Despite many advances in the understanding and treatment of gliomas in general and glioblastoma in particular, this group of tumors still presents a great challenge to clinicians and, above all, to patients and their loved ones. Surgery remains the mainstay of treatment followed by radio-chemotherapy. The aim of surgery is to establish a diagnosis, remove the mass effect, and if possible, achieve a gross total resection of the mass. The latter has proved to be one of the major determinants of survival, along with age, functional status, tumor grade, and more recently, tumor genotype [7, 24]. The extent of resection (EOR) is probably the only surgeon modifiable factor, and therefore, many tools have been introduced to help surgeons achieve maximum safe tumor resection.
In this study, we revisited the topic of intraoperative ultrasonography (IOUS) as an image guidance modality to help neurosurgeons achieve the goals of surgery. In the time where inflated health care budgets in developing countries are ringing many bells, while developing countries continue to struggle with limited resources, IOUS offers a cost-effective and valuable tool in surgery of intrinsic brain tumors. The aim of this study was to evaluate the impact of introducing IOUS on the ability to safely achieve higher extent of tumor resection (EOR).
Multiple studies have reported on their EOR and its impact on the overall survival in patients with both high- and low-grade gliomas [3, 9, 10, 25]. Modern era neurosurgical series, in which microsurgical techniques in addition to neuronavigation were employed, reported EOR ranging from 87 to 96% for high-grade gliomas with about 25–35% gross total resection rate [9, 21, 26]. Additional intraoperative assisting techniques were able to increase this rate to 50% as shown in the aminolevulinic acid (ALA) study where ALA fluorescence further guided resection [27]. In 2011, Sanai and colleagues challenged the status quo maintained since the late 1990s that only GTR and NTR were beneficial in terms of survival when they demonstrated in a large series of 500 patients that as low as 78% resection was still beneficial in terms of survival, but not as well as higher degrees of resection, arguing that more modest resection goals can be beneficial if met, especially with complex, eloquent tumors [26]. In 2014, Chaichana and colleagues were able to demonstrate a further reduction in that threshold to 70% resection and added another variable which is residual tumor volume (RV) when they showed that RV < 5 cm3 lead to a better survival irrespective of the EOR [21].
In our IOUS series, and despite the lack of frameless stereotaxy navigation or fluorescence, we were able to achieve a median resection of 83% with a GTR rate of 29% and combined GTR/NTR (resection > 90%) of 53% (Fig. 6). This seems acceptable by international standards, and it was achieved using ultrasound guidance, while the results in the control group were significantly worse with median EOR of 66% and 0% GTR rate. The reason behind this is that surgery without image guidance, depending only on microscopic visualization, usually misses small nodular residuals that can be detected by IOUS and subsequently removed. Despite an adequate microscopic appearance of total resection, small nodular residual tumor scattered in different places along the tumor periphery can easily be missed. These small nodules left behind simply make the resection subtotal and deprive patients from the advantages of a gross total resection.
The study included multiple pathological entities with glioblastoma being the most prevalent (67%). It also included both diffuse and focal low-grade astrocytomas, which enriched the experience gained with the echogenic differentiation of these various pathologies. Future analysis of survival trends based on long-term follow-up is expected to produce survival benefits in specific entities as the study represents the first cohort in an ongoing prospective registry. After these primary results, we were compelled to stop the control group and to recommend ultrasound guidance in all new patients.
Preoperative KPS is one of the most consistent prognostic factors affecting survival in glioma patients. Studies have shown that KPS of 80% or above was associated with better overall survival following surgery [7]. The preoperative neurological function, better expressed in performance scores, was probably better in the IOUS group than the control group with near statistical significance. The postoperative KPS of IOUS group was significantly better than the control group. It is not clear whether this difference is a true reflection of the IOUS benefit or a bias caused by differences in basic characteristics between groups. On the other hand, the mean postoperative KPS in the IOUS group (83%) was higher than preoperative KPS in the same group (81%), albeit without significant statistical difference, indicating that more radical resection did not have an obvious negative impact on neurological outcomes.
Among tumors operated, 15 (50%) were in eloquent areas. The rate of new or worsened postoperative neurological deficits in the early postoperative period was 13.3% (4 patients), which probably could have been avoided if cortical mapping and awake craniotomy techniques were used. Within 1 month, 2 patients returned to their baseline making the 1-month postoperative neurological deficit rate 6.7% equally divided between both groups. This general low incidence and the small sample size did not allow to draw any conclusions regarding difference between groups. No patient died within the first 30 days after surgery.
Stummer reported a 7% neurological complication rate while there was around 3% mortality rate within 30 days of surgery of 260 patients [27]. Chaichana reported a 13% neurological deficit rate following surgery for 259 patients [21]. In both studies, the patients were mixed with both eloquent and non-eloquent tumors. Ius and colleagues used cortical mapping and fMRI navigation on 190 patients with LGG in eloquent areas and found an immediate postoperative neurological deficit of 43.7% that dramatically improved to 3.16% in 6 months [3].
One of the important benefits of this study was the steep learning curve of IOUS. After the first few cases, surgeons were more comfortable using and interpreting ultrasound images. Preoperative MRI scans and intraoperative US images where compared in the same orientation to produce a better understanding of the surgical field anatomical landmarks.
There was a clear relationship between MRI contrast enhancement in the preoperative images and the lesion echogenicity intraoperatively. Contrast-enhanced lesions were generally hyperechoic, making them sonographically well localized and with better defined margins. Non-contrasted lesions, like diffuse low-grade astrocytomas, were generally isoechoic, making it difficult to distinguish them from surrounding normal brain. But this does not mean that echogenicity corresponded to tumor grade, since focal low-grade tumors like pilocytic astrocytoma and pleomorphic xanthoastrocytoma that had contrast enhancement did appear hyperechoic with IOUS and were generally well localized. This is an interesting topic that needs further studies, but until then, it is advisable not to rely on IOUS alone when tackling non-enhancing lesions like diffuse low-grade gliomas. Intraoperative MRI guidance seems to be helpful when resecting these tumors, but intraoperative MRI has its considerable cost and special setting [14].
The study had the advantage of being prospective, yet it had some weaknesses. First, there is a lack of patient randomization, which may have contributed to selection bias. Second, the relatively small number of patients, and particularly in the control group, did not allow to draw statistically significant difference, if one does exist, in some comparisons including the rate of complications. Also, a separate pathological examination of residual nodules identified and removed could have strengthened the results. The future goal is to acquire multiple biopsies from the homogenous thin hyperechoic margins thought to be due to edema and that do not show contrast enhancement on postoperative MRI. Despite the weaknesses, the study showed the image guidance advantage of IOUS and helped establish IOUS as a routine tool in our surgeries. It also accelerated the IOUS learning curve and made surgeons more comfortable using and interpreting IOUS images.