evaluable. The NBL cohort could be expanded to 18 patients: 4 of 18 patients stabilized with MC treatment for 6 (n = 1) and 12 (n = 3) months. In STS, two of seven patients (metastatic hemangioendothelioma and angiosarcoma) had SD for > 2 cycles. One of nine Misc. (metastatic myoepithelial carcinoma) had SD for one year. All patients with BS had progressive disease. One‐year progression‐free survival of the whole cohort was 6.8% and one‐year overall survival was 55.3%. Grade 3 toxicity occurred in 18 patients and grade 4 in 15 patients. The most frequent toxicity was hematologic, predominantly neutropenia. Conclusions This MC has no activity in BS and limited though interesting activity in NBL with some patients being stable for > 1 year. It is not possible to conclude activity in STS and Misc.

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Section: Discussionmentioning

confidence: 99%

SFCE METRO‐01 four‐drug metronomic regimen phase II trial for pediatric extracranial tumor

Heng-Maillard

Verschuur

Aschero

et al. 2019

Pediatric Blood & Cancer

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“…Our own group published the first randomized controlled trial in relapsed refractory solid tumors, and showed that metronomic therapy was no better than placebo; however, subgroup analysis revealed that tumors other than bone sarcoma showed benefit for both progression‐free survival and overall survival (OS) with the use of metronomic therapy. Further, specific tumor‐related studies with metronomics showed that this form of treatment appears to work in neuroblastoma and RMS, but not so in osteosarcoma …”

Section: Clinical Usage In Pediatricsmentioning

confidence: 99%

“…A recent Phase II study of oral etoposide in 30 patients of R/R osteosarcoma gave modest results . However, a large randomized study using oral methotrexate and cyclophosphamide as a maintenance strategy after curative treatment of nonmetastatic osteosarcoma reported no difference in OS …”

Section: Experience In Individual Pediatric Malignanciesmentioning

confidence: 99%

“…Studies such as METRO‐MALI1,2 have successfully used combination metronomics in such setups with limited resources . The Latin American study recently published a large randomized controlled trials (RCT) on metronomic maintenance in osteosarcoma and showed its lack of efficacy . The first RCT in the palliative setting and retrospective analysis of medulloblastomas with the COMBAT regimen have been reported from India .…”

Section: Enthusiasm In Low‐ and Middle‐income Countries: Pharmaco‐ecomentioning

confidence: 99%

“…Further, specific tumorrelated studies with metronomics showed that this form of treatment appears to work in neuroblastoma 68 and RMS, 60 but not so in osteosarcoma. 66 It is also noted that in some studies, addition of radiotherapy may have contributed substantially to the good response rather than metronomic chemotherapy itself. 58…”

Section: Timelinementioning

confidence: 99%

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Metronomic therapy in pediatric oncology: A snapshot

Pramanik

Bakhshi

2019

Pediatric Blood & Cancer

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Metronomic chemotherapy transitioned from the bench to bedside in the early 2000s and since then has carved a niche for itself in pediatric oncology. It has been used solely or in combination with other modalities such as radiotherapy, maximum tolerated dose chemotherapy, and targeted agents in adjuvant, palliative, as well as maintenance settings. No wonder, the resulting medical literature is extremely heterogeneous. In this review, the authors review and synthesize the published literature in pediatric metronomics giving a glimpse of its history, varied applications, and evolution of this genre of chemotherapy in pediatric cancers. Limitations, future prospects, and grey areas are also highlighted.

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LncRNA CRNDE is activated by SP1 and promotes osteosarcoma proliferation, invasion, and epithelial‐mesenchymal transition via Wnt/β‐catenin signaling pathway

Ding

Cai

et al. 2020

J of Cellular Biochemistry

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Long noncoding RNAs (lncRNAs) were identified as a vital part in the development and progression of cancer in recent years. Colorectal neoplasia differentially expressed (CRNDE), a lncRNA, functions as an oncogene in some malignant neoplasias, but its role in the progression of osteosarcoma (OS) is still poorly understood. To dissect the difference in the expression of CRNDE, quantitative real-time polymerase chain reaction was utilized to evaluate it in OS tissues and cell lines (U2OS, MG63, and MNNG/HOS) compared with that in the adjacent normal tissues/osteoblast cells (hFOB1.19). The role of CRNDE in OS lines was assessed using Cell Counting Kit-8, colony formation, 5-ethynyl-2′-deoxyuridine staining, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, flow cytometry, Transwell assays, and Western blot, respectively. The results demonstrated that the expression of CRNDE was high in OS tissues and cell lines, and partly induced by SP1. CRNDE knockdown attenuated OS cell proliferation and invasion and induced apoptosis and G0/G1 arrest. Moreover, the expression of mesenchymal markers N-cadherin, Vimentin and Snail were downregulated, while the expression of epithelial markers E-cadherin and ZO-1 were conversely upregulated due to CRNDE knockdown. The mechanistic investigations showed that CRNDE promoted glycogen synthase kinase-3β phosphorylation to activate the Wnt/β-catenin pathway. The results suggested that lncRNA CRNDE indeed contributed to OS proliferation, invasion, and epithelialmesenchymal transition, working as an oncogene, demonstrating that lncRNA CRNDE may be a valid therapeutic target for the OS.

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Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high‐grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment

Abstract: According to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.

Cited by 52 publications

References 35 publications

SFCE METRO‐01 four‐drug metronomic regimen phase II trial for pediatric extracranial tumor

SFCE METRO‐01 four‐drug metronomic regimen phase II trial for pediatric extracranial tumor

Metronomic therapy in pediatric oncology: A snapshot

LncRNA CRNDE is activated by SP1 and promotes osteosarcoma proliferation, invasion, and epithelial‐mesenchymal transition via Wnt/β‐catenin signaling pathway

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