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

Abstract

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.

<p>The Efficacy and Safety of Apatinib in Refractory/Relapse Advanced Pediatric Solid Tumor: A Retrospective Study</p>

“…30 The metronomic therapy concepts continuously use of low-dose chemotherapeutic, anti-angiogenetic and immunomodulating drugs, which is demonstrated to obtain a sustained antitumor effect through modulating the tumor microenvironment. 31 However, a recent randomized clinical trial showed that the metronomic chemotherapy only reached 3.5% ORR in progressive pediatric solid malignant tumors and did not prolong progression-free survival compared with placebo. 32 In a phase II study, apatinib combined with MC reached 54% ORR and 8-month PFS in patients with platinum-resistant or platinum-refractory ovarian cancer.…”

Metro‐SMHOP 01: Metronomics combination with cyclophosphamide‐etoposide and valproic acid for refractory and relapsing pediatric malignancies

“…In our study, the median PFS was three months and depended on the diagnosis, in line with previous studies on metronomics in palliative care settings. 11,[17][18][19] Although the number of patients treated in this study is higher than in most metronomic pediatric trials, 9,10,15,17,23,26 the design of the study with the lack of cohort of patients with different type of diseases and phase 2 design (i.e., Simon 2 steps) does not allow us to formally demonstrate its activity or absence of activity in specific tumors. Nevertheless, as reported in previous studies, our osteosarcoma patients were not good responders to metronomic chemotherapy.…”

“…Nevertheless, as reported in previous studies, our osteosarcoma patients were not good responders to metronomic chemotherapy. 11,17 Therefore, we do not believe that patients with osteosarcoma should be treated with this MC protocol. Conversely, some tumors such as neuroblastoma or lymphoma or low-grade glioma are good candidates for MC.…”

“…9,14,26 We also observed that this regimen was well tolerated with very little hematological toxicity, frequently observed when using a more intense metronomic protocol. 17,22,23 Quality of life during metronomic therapy has rarely been reported. Porkholm et al have reported that the Karnofsky-Lansky scores increased significantly during MC in 17 children, with 35% of the patients having a transient improvement in their clinical status.…”

Metronomic Chemotherapy

“…Two different areas of research can be identified: mCHT as maintenance treatment in different pediatric cancer [ 109 ] Metronomic combination of different chemotherapy drugs [ 110 , 111 ] mCHT in combination with other drugs [ 112 , 113 , 114 ] …”