Written by | Xu Shuo, editor of | Gu Guocan
For high-risk neuroblastoma children (age > metastases at the time of diagnosis in 18 months, or MYCN gene amplification at any age), induction chemotherapy (Induction chemotherapy) can reduce the primary tumor size, reduce the metastases, and prepare for the next step of surgical resection of the tumor, which is a key part of the treatment of such children. As a result of higher intensity chemotherapy, better primary focus control, and the use of high-dose chemotherapy alone and in combination with high-dose chemotherapy and immunotherapy, the 3-year survival rate of high-risk children has increased from less than 20% to more than 50%. In recent years, research hopes to identify the most optimized chemotherapy regimens for patients with high-risk neuroblastoma in order to reduce the side effects of chemotherapy while ensuring the effectiveness of treatment.
The rapid COJEC regimen commonly used in Europe consists of cisplatin (Cisplatin, C), vincristine (O), carboplatin (Carboplastin, J), etoposide (Etoposide, E), and cyclophosphamide (C), with eight rounds of chemotherapy at intervals of 10 days over 70 days. A 2008 study showed a five-year event-free survival rate of 30.2 percent. The MSKCC-N5 regimen at Memorial Sloan Kettering Cancer Center in the United States uses a combination of high-dose cyclophosphamide, doxorubicin and vincristine (CAV) with alternating chemotherapy every three weeks with cisplatin and etoposide (PE), and the MSKCC reported a local response rate of about 80%. There have been no previous clinical randomized controlled trials comparing the therapeutic effects of the two.
In June 2021, the International Society of Pediatric Oncology European Neuroblastoma Group (SIOPEN) published a random trial of Two Induction in the Journal of Clinical Oncology Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study, comparing European rapid COJEC (rCOJEC) The results of the program, as well as the Memorial Sloan Kettering Cancer Center (MSKCC-N5) Metastases Complete Response (mCR) and Event Free Survival and Overall Survival, showed no significant difference in treatment efficacy, but the European regimen had lower toxicity.
The trial was an international, multi-arm, open-label Phase III clinical trial in which 941 patients with high-risk neuroblastoma were recruited from 160 SIOPEN centers in Europe, Israel, Australia and Hong Kong, China from October 2011 to June 2017, and 630 patients were randomly assigned to the rCOJEC protocol group (n=313) or the MSKCC-N5 regimen group (n=317) for chemotherapy.
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The two groups were similar in sex, age at diagnosis, primary tumor location, metastases, and MYCN gene amplification, with a median age of 3.2 years and a median follow-up of 3.6 years. Results showed that the rCOJEC group and the MSKCC-N5 group had a complete response rate (mCR) (32% vs. 35%, P=0.368), an overall response rate (70% vs. 74%, P=0.273), a three-year event-free survival rate (44% (38%-50%)vs. 47% (CI, 41%-53%), P=0.527), a three-year overall survival rate [60% (54%-66%) vs. 65% (58%-70%), ( There was no significant difference in the results in P = 0 .379)].
Toxicity mortality was 1% in both regimens, but the incidence of non-hematologic grade 3-4 toxicity was higher in patients with the MSKCC-N5 regimen (68% vs. 48%, P
EFS and OS in both groups of patients
The authors conclude that to date there have been only 4 randomized clinical trials of high-risk induction chemotherapy for high-risk mothers, and that randomized trials can better guide the choice of clinical regimen. The most widely used high-risk induction chemotherapy in the world is the Children's Oncology Group (COG) regimen, but the MSKCC-N5 regimen reported the best response rate and event-free survival outcomes, so the trial compared rCOJEC with the MSKCC-N5 regimen, and the results showed that the European regimen was as effective as the MSKCC-N5 regimen, but the incidence of short-term toxic side effects was lower. As survival rates in high-risk mother patients improved, the long-term side effects of chemotherapy were also more considered, and the European regimen did not use cardiotoxic doxorubicin compared to the MSKCC-N5 regimen, and used a lower total dose of cisplatin, so nephrotoxicity and ototoxicity were lower. The authors believe that the long-term side effects of chemotherapy also deserve more research.
In addition, although similarly good results were achieved in both sets of regimens, the complete response rate (mCR) of metastatic lesions with induction chemotherapy was only 30-35%, which was not improved by adding other chemotherapy drugs or extending the course of chemotherapy. Other results from this trial showed that the addition of two rounds of TVD chemotherapy (T, Topotecan; V, Vincristine, D, Doxorubicin) to patient groups with poor rCOJEC effects improved remission but did not improve survival. Therefore, more other treatment options are also being explored: for example, COG is currently investigating the inclusion of mIBG therapy in the standard induction chemotherapy regimen; the good effect of anti-GD2 monoclonal antibody combination chemotherapy in the treatment of relapsing mothers has led to more clinical trials planned by COG and SIOPEN.
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