Cervical CHOs are distinct from CHOs of other areas of the neuro-axis in that there is significant risk associated with close relation and often times juxtaposition of structures such as the vertebral arteries, cervical spinal cord, and esophagus. Surgical resection with en bloc spondylectomy is typically regarded as more challenging than resection of a tumor in another region such as the lumbar spine or sacrum, because damage to the aforementioned structures will lead to catastrophic complications and even death. GTR with either en bloc spondylectomy or intralesional-GTR of CHOs requires extensive planning and should typically be performed by spine surgeons at high volume tertiary academic centers with extensive experience managing these tumors. Literature has typically favored en bloc resection of CHOs in the sacrum, but there is limited data for or against this resection strategy in the cervical spine. 
Our study represents the first and only meta-analysis of patients with cervical CHO. This manuscript is also unique in that we performed an individual patient data meta-analysis which gives us the opportunity to assess PFR and OS for the all of the groups together to assess the effect of extent of resection on PFS and OS. We discovered that patients with GTR of their tumor did have an increased PFS and OS of their tumors compared to those with STR of their tumor. This forms the highest level of evidence to advocate for GTR of cervical CHOs and is consistent with previously published articles for sacral CHOs. Of note, the GTR group includes intralesional-GTR which involves piecemeal resection of the tumor, as well as en bloc spondylectomy with clear margins. Patients with positive margins were included in the intralesional-GTR group. Because these resection strategies are completely different, we performed a meta-regression analyses to determine if one particular type of GTR strategy should be favored over another. We also performed an intention-to-treat analysis including all patients with attempted en bloc resection in one group, regardless of the postoperative margins.
PFS was improved by GTR of the tumors in patients with cervical CHO. Unfortunately, our study was unable to perform an analysis to compare the intralesional-GTR and en bloc cases, as the number of events was insufficient for this comparison. However, it is important to note that there was a significant improvement in disease progression for patients en bloc spondylectomy (pooled HR = 0.06; 95%CI = 0.01–0.77; p = 0.030) and intralesional-GTR (pooled HR = 0.25; 95%CI = 0.08–0.79; p = 0.019) when compared to STR. Although we could not compare the intralesional-GTR and en bloc groups, the HR for en bloc was higher, which could at least indicate more benefit in risk of recurrence with en bloc resection of tumors. Although our case series was underpowered, using volumetric assessment of the pre-and postoperative tumors volumes, we were able to determine that there is a moderate correlation between the preoperative tumor size and the extent of resection, with smaller tumors being more likely to result in a more extensive resection. For OS, there was a significant improvement with intralesional-GTR, but not with en bloc-GTR. While this could be attributed to low numbers for this assessment, it is reasonable to conclude that. En bloc spondylectomy is a high-risk technique that requires specialized training; thus, should only be performed by experienced spinal surgeons. It is possible that more extensive surgeries may result in greater morbidity and delayed radiation. Unfortunately, there was no way to determine that specific cause of death in the patients, which would provide more insight into this analysis. Our intent-to-treat analysis revealed that when all patients that had attempted en bloc resection (including those with violated margins) were compared to the STR cohort, there was a nearly significant improvement in OS (pooled HR: 0.15; 95%CI:0.02–1.22; p = 0.054). The surgical steps for performing an en bloc resection are much different than those for performing an intralesional resection of a tumor and subject a patient to a different set of complications and morbidity, but also may have more benefit that performing a planned intralesional resection. The improvement in OS when including all patients with attempted en bloc resection indicates that there may be a benefit in the procedure of en bloc resection, even if the surgery results in violated margins.
Radiation therapy with either proton or protons is considered the standard of care for patients with CHO of the skull base or spine. In this study, we sought the better understand the effect of radiation on patients with surgical resection of their CHO. Unfortunately, not all of the included studies commented on the use of radiation, and for the studies that did, there were very few patients who did not receive radiation, which is to be expected. Furthermore, these studies did not report on dosage, or timing of radiation. However, we were able to review the data from our series to determine the effect of high dose (> 70Gy) radiation. There was a higher mean PFS for patients that had high dose proton-based radiation (49 months), while patients who received < 70Gy radiation had a PFS of 31 months. Although this analysis was not significant due to low numbers, this poses the question of whether the differences in PFS for the surgical groups are partially related to the dose of radiation given to the patients, but unfortunately, this data was not available in the larger study. However, 43% of the patients with GTR received high dose radiation, while 54% of patients with STR received high dose radiation, which indicates that patients who had residual tumor were slightly more likely to have received high dose radiation which possibly played a role in the outcomes.
Although there was more than two-fold increase in PFS for patients with primary cervical tumors of the subaxial spine when compared to those with tumors involving the atlas or axis, there was no significant difference in this analysis, but would likely have been significant if there were more numbers. When we look at all of the patients in all studies, there was a trend toward significance for the effect of tumor location (upper versus lower cervical) on PFS (p = 0.063). In addition to this, there was a trend toward significance for the effect that tumor location had on the type of resection achieved, with subaxial tumors being more likely to receive an extensive GTR (p = 0.075). In our cohort, we also assessed the effect of targeted therapy on PFS, but there was no significant difference between the groups. This is likely due to the fact that most patients undergoing targeted therapy for CHO had progressive and advanced disease at the time of initiation of the drug.
Limitations & Strengths
Cervical chordomas are rare tumors, and thus the case series was limited by numbers, which is why a meta-analysis was needed to be able to draw conclusions on this topic. This manuscript is subject to the inherent limitations of meta-analyses papers, as the quality of this manuscript primarily relies on the quality of the included studies. This manuscript was unable to quantitatively assess the use of high dose radiation in the large cohort due to lack of data from some of the included manuscripts. We were unable to separate patients with recurrent CHO from those with primary CHO, which may lead to slight skewing of the data, but this remains the highest level of evidence for patients with cervical CHO. Also, ideally our study would stratify STR patients into categories such as < 50% resection and 50–99% resection, to determine if there is benefit from the amount of tumor resection, even if a GTR cannot be achieved, but the study design did not allow for this in-depth analysis. Also, we were unable to confirm the extent of resection for the included studies. Our quality assessment revealed that quality of most of the assessments were rated as low certainty. This is not surprising due to the low numbers available for this specific pathology and should be considered when interpreting the results. CHOs are slow growing tumors, and follow-up of 5–10 years would be ideal for studies involving patients with CHO. This study was limited by variable follow-up of the included studies, but 8 of the included studies had a mean follow-up of at least 50 months. Future studies should consider assessing the percentage of resection to help guide clinicians when a GTR cannot be safely achieved. We were able to perform an individual participant data meta-analysis, which provides an advantage over normal meta-analyses studies with time-to-event outcomes for this large cohort. An additional strength of this study is the geographic location of the included institutions in the case series, with representation from the Southwest, Southeast, and Midwest.