Complete excision improves survival after induction therapy for high-risk neuroblastoma
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Complete macroscopic excision of the primary tumor after induction chemotherapy appeared to improve survival outcomes among children with stage IV high-risk neuroblastoma, according to study results published in Journal of Clinical Oncology.
Researchers observed higher rates of 5-year EFS and OS and lower rates of local recurrence, compared with incomplete macroscopic resection, during the pre-immunotherapy and immunotherapy eras.
“Despite recent therapeutic advances, many patients with high-risk neuroblastoma will not be long-term survivors. ...To date, clinical trials have focused on induction, high-dose therapy and immunotherapy, with less attention directed to local therapy, and there have been no randomized trials to examine the effect of the extent of excision of the primary tumor,” Keith Holmes, ChM, DCH, FRCS, researcher in the department of pediatric surgery at St. George’s Hospital London and Royal Marsden Hospital in the U.K., and colleagues wrote. “Complete macroscopic excision can be performed for the most extensive tumors with low morbidity and mortality. However, there are conflicting reports as to the benefit.”
Holmes and colleagues sought to determine the impact of the extent of surgeon-assessed primary tumor resection on local progression and survival among 1,531 children with high-risk neuroblastoma. The children, enrolled across 128 institutions in 18 countries, received treatment in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial.
Researchers recruited children with stage IV disease for more than 1 year or stage IV/4S with MYCN amplification for less than 1 year who completed induction chemotherapy without disease progression, achieved response criteria for high-dose therapy and had no resection before induction. They analyzed data on primary tumor excision, severe operative complications and survival outcomes.
Between June 2002 and September 2009, all children received treatment with oral isotretinoin after completion of radiotherapy. Between October 2009 and August 2013, they underwent random assignment to dinutuximab (Unituxin, United Therapeutics) and isotretinoin or dinutuximab with subcutaneous interleukin 2 and isotretinoin, followed by dinutuximab and isotretinoin between September 2013 and December 2015.
The log-rank test and Cox regression were used for statistical comparisons among the entire cohort and separately for children included between June 2002 and June 2009 and those included between July 2009 and December 2015.
Median observation time was 6.1 years.
Most children (77%; n = 1,172) underwent complete macroscopic excision, whereas 23% (n = 359) underwent incomplete macroscopic resection. Seven children (0.46%) died of operation-related causes, 142 children (9.7%) experienced severe complications and 124 (8.8%) underwent nephrectomy.
Researchers presented data as 3-year and 5-year point estimates with standard errors.
Compared with incomplete excision, complete excision resulted in significantly higher 5-year EFS (0.4 ± 0.01 vs. 0.33 ± 0.03; P < .001) and 5-year OS (0.45 ± 0.02 vs. 0.37 ± 0.03; P = .004), as well as lower cumulative incidence of local progression (0.17 ± 0.01 vs. 0.3 ± 0.02; P .001).
Between June 2002 and June 2009, 5-year EFS was 0.33 ± 0.02 after complete excision vs. 0.27 ± 0.03 after incomplete excision (adjusted HR [aHR] = 1.3; 95% CI, 1-1.6), 5-year OS was 0.36 ± 0.02 vs. 0.29 ± 0.03 (aHR = 1.3; 95% CI, 1-1.6) and 5-year cumulative incidence of local progression was 0.2 ± 0.02 vs. 0.33 ± 0.04 (aHR = 2.1; 95% CI, 1.5-2.9).
Outcomes with complete excision remained superior in the immunotherapy era, starting in June 2009. Five-year EFS was 0.47 ± 0.01 vs. 0.39 ± 0.04 after incomplete excision (aHR = 1.3; 95% CI, 1-1.6), 5-year OS was 0.54 ± 0.02 vs. 0.45 ± 0.02 (aHR = 1.3; 95% CI, 1-1.7; P = .049) and cumulative incidence of local progression was 0.14 ± 0.02 vs. 0.27 ± 0.03 (HR = 1.8; 95% CI, 1.2-2.7).
“To our knowledge, this study of 1,531 patients is the largest analysis of the influence of surgical excision on the survival of patients with stage IV high-risk neuroblastoma in a single trial to date,” Holmes and colleagues wrote. “An improvement in survival and a reduction in local progression were associated with [complete macroscopic excision] and radiotherapy to the preoperative volume of the primary tumor and involved regional lymph nodes. Furthermore, the association of [complete macroscopic excision] with a superior outcome persisted with immunotherapy using dinutuximab beta. In conclusion, the low severe operative complication and mortality rates justify determined attempts at [complete macroscopic excision] of the primary tumor after appropriate chemotherapy.”
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