DISCUSSION
MYCNA neuroblastoma is often unresectable at initial diagnosis because of its size, location or IDRFs, and vascularity.8 9 The efficacy of current neoadjuvant therapy can render infiltrative tumors more readily resectable with less risks.10 A tumor’s resectability takes into consideration all of the aforementioned factors and a surgeon’s judgment that the surgical goal can be met with minimal morbidity. From the surgeon’s perspective, the ability to predict a tumor’s response to chemotherapy allows the opportunity for adequate surgical planning.
We selected four response measures that were believed to be related to the safe conduct of surgery. The reduction in tumor volume during induction chemotherapy had been reported to be predictive of outcome in high-risk neuroblastoma.4 5 Such a response would have significant surgical implications as it would decrease tumor vascularity and hence improve tumor resectability.11 IDRFs were surgical risk factors introduced in the INRGSS.6 Although these factors were not contraindications to surgery, they had been predictive of outcome, surgical complications, and the completeness of resection.12–14 The resolution of these factors was used here as a response measure for preoperative chemotherapy. The amount of tumor necrosis represented the tumor’s histological response to preoperative chemotherapy. Tumor necrosis would be considered a predisposition for less bleeding at tumor dissection. The incidence of surgical complications was chosen as a response measure as these were typically related to the difficulty of the surgery.
When compared with Bagatell et al’s study,5 we found a similar proportion (86%) of MYCNA patients achieved TVR>50. However, we saw significantly fewer patients achieved TVR>65 than published (66% vs 87%, p=0.003). The reason behind this result remained unclear, but it could be related to the lack of compliance to standardized protocols across our referring centers. It was also noteworthy to learn from the same reference study that even though volume-based response assessment was not associated with the extent of tumor resection, it was predictive of survival. In our study, significantly more patients with TVR>65 experienced reduced IDRFs and Nec>50 as well, hence more favorable conditions for surgery.
In the International Neuroblastoma Risk Group (INRG) concept, patients with at least one IDRF have potential surgical risks, and the implication of proportionate resolution of IDRFs has not yet been discussed. In our experience, even the resolution of one or few, but not all, IDRFs would have reduced surgical risks and led to safer surgeries. Only few in our cohort had complete disappearance of IDRFs while more showed numerical reduction after preoperative chemotherapy. Despite larger TVR (>65), only 46% had reduced IDRFs after chemotherapy. This proportion was significantly higher than those with smaller TVR. At the time of surgery, 83.9% continued to have one or more IDRFs. The four most common IDRFs were also most refractory to resolution, namely, renal pedicles, SMA, celiac axis, and aorta/inferior vena cava. We believed these sites represented the tumors’ origin in peri-arterial sympathetic nervous system.
When compared with non-MYCNA tumors, MYCNA neuroblastoma had been known to be associated with significantly more tumor necrosis after chemotherapy.15 Our study showed similar findings where 76% of tumors achieved Nec>50, of which 60% had Nec>90.
Previous publications have reported that tumor response was most prominent in the first few cycles of chemotherapy.11 16 Those who required more may have acquired chemoresistance. As our patients received diverse treatment protocols with many lacking in details of treatment, we were not able to make reasonable inference. Nevertheless, we believed there was a misconception that more chemotherapy could further reduce IDRFs that were present.
MYCN testing was not consistently available in some of the referring centers in the early half of this decade. Awareness and availability of MYCN testing has improved with time. In its absence, 10 patients received less intensive treatment when they were stratified to intermediate-risk group protocols. Nevertheless, these MYCNA tumors showed remarkable chemosensitivity, with 80% achieving TVR>65 and 100% Nec>50.
The presence of metastatic disease was not associated with TVR, reduced IDRFs, and Nec. However, it was noteworthy that non-metastatic patients were significantly more prone to develop surgical complications, and the underlying reasons were unclear. Though all MYCNA patients were stratified as high-risk group regardless of age, patients <1.5 years were more chemo-responsive, achieving Nec>50.
In conclusion, the majority of our MYCNA neuroblastoma were highly chemo-sensitive. They were good responders to preoperative chemotherapy as they experienced high TVR, reduced IDRFs, and high Nec, and hence favorable conditions were created for surgical resection. Poor responders and persistent IDRFs were commonly refractory to chemotherapy, and they remained a surgical challenge.
