Outcomes following attempted en bloc resection of cervical chordomas in the C-1 and C-2 region versus the subaxial region: a multiinstitutional experience

Clinical article

Full access

Object

Chordomas involving the mobile spine are ideally managed via en bloc resection with reconstruction to optimize local control and possibly offer cure. In the cervical spine, local anatomy poses unique challenges, limiting the feasibility of aggressive resection. The authors present a multi-institutional series of 16 cases of cervical chordomas removed en bloc. Particular attention was paid to clinical outcome, complications, and recurrence. In addition, outcomes were assessed according to position of tumor at the C1–2 level versus the subaxial (SA) spine (C3–7).

Methods

The authors reviewed cases involving patients who underwent en bloc resection of cervical chordoma at 4 large spine centers. Patients were included if the lesion epicenter involved the C-1 to C-7 vertebral bodies. Demographic data and details of surgery, follow-up course, exposure to adjuvant therapy, and complications were obtained. Outcome was correlated with presence of tumor in C1–2 versus subaxial spine via a Student t-test.

Results

Sixteen patients were identified (mean age at presentation 55 ± 14 years). Seven cases (44%) cases involved C1–2, and 16 involved the subaxial spine. Median survival did not differ significantly different between the C1–2 (72 months) and SA (60 months) groups (p = 0.65). A combined (staged anteroposterior) approach was used in 81% of the cases. Use of the combined approach was significantly more common in treatment of subaxial than C1–2 tumors (100% vs 57%, p = 0.04). En bloc resection was attempted via an anterior approach in 6% of cases (C1–2: 14.3%; SA: 0%; p = 0.17) and a posterior approach in 13% of cases (C1–2: 29%; SA: 0%; p = 0.09). The most commonly reported margin classification was marginal (56% of cases), followed by violated (25%) and wide (19%). En bloc excision of subaxial tumors was significantly more likely to result in marginal margins than excision of C1–2 tumors (C1–2: 29%; SA: 78%; p = 0.03). C1–2 tumors were associated with significantly higher rates of postoperative complications (C1–2: 71%; SA: 22%; p = 0.03). Both local and distant tumor recurrence was greatest for C1–2 tumors (local C1–2: 29%; local SA: 11%; distant C1–2: 14%; distant SA: 0%). Statistical analysis of tumor recurrence based on tumor location was not possible due to the small number of cases. There was no between-groups difference in exposure to postoperative adjuvant radiotherapy. There was no difference in median survival between groups receiving proton beam radiotherapy or intensity-modulated radiotherapy versus no radiation therapy (p = 0.8).

Conclusions

Compared with en bloc resection of chordomas involving the subaxial cervical spine, en bloc resection of chordomas involving the upper cervical spine (C1–2) is associated with poorer outcomes, such as less favorable margins, higher rates of complications, and increased tumor recurrence. Data from this cohort do not support a statistically significant difference in survival for patients with C1–2 versus subaxial disease, but larger studies are needed to further study survival differences.

Abbreviations used in this paper:IMRT = intensity-modulated radiotherapy; PBRT = proton beam radiotherapy; SA = subaxial; UCSF = University of California, San Francisco; USC = University of Southern California.

Object

Chordomas involving the mobile spine are ideally managed via en bloc resection with reconstruction to optimize local control and possibly offer cure. In the cervical spine, local anatomy poses unique challenges, limiting the feasibility of aggressive resection. The authors present a multi-institutional series of 16 cases of cervical chordomas removed en bloc. Particular attention was paid to clinical outcome, complications, and recurrence. In addition, outcomes were assessed according to position of tumor at the C1–2 level versus the subaxial (SA) spine (C3–7).

Methods

The authors reviewed cases involving patients who underwent en bloc resection of cervical chordoma at 4 large spine centers. Patients were included if the lesion epicenter involved the C-1 to C-7 vertebral bodies. Demographic data and details of surgery, follow-up course, exposure to adjuvant therapy, and complications were obtained. Outcome was correlated with presence of tumor in C1–2 versus subaxial spine via a Student t-test.

Results

Sixteen patients were identified (mean age at presentation 55 ± 14 years). Seven cases (44%) cases involved C1–2, and 16 involved the subaxial spine. Median survival did not differ significantly different between the C1–2 (72 months) and SA (60 months) groups (p = 0.65). A combined (staged anteroposterior) approach was used in 81% of the cases. Use of the combined approach was significantly more common in treatment of subaxial than C1–2 tumors (100% vs 57%, p = 0.04). En bloc resection was attempted via an anterior approach in 6% of cases (C1–2: 14.3%; SA: 0%; p = 0.17) and a posterior approach in 13% of cases (C1–2: 29%; SA: 0%; p = 0.09). The most commonly reported margin classification was marginal (56% of cases), followed by violated (25%) and wide (19%). En bloc excision of subaxial tumors was significantly more likely to result in marginal margins than excision of C1–2 tumors (C1–2: 29%; SA: 78%; p = 0.03). C1–2 tumors were associated with significantly higher rates of postoperative complications (C1–2: 71%; SA: 22%; p = 0.03). Both local and distant tumor recurrence was greatest for C1–2 tumors (local C1–2: 29%; local SA: 11%; distant C1–2: 14%; distant SA: 0%). Statistical analysis of tumor recurrence based on tumor location was not possible due to the small number of cases. There was no between-groups difference in exposure to postoperative adjuvant radiotherapy. There was no difference in median survival between groups receiving proton beam radiotherapy or intensity-modulated radiotherapy versus no radiation therapy (p = 0.8).

Conclusions

Compared with en bloc resection of chordomas involving the subaxial cervical spine, en bloc resection of chordomas involving the upper cervical spine (C1–2) is associated with poorer outcomes, such as less favorable margins, higher rates of complications, and increased tumor recurrence. Data from this cohort do not support a statistically significant difference in survival for patients with C1–2 versus subaxial disease, but larger studies are needed to further study survival differences.

Chordomas are tumors that originate from vestigial remnants of the notochord.28 With the exception of plasmacytomas, chordomas are the most common primary malignancies of the spine.24 The most commonly affected group is middle-aged adults.28 Typically, the disease course is slow, with metastasis occurring late and death most often the result of local disease extension.29 Management is often difficult, as chordomas are largely refractory to chemotherapy and conventional radiation therapy, making en bloc resection the ideal treatment modality.4,15–17,23,30,34,35

The most common anatomical sites for chordoma are the sacrum and clivus, followed by the cervical spine.5,6,14,24,26 En bloc resection of tumors affecting the sacrum and clivus has been described,4,15,17,22,35 with each location possessing inherent difficulties to achieving en bloc excision. Similarly, due to the cervical spine's complex anatomy, en bloc excision of cervical chordoma presents unique challenges, such as the necessity to preserve cervical nerve roots, protection of the vertebral arteries, and the complex osseous anatomy.29 Despite the recognition that en bloc resection was ideal, cervical chordomas, particularly if located in the C1–2 segments, have largely been managed via intralesional resection, as with clival lesions.2,12,31,32

Advancement in surgical techniques and reconstruction has permitted more of these neoplasms to be removed en bloc.1,13,18,21,27,29,32 With the exception of a series of 5 cases published by Hsieh et al.,20 who demonstrated that wide or marginal en bloc chordoma excision was optimal for prolonging disease-free survival, the majority of literature addressing en bloc removal of cervical chordomas has been limited to reports of 3 cases or fewer.1,13,18,21,27,29,32 In this article, we report clinical and neurological outcomes of a multi-institutional case series of 16 patients who underwent en bloc cervical chordoma excision. To our knowledge, this is the largest such case series published to date.

Methods

Patient Sample

Spine tumor databases at the authors' institutions were retrospectively reviewed. Inclusion criteria for the present study were as follows: 1) diagnosis of cervical chordoma arising from the cervical spine, 2) no prior history of tumor treatment with the exception of needle biopsy, and 3) definitive en bloc tumor excision. Exclusion criteria were as follows: 1) prior treatment, including surgical and non-surgical management; 2) tumors not originating from the cervical spine; and 3) any prior history of other malignancies. De-identified medical record data were provided from the University of Southern California (USC), MD Anderson Cancer Center, and the University of California, San Francisco (UCSF). All patient identifiers, including date of birth and medical record number, were removed from the data set to protect patient identity. All patient data from the Johns Hopkins Hospital were collected following approval of the institutional review board.

Between 2000 and 2008, 16 patients underwent en bloc excision for primary surgical management of cervical chordomas at the authors' institutions and qualified for inclusion in this study: 1 patient was treated at USC, 3 patients were treated at the Johns Hopkins Hospital, 7 were treated at MD Anderson, and 5 were treated at UCSF. We report on surgical technique, margins achieved, peri- and postoperative complications, local and distant tumor recurrence, use of adjuvant therapy, and survival. Surgical technique was classified as being anterior, posterior, or combined anterior and posterior.

Surgical Approach

Authors from each institution submitted detailed descriptions of surgical approaches to confirm uniform technique across institutions. Prior to surgery, all patients underwent MRI with and without a contrast agent to visualize the cervical spine. Computed tomography angiography was used if the tumor was thought to involve the transverse foramen and vertebral arteries for identification of contralateral vessel patency for surgical planning. If tumor encasement or involvement of the vertebral artery necessitated sacrifice, digital-subtraction 4-vessel cerebral angiograms were employed to better visualize the patient's vascular anatomy. Trial balloon occlusion was performed by interventional radiology to assess the feasibility of vertebral artery resection.

Among the 7 patients with C1–2 tumors, 4 patients (57%) underwent a staged posterior-anterior surgical procedure. Generally, this approach involved posterior midline dissection with release osteotomies, tumor dissection, ligation of cervical nerve roots and the vertebral artery if indicated, and placement of instrumentation. The anterior approach to C1–2 and the skull base was achieved using a midline incision at the anterior neck, followed by opening the fascia at the anterior sternocleidomastoid muscle from the skull base to the patient's clavicle. The sternocleidomastoid muscles were then mobilized posteriorly. The carotid artery and internal jugular vein were then identified and retracted posteriorly to visualize the prevertebral space. Blunt dissection was then used to remove soft tissue from the mass. For 2 patients with C1–2 involvement (29%), the posterior-only approach was sufficient for en bloc resection. This was achieved with vertebral artery resection in 1 case. One patient (14%) required only an anterior approach; the approach involved a transoral exposure to the clivus and C-1 using a mucosal flap extending over the lateral nasopharynx, deep to the prevertebral fascia. The prevertebral fascia was elevated, allowing tumor dissection under microscopic guidance.

All patients with subaxial (C3–7) tumor involvement underwent a staged surgical approach involving posterior release osteotomies followed by tumor dissection and instrumentation placement, with anterior neck dissection and en bloc tumor excision performed at a later date. Specifically, the posterior approach to the subaxial spine began with a midline incision followed by dissection of the paraspinous musculature and subperiosteal dissection. Bilateral laminectomy with or without facetectomy followed, with tumor dissection and ligation of cervical nerve roots and the vertebral artery if indicated. Instrumentation was placed for all patients during the posterior approach. Anterior approaches included an incision along the border of the sternocleidomastoid muscle for access to subaxial spine lesions with skeletonization of the vertebral artery on the affected side and identification of the tumor mass. En bloc excision of the tumor followed, with placement of a cage packed with allograft bone if the vertebral body was resected.

Margin quality was determined by histopathological analysis and reported as wide, marginal, or violated based upon the classification scheme reported by Boriani et al.8 Perioperative complications were defined as complications occurring during the time period from hospitalization for surgery until discharge. All complications occurring after this period were classified as postoperative complications. Local tumor recurrence was reported when tumor recurred in any of the originally affected spinal segments. All other incidences of recurrence were classified as distant.

Statistical Analysis

Patient survival was reported in 3 formats: follow-up time (only for patients alive at last follow-up), mean survival time (for patients who were deceased at last follow-up), and survival rate—defined as the percentage of patients alive at last follow-up time. Collected outcomes were stratified according to tumor location. More specifically, stratified data were analyzed according to whether the tumor originated from C1–2 or the subaxial (SA) spine. Statistical outcome analysis was accomplished via the Student t-test, the Mantel-Cox test, and Kaplan-Meier curves (GraphPad Prism v5.0, GraphPad Software). Confidence intervals (95% CIs) were calculated using the online McCallum-Layton Confidence Interval Calculator for Proportions (https://www.mccallum-layton.co.uk). Threshold for statistical significance was set at p ≤ 0.05.

Results

The current study includes 16 patients from Johns Hopkins Hospital, UCSF, USC, and MD Anderson Cancer Center treated between 2000 and 2008. Data are presented in tabular (Tables 1 and 2) and graphic (Figs. 14) formats. The following is an analysis of these data.

TABLE 1:

Demographic and clinical characteristics of the study group*

Case No.Pt Age (yrs)Tumor LocationSurgical ApproachMarginsPeriop ComplicationsPostop ComplicationsRecurrenceFU Time (mos)Status at Last FU
161C2–4posteriorWnonesevere dysphagia w/ FT >1 yr, intermittent pneumonianone51alive
265C-2combinedMnonepermanent FT & trach; posterior pharyngeal dehiscencenone46deceased (46 mos)
382C-2posteriorVnonenonelocal55alive
435C2–3combinedVnonedysphagia; pneumoniadistant62alive
556C-1 clivalanteriorWnonenonenone66alive
654C2–4combinedMnonehardware failurenone72deceased (72 mos)
746C-2combinedVnonedysphagia; pharyngeal erosionlocal115alive
826C7–T5combinedWnonenonenoneNANA
959C3–4combinedMnonenonenone32alive
1060C3–6combinedMnonehoarseness; pneumonianone33alive
1162C3–5combinedMnonenonenone44alive
1248C-3combinedMdurotomynonenone48alive
1351C-4combinedVnonenonenone48alive
1470C3–4combinedMnonenonenone24deceased (43 mos)
1563C7–T1combinedMnoneUE weakness; hardware failurelocal60deceased (60 mos)
1638C-6combinedMnonenonenone96alive

FT = feeding tube; FU = follow-up; M = marginal; NA = not available; Pt = patient; trach = tracheostomy; UE = upper extremity; V = violated; W = wide.

Values in parentheses denote survival time for deceased patients.

TABLE 2:

Collected outcome analysis stratified according to tumor location*

VariableOverallC1–2Subaxialp Value
total no. of cases1679
mean age in yrs55 ± 1457 ± 1553 ± 140.28
approach
 anterior6%14.3%0%0.17
 posterior13%29%0%0.09
 combined81%57%100%0.04
margins
 wide19%29%11%0.22
 marginal56%29%78%0.03
 violated25%43%11%0.10
complication rate
 periop6%0%11%0.17
 postop44%71%22%0.03
recurrence
 local19%29%11%0.22
 distant6%14%0%0.18
survival
 mean FU time in mos57 ± 2467 ± 2348 ± 220.07
 survival rate73%71%75%0.44
 mean survival time in mos55 ± 959 ± 952 ± 12NA

Means are presented ± SD.

Statistically significant.

Survival time for deceased patients at last follow-up.

Fig. 1.
Fig. 1.

Surgical approach stratified according to tumor location.

Fig. 2.
Fig. 2.

Classification of surgical margins stratified according to tumor location.

Fig. 3.
Fig. 3.

Frequency of perioperative and postoperative surgical complications stratified according to tumor location.

Fig. 4.
Fig. 4.

Frequency of local and distant tumor recurrence stratified according to tumor location.

Patient Demographic Data

There were a total of 7 male and 9 female patients. Their mean age (± SD) at the time of diagnosis was 55 ± 14 years. Substratification of age according to tumor location revealed no significant difference among the age in which these tumors localize to cervical segment subdivisions (C1–2: 57 ± 15 years; SA: 53 ± 14 years; p = 0.28).

Surgical Approach

The surgical approach to achieve en bloc excision was classified as solely anterior, posterior, or combined (anterior and posterior). The most common overall approach was combined (81%), with only 6% and 13% of the approaches being anterior or posterior, respectively. When surgical approach was stratified according to tumor location, resection via a combined approach was statistically more common for subaxial tumors than C1–2 tumors (C1–2: 57%; SA: 100%; p = 0.04). No statistically significant difference in the usage of the anterior (C1–2: 14.3%; SA: 0%; p = 0.17) or posterior (C1–2: 29%; SA: 0%; p = 0.09) approaches was found (Table 2 and Fig. 1).

Tumor Margins

Tumor margins were reported as wide, marginal, or violated. The most commonly reported margins were marginal (M: 56%), followed by violated (V: 25%), and wide (W: 19%). Patients were significantly more likely to undergo marginal rather than wide margin (M: 56%; W: 19%; p = 0.01) or violated margin (M: 56%; V: 25%; p = 0.04) tumor excision. Patients were equally likely to have wide or violated margins (W: 19%; V: 25%; p = 0.34). When stratifying data according to tumor location it was found that the most commonly reported margins for C1–2 tumors were violated margins (43%), whereas the most commonly reported margins for subaxial tumors were marginal (78%)—with only 11% of the subaxial located tumor margins being reported as violated. No statistically significant difference was found when comparing the incidence of violated margins based on tumor location. However, it was found that en bloc excision of subaxial tumors was statistically more likely to result in marginal margins than C1–2 tumors (C1–2: 29%, SA: 78%; p = 0.03). The likelihood of wide excision was not affected by tumor location (Table 2 and Fig. 2).

Complication Rate

Complications were classified as perioperative or postoperative (Table 2). The types of complications are listed in Table 1. The rate of postoperative complications was significantly higher than that of perioperative complications for all patients (44% vs 6%, p = 0.01). When data were stratified according to tumor location it was noted that C1–2 tumors were associated with significantly higher rates of postoperative complications (C1–2: 71%; SA: 22%; p = 0.03) (Table 1 and Fig. 3). Complications in patients with C1–2 tumors included severe dysphagia (n = 2), pharyngeal erosion or dehiscence (n = 2), and instrumentation failure (n = 1). Among patients with subaxial disease, one patient experienced hoarseness and another experienced instrumentation failure. Two patients in the SA group experienced milder complications, specifically hoarseness, pneumonia, upper-extremity weakness, and hardware failure (Table 1).

Tumor Recurrence

There were only 3 cases (19%) of local tumor recurrence and only 1 case (6%) of distant recurrence over the mean follow-up period (57 ± 24 months). The difference in incidence of local and distant tumor recurrence was not statistically significant. Although the incidence of local tumor recurrence was more than twice as a high for C1–2 localized tumors (29%) than for subaxial tumors (11%), this difference was not amenable to statistical analysis per paucity of cases. Similarly, the incidence of distant recurrence was higher for C1–2 localized tumors (C1–2: 14%; SA: 0%;), but this difference was also not amenable to statistical analysis per paucity of cases (Table 2 and Fig. 4).

Adjuvant Radiotherapy

Patient exposure to postoperative intensity-modulated radiotherapy (IMRT) and proton beam radiotherapy (PBRT) was reviewed. There was no significant difference in exposure to postoperative radiotherapy between groups. Among patients with C1–2 disease (n = 7), 3 patients (43%, 95% CI 6%–80%) received PBRT, and 1 patient (14%, 95% CI 0%–40%) received IMRT. Among patients with subaxial disease (n = 9), 3 patients (33%, 95% CI 2%–64%) received PBRT, and 2 patients (22%, 95% CI 0%–49%) received IMRT.

When stratifying by exposure to PBRT/IMRT or no radiation irrespective of disease level, there was no difference in median survival between groups on Mantel-Cox testing (p = 0.8). Median survival for the PBRT/IMRT group was undefined (less than 50% of patients died) versus 72 months in the no-radiation group (Fig. 5).

Fig. 5.
Fig. 5.

Kaplan-Meier curve depicting survival percentage as a function of time for patients receiving radiation (PBRT or IMRT) or no radiation in the postoperative period. When stratifying by exposure to PBRT/IMRT or no radiation irrespective of disease level, there was no difference in median survival between groups on Mantel-Cox testing (p = 0.8). Median survival for the PBRT/IMRT group was undefined (< 50% of patients died) versus 72 months in the no-radiation group.

Survival Status

Representative pre- and postoperative images are provided in Fig. 6. The mean follow-up time was 57 ± 24 months. The median survival for patients with C1–2 disease was 72 months versus 60 months for patients with subaxial disease. Overall survival was no different between patients with C1–2 versus subaxial tumor location on Mantel-Cox testing (p = 0.65) (Fig. 7). No significant differences were found when stratifying the mean follow-up time and survival rate based on tumor location (Table 2). Of note, 4 patients were deceased at last follow-up; 2 of these patients had C1–2 involvement, and 2 had subaxial spine tumors. All patients that were deceased at last follow-up had undergone resection with marginal margins (Table 1).

Fig. 6.
Fig. 6.

Representative pre- and postoperative MR images from 3 cases. A: Case 1. Sagittal T2-weighted MR image obtained in 61-year-old man with chordoma extending from C-3 with paravertebral extension from C-2 to C-4. Case from UCSF. B and C: Case 11. Sagittal (B) and axial (C) T2-weighted MR images obtained in a 62-year-old woman with chordoma extending from C-4 into the spinal canal. Case from USCF. D–F: Case 5. Preoperative (D and E) and postoperative (F) MR images obtained in a 56-year-old woman with C-1/clival chordoma who underwent a resection via a transoral approach. The preoperative sagittal T1-weighted (D) and axial T1-weighted FLAIR (E) MR images demonstrate a lesion at C1–clivus. The postoperative T1-weighted MR image was obtained 3 years after surgery and demonstrates no tumor recurrence. Case from Johns Hopkins Hospital.

Fig. 7.
Fig. 7.

Kaplan-Meier curve depicting survival percentage as a function of time for all patients. Median survival for patients with C1–2 disease was 72 months versus 60 months for patients with subaxial disease. Overall survival was not significantly different between patients with C1–2 versus subaxial tumor location on Mantel-Cox testing (p = 0.65).

Discussion

Chordomas are the most common primary malignant tumors of the osseous spine and constitute 1%–4% of all malignant bone tumors.4,10,23,25,35 Their location along the spinal canal is in direct relation to the location of notochordal remnants—which is greatest at the most proximal and distal segments of the bony spine (the cervical and sacral spine).2 It has been shown that en bloc resection of chordoma with wide or marginal margins results in a significantly higher rate of control than intralesional resection.4,7,13,23 However, achieving favorable oncological margins of cervical chordomas is exceedingly challenging due to a number of anatomical factors including 1) the proximity of the vertebral arteries, 2) the difficulty of cutting the cervical pedicles, and 3) the necessity of preserving the cervical nerve roots.29

The cervical spine, however, is not a single entity, and additional challenges arise based on tumor location within the cervical spine. Hence, high cervical atlantoaxial (C1–2) tumors present challenges that are different from those presented by subaxial (C3–7) tumors. For example, atlantoaxial chordomas frequently involve both the cervical roots and vertebral arteries. Although the C1–4 roots can generally be sacrificed without ensuing neurological deficit, vertebral artery sacrifice can result in significant neurological deficits, particularly if the dominant vertebral artery is sacrificed in the setting of insufficient collateral flow. Tumors that do not involve the vertebral arteries bilaterally are more amenable to en bloc resection, as are lesions that do not circumferentially involve the vertebral body. In addition, the high cervical spine itself is more difficult to access than the subaxial spine and often requires complex surgical techniques, such as transor submandibular approaches with posterior pharyngeal incision and tracheostomy.

Despite the perceived higher level of difficulty of removing high cervical chordomas, no studies to date have investigated whether the additional complexity translates to differences in clinical outcomes. In this study, we retrospectively analyzed outcomes from a multi-institutional patient database according to tumor location. To our knowledge, this is the largest series reporting outcomes for patients afflicted with cervical chordoma. A total of 16 cases were identified with the following surgical and outcome data collected and analyzed: 1) surgical approach, 2) tumor margins, 3) complication rate, 4) tumor recurrence, 5) exposure to adjuvant therapy, and 6) survival.

The most common surgical approach was combined anterior and posterior, with 81% of all cases, 100% of subaxial cases, and 54% of C1–2 cases utilizing the combined approach. Interestingly, as noted above, all of the subaxial cases were treated with the combined approach, and while the majority of C1–2 cases also were treated the combined approach (57%), in some of the C1–2 cases the single-stage anterior (14.3%) and posterior (29%) approaches were employed. This is consistent with similar cases reported in the literature, with 5 of 6 case reports addressing en bloc cervical chordoma resection reporting a combined anterior-posterior surgical approach.1,13,18,27,29,32

Resection with tumor-free margins has already been validated for effectiveness in both local control and long-term prognosis for chordomas arising from the thoracic, lumbar, or sacral spine.3,4,9,19,23,27,33 Hence, the ideal aim of en bloc cervical chordoma resecion is to achieve tumor-free margins, with wide margins being the goal for the pathology report and marginal margins being a nonideal but acceptable outcome. We found that, although marginal margins (attained in 56% of cases) were reported overall significantly more frequently than both wide (19%) and violated (25%) margins, this relationship was not conserved when the cases were stratified according to tumor location. Specifically, the most commonly reported margin classification for subaxial tumors was marginal, whereas the most commonly reported margin classification for C1–2 tumors was violated (SA: 78% vs C1–2: 29%; p = 0.03). Although the difference in reported violated margins between C1–2 (43%) and subaxial (11%) tumors was not statistically significant, this difference is nonetheless clinically relevant and will most likely prove to be statistically significant as larger studies become possible. The ample difference in ability to achieve favorable margins based on tumor location is representative of the anatomical complexity of the upper cervical spine and confirms that it is a significant obstacle in performing en bloc tumor resections.

Of note, the 4 patients in this sample who were deceased at last follow-up underwent resection with marginal margins. Two of these patients experienced a post-operative hardware failure and one reported pharyngeal dehiscence. One patient who was deceased at last follow-up did not have any reported postoperative complications. It is possible that a complicated postoperative course may have contributed to the higher death rate in this subset of patients, but due to the relatively small sample size and heterogeneity of the sample (2 patients were in the SA group and 2 patients were in the C1–2 group), interpretation of these data is limited.

Complication rates provide a direct marker of procedure complexity.20 Postoperative complication rates were found to be statistically greater for C1–2 tumors versus subaxial tumors (C1–2: 71% vs SA: 22%, p = 0.03). Furthermore, complications in the C1–2 group were severe, with 2 patients experiencing pharyngeal erosion or dehiscence. There is no evidence that this difference is rooted in a biological difference of C1–2 versus subaxial tumors, as all tumors in this series were chordomas. One explanation for the difference in complication rates is that the approach required to access the occipitocervical junction and the subsequent occipitocervical fixation likely contributes to postoperative morbidity. Biomechanically, occipitocervical fusion limits a patient's ability to flex the neck to facilitate all stages of swallowing, and this decreased range of motion may have contributed to the C1–2 tumor patients experiencing a higher rate of pharyngeal erosion and dysphagia. Notably, this increase in complications does not significantly impact survival; however, a larger case series is needed in order to discern whether a true difference exists. Consistent with the case series published by Hsieh et al.,21 our rate of perioperative complications was low (6%). Similar to low perioperative complication rates, the incidence of local (3 cases) and distant (1 case) tumor recurrence was not large enough to permit statistical analysis. However, as would be expected by the higher incidence of violated margins in the C1–2 group, the incidence of local tumor recurrence was greater in the C1–2 cohort (C1–2: 29% vs SA: 11%). Importantly, tumor recurrence patterns were similar to those found a meta-analysis conducted by Cloyd et al., who reviewed literature encompassing a total of 18 cervical cases and found 3 cases of local and 1 case of distant recurrence.11 Of note, the use of PBRT and IMRT did not differ between groups. As chordoma is not classically a chemosensitive lesion, chemotherapy analyses were not included in this study.

Despite a higher rate of violated margins, postoperative complications, and tumor recurrence for the C1–2 tumor cohort, the study was insufficiently powered to detect any potential differences in survival rate based on tumor location. Specifically, the survival metrics collected included mean follow-up time, survival rate, and mean survival time. Although there were no statistically significant differences in follow-up time (C1–2: 67 ± 23 months vs SA: 48 ± 22 months, p = 0.07) or survival (C1–2: 72 months vs SA: 60 months), there were only 2 deaths in each group, limiting the utility of this survival analysis. Larger studies are needed to determine if statistically significant differences in survival exist.

Given the higher complication rates with C1–2 en bloc resection and the high rates of contaminated margins, one should carefully consider possible intralesional resection of lesions in this anatomical location if less destructive approaches, such as image-guided transcervical, endoscopic transoral, or all-posterior transpedicular approaches, can be employed. Combined hybrid surgical/radiosurgical techniques and hadron or particle therapy (such as carbon ion therapy) may yield improved treatment success for these difficult lesions as is the case for clival chordomas. For subaxial lesions, however, where en bloc marginal excision is associated with higher success rates and lower complication rates, we favor attempted en bloc resection at specialty centers.

Conclusions

When possible, chordomas are ideally managed via en bloc resection. However, the feasibility of achieving en bloc resection is in large part affected by lesion location, as demonstrated by the lower rate of favorable margins for atlantoaxial tumors in this study. Tumors of the C1–2 vertebral bodies are associated with the perceived higher operative difficulty presented by the complex anatomy of the upper cervical spine, which translates to poorer outcomes such as less favorable margins, higher rates of complications, and increased tumor recurrence. Given the higher rate of unfavorable outcomes for en bloc resection of atlantoaxial chordomas, we advocate intralesional resection of such lesions when less destructive approaches (endoscopic transoral resections) can be employed. For subaxial chordomas, we favor en bloc resection at specialty centers.

Disclosure

Dr. Ames reports a consultant relationship with DePuy, Medtronic, and Stryker; receipt of a grant from Trans1; a patent holder relationship with Fish & Richardson, P.C.; receipt of royalties from Lanx and Aesculap; and owning stock or stock options with Trans1, Visualase, and Doctors Research Group. Dr. Gokaslan reports direct stock ownership in US Spine and Spinal Kinetics. Dr. Sciubba reports a consultant relationship with DePuy, Medtronic, NuVasive, and Globus; and support of non–study-related clinical or research effort from DePuy. Dr. Chou reports a consultant relationship with DePuy, Medtronic, Orthofix, and Globus. Dr. Hsieh reports a consultant relationship with Medtronic and DePuy.

Author contributions to the study and manuscript preparation include the following. Conception and design: Sciubba, Molina. Acquisition of data: Molina, Ames, Chou, Rhines, Hsieh, Wolinsky, Gokaslan. Analysis and interpretation of data: Molina. Drafting the article: Molina. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sciubba. Statistical analysis: Molina. Study supervision: Sciubba.

References

  • 1

    Bailey CSFisher CGBoyd MCDvorak MF: En bloc marginal excision of a multilevel cervical chordoma. Case report. J Neurosurg Spine 4:4094142006

    • Search Google Scholar
    • Export Citation
  • 2

    Barrenechea IJPerin NITriana ALesser JCostantino PSen C: Surgical management of chordomas of the cervical spine. J Neurosurg Spine 6:3984062007

    • Search Google Scholar
    • Export Citation
  • 3

    Bas TBas PPrieto MRamos VBas JLEspinosa C: A lumbar chordoma treated with a wide resection. Eur Spine J 3:1151171994

  • 4

    Bergh PKindblom LGGunterberg BRemotti FRyd WMeis-Kindblom JM: Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer 88:212221342000

    • Search Google Scholar
    • Export Citation
  • 5

    Bjornsson JWold LEEbersold MJLaws ER: Chordoma of the mobile spine. A clinicopathologic analysis of 40 patients. Cancer 71:7357401993

    • Search Google Scholar
    • Export Citation
  • 6

    Bohlman HHSachs BLCarter JRRiley LRobinson RA: Primary neoplasms of the cervical spine. Diagnosis and treatment of twenty-three patients. J Bone Joint Surg Am 68:4834941986

    • Search Google Scholar
    • Export Citation
  • 7

    Boriani SChevalley FWeinstein JNBiagini RCampanacci LDe Iure F: Chordoma of the spine above the sacrum. Treatment and outcome in 21 cases. Spine (Phila Pa 1976) 21:156915771996

    • Search Google Scholar
    • Export Citation
  • 8

    Boriani SWeinstein JNBiagini R: Primary bone tumors of the spine. Terminology and surgical staging. Spine (Phila Pa 1976) 22:103610441997

    • Search Google Scholar
    • Export Citation
  • 9

    Bosma JJPigott TJPennie BHJaffray DC: En bloc removal of the lower lumbar vertebral body for chordoma. Report of two cases. J Neurosurg 94:2 Suppl2842912001

    • Search Google Scholar
    • Export Citation
  • 10

    Chou DAcosta F JrCloyd JMAmes CP: Parasagittal osteotomy for en bloc resection of multilevel cervical chordomas. Technical note. J Neurosurg Spine 10:3974032009

    • Search Google Scholar
    • Export Citation
  • 11

    Cloyd JMChou DDeviren VAmes CP: En bloc resection of primary tumors of the cervical spine: report of two cases and systematic review of the literature. Spine J 9:9289352009

    • Search Google Scholar
    • Export Citation
  • 12

    Cohen ZRFourney DRMarco RARhines LDGokaslan ZL: Total cervical spondylectomy for primary osteogenic sarcoma. Case report and description of operative technique. J Neurosurg 97:3 Suppl3863922002

    • Search Google Scholar
    • Export Citation
  • 13

    Currier BLPapagelopoulos PJKrauss WEUnni KKYaszemski MJ: Total en bloc spondylectomy of C5 vertebra for chordoma. Spine (Phila Pa 1976) 32:E294E2992007

    • Search Google Scholar
    • Export Citation
  • 14

    Ferraresi VNuzzo CZoccali CMarandino FVidiri ASalducca N: Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer 10:222010

    • Search Google Scholar
    • Export Citation
  • 15

    Fourney DRGokaslan ZL: Current management of sacral chordoma. Neurosurg Focus 15:2E92003

  • 16

    Fourney DRRhines LDHentschel SJSkibber JMWolinsky JPWeber KL: En bloc resection of primary sacral tumors: classification of surgical approaches and outcome. J Neurosurg Spine 3:1111222005

    • Search Google Scholar
    • Export Citation
  • 17

    Fuchs BDickey IDYaszemski MJInwards CYSim FH: Operative management of sacral chordoma. J Bone Joint Surg Am 87:221122162005

    • Search Google Scholar
    • Export Citation
  • 18

    Fujita TKawahara NMatsumoto TTomita K: Chordoma in the cervical spine managed with en bloc excision. Spine (Phila Pa 1976) 24:184818511999

    • Search Google Scholar
    • Export Citation
  • 19

    Heary RFVaccaro ARBenevenia JCotler JM: “En-bloc” vertebrectomy in the mobile lumbar spine. Surg Neurol 50:5485561998

  • 20

    Hee HTMajd MEHolt RTWhitecloud TS IIIPienkowski D: Complications of multilevel cervical corpectomies and reconstruction with titanium cages and anterior plating. J Spinal Disord Tech 16:192003

    • Search Google Scholar
    • Export Citation
  • 21

    Hsieh PCGalia GLSciubba DMBydon AMarco RARhines L: En-bloc excision of chordomas in the cervical spine: review of 5 consecutive cases with over 4-year follow-up. Spine (Phila Pa 1976) 36:E158115872011

    • Search Google Scholar
    • Export Citation
  • 22

    Hsieh PCXu RSciubba DMMcGirt MJNelson CWitham TF: Long-term clinical outcomes following en bloc resections for sacral chordomas and chondrosarcomas: a series of twenty consecutive patients. Spine (Phila Pa 1976) 34:223322392009

    • Search Google Scholar
    • Export Citation
  • 23

    Hsu KYZucherman JFMortensen NJohnston JOGartland J: Follow-up evaluation of resected lumbar vertebral chordoma over 11 years: a case report. Spine (Phila Pa 1976) 25:253725402000

    • Search Google Scholar
    • Export Citation
  • 24

    Hsu WKosztowski TAZaidi HAGokaslan ZLWolinsky JP: Image-guided, endoscopic, transcervical resection of cervical chordoma. Technical note. J Neurosurg Spine 12:4314352010

    • Search Google Scholar
    • Export Citation
  • 25

    Huang WCao DMa JYang XXiao JZheng W: Solitary plasmacytoma of cervical spine: treatment and prognosis in patients with neurological lesions and spinal instability. Spine (Phila Pa 1976) 35:E278E2842010

    • Search Google Scholar
    • Export Citation
  • 26

    Kelley SPAshford RURao ASDickson RA: Primary bone tumours of the spine: a 42-year survey from the Leeds Regional Bone Tumour Registry. Eur Spine J 16:4054092007

    • Search Google Scholar
    • Export Citation
  • 27

    Leitner YShabat SBoriani LBoriani S: En bloc resection of a C4 chordoma: surgical technique. Eur Spine J 16:223822422007

  • 28

    McMaster MLGoldstein AMBromley CMIshibe NParry DM: Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12:1112001

    • Search Google Scholar
    • Export Citation
  • 29

    Rhines LDFourney DRSiadati ASuk IGokaslan ZL: En bloc resection of multilevel cervical chordoma with C-2 involvement. Case report and description of operative technique. J Neurosurg Spine 2:1992052005

    • Search Google Scholar
    • Export Citation
  • 30

    Sciubba DMChi JHRhines LDGokaslan ZL: Chordoma of the spinal column. Neurosurg Clin N Am 19:5152008

  • 31

    Štulík JKozák JŠebesta PVyskočil TKryl JKlezl Z: Total spondylectomy of C2: report of three cases and review of the literature. J Spinal Disord Tech 23:e53e582010

    • Search Google Scholar
    • Export Citation
  • 32

    Suchomel PBuchvald PBarsa PFroehlich RChoutka OKrejzar Z: Single-stage total C-2 intralesional spondylectomy for chordoma with three-column reconstruction. Technical note. J Neurosurg Spine 6:6116182007

    • Search Google Scholar
    • Export Citation
  • 33

    Sundaresan NSteinberger AAMoore FSachdev VPKrol GHough L: Indications and results of combined anteriorposterior approaches for spine tumor surgery. J Neurosurg 85:4384461996

    • Search Google Scholar
    • Export Citation
  • 34

    Vassal FDumas BNuti C: Margin-free, en bloc resection of a multilevel cervical chordoma with C-2 involvement: case report with 2-year follow-up and description of operative technique. Br J Neurosurg 26:9299312012

    • Search Google Scholar
    • Export Citation
  • 35

    York JEKaczaraj AAbi-Said DFuller GNSkibber JMJanjan NA: Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery 44:74801999

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: Daniel M. Sciubba, M.D., 600 N. Wolfe St., Meyer 5-185A, Baltimore, MD 21287. email: dsciubb1@jhmi.edu.

Please include this information when citing this paper: published online June 13, 2014; DOI: 10.3171/2014.5.SPINE121045.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Surgical approach stratified according to tumor location.

  • View in gallery

    Classification of surgical margins stratified according to tumor location.

  • View in gallery

    Frequency of perioperative and postoperative surgical complications stratified according to tumor location.

  • View in gallery

    Frequency of local and distant tumor recurrence stratified according to tumor location.

  • View in gallery

    Kaplan-Meier curve depicting survival percentage as a function of time for patients receiving radiation (PBRT or IMRT) or no radiation in the postoperative period. When stratifying by exposure to PBRT/IMRT or no radiation irrespective of disease level, there was no difference in median survival between groups on Mantel-Cox testing (p = 0.8). Median survival for the PBRT/IMRT group was undefined (< 50% of patients died) versus 72 months in the no-radiation group.

  • View in gallery

    Representative pre- and postoperative MR images from 3 cases. A: Case 1. Sagittal T2-weighted MR image obtained in 61-year-old man with chordoma extending from C-3 with paravertebral extension from C-2 to C-4. Case from UCSF. B and C: Case 11. Sagittal (B) and axial (C) T2-weighted MR images obtained in a 62-year-old woman with chordoma extending from C-4 into the spinal canal. Case from USCF. D–F: Case 5. Preoperative (D and E) and postoperative (F) MR images obtained in a 56-year-old woman with C-1/clival chordoma who underwent a resection via a transoral approach. The preoperative sagittal T1-weighted (D) and axial T1-weighted FLAIR (E) MR images demonstrate a lesion at C1–clivus. The postoperative T1-weighted MR image was obtained 3 years after surgery and demonstrates no tumor recurrence. Case from Johns Hopkins Hospital.

  • View in gallery

    Kaplan-Meier curve depicting survival percentage as a function of time for all patients. Median survival for patients with C1–2 disease was 72 months versus 60 months for patients with subaxial disease. Overall survival was not significantly different between patients with C1–2 versus subaxial tumor location on Mantel-Cox testing (p = 0.65).

References

  • 1

    Bailey CSFisher CGBoyd MCDvorak MF: En bloc marginal excision of a multilevel cervical chordoma. Case report. J Neurosurg Spine 4:4094142006

    • Search Google Scholar
    • Export Citation
  • 2

    Barrenechea IJPerin NITriana ALesser JCostantino PSen C: Surgical management of chordomas of the cervical spine. J Neurosurg Spine 6:3984062007

    • Search Google Scholar
    • Export Citation
  • 3

    Bas TBas PPrieto MRamos VBas JLEspinosa C: A lumbar chordoma treated with a wide resection. Eur Spine J 3:1151171994

  • 4

    Bergh PKindblom LGGunterberg BRemotti FRyd WMeis-Kindblom JM: Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer 88:212221342000

    • Search Google Scholar
    • Export Citation
  • 5

    Bjornsson JWold LEEbersold MJLaws ER: Chordoma of the mobile spine. A clinicopathologic analysis of 40 patients. Cancer 71:7357401993

    • Search Google Scholar
    • Export Citation
  • 6

    Bohlman HHSachs BLCarter JRRiley LRobinson RA: Primary neoplasms of the cervical spine. Diagnosis and treatment of twenty-three patients. J Bone Joint Surg Am 68:4834941986

    • Search Google Scholar
    • Export Citation
  • 7

    Boriani SChevalley FWeinstein JNBiagini RCampanacci LDe Iure F: Chordoma of the spine above the sacrum. Treatment and outcome in 21 cases. Spine (Phila Pa 1976) 21:156915771996

    • Search Google Scholar
    • Export Citation
  • 8

    Boriani SWeinstein JNBiagini R: Primary bone tumors of the spine. Terminology and surgical staging. Spine (Phila Pa 1976) 22:103610441997

    • Search Google Scholar
    • Export Citation
  • 9

    Bosma JJPigott TJPennie BHJaffray DC: En bloc removal of the lower lumbar vertebral body for chordoma. Report of two cases. J Neurosurg 94:2 Suppl2842912001

    • Search Google Scholar
    • Export Citation
  • 10

    Chou DAcosta F JrCloyd JMAmes CP: Parasagittal osteotomy for en bloc resection of multilevel cervical chordomas. Technical note. J Neurosurg Spine 10:3974032009

    • Search Google Scholar
    • Export Citation
  • 11

    Cloyd JMChou DDeviren VAmes CP: En bloc resection of primary tumors of the cervical spine: report of two cases and systematic review of the literature. Spine J 9:9289352009

    • Search Google Scholar
    • Export Citation
  • 12

    Cohen ZRFourney DRMarco RARhines LDGokaslan ZL: Total cervical spondylectomy for primary osteogenic sarcoma. Case report and description of operative technique. J Neurosurg 97:3 Suppl3863922002

    • Search Google Scholar
    • Export Citation
  • 13

    Currier BLPapagelopoulos PJKrauss WEUnni KKYaszemski MJ: Total en bloc spondylectomy of C5 vertebra for chordoma. Spine (Phila Pa 1976) 32:E294E2992007

    • Search Google Scholar
    • Export Citation
  • 14

    Ferraresi VNuzzo CZoccali CMarandino FVidiri ASalducca N: Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer 10:222010

    • Search Google Scholar
    • Export Citation
  • 15

    Fourney DRGokaslan ZL: Current management of sacral chordoma. Neurosurg Focus 15:2E92003

  • 16

    Fourney DRRhines LDHentschel SJSkibber JMWolinsky JPWeber KL: En bloc resection of primary sacral tumors: classification of surgical approaches and outcome. J Neurosurg Spine 3:1111222005

    • Search Google Scholar
    • Export Citation
  • 17

    Fuchs BDickey IDYaszemski MJInwards CYSim FH: Operative management of sacral chordoma. J Bone Joint Surg Am 87:221122162005

    • Search Google Scholar
    • Export Citation
  • 18

    Fujita TKawahara NMatsumoto TTomita K: Chordoma in the cervical spine managed with en bloc excision. Spine (Phila Pa 1976) 24:184818511999

    • Search Google Scholar
    • Export Citation
  • 19

    Heary RFVaccaro ARBenevenia JCotler JM: “En-bloc” vertebrectomy in the mobile lumbar spine. Surg Neurol 50:5485561998

  • 20

    Hee HTMajd MEHolt RTWhitecloud TS IIIPienkowski D: Complications of multilevel cervical corpectomies and reconstruction with titanium cages and anterior plating. J Spinal Disord Tech 16:192003

    • Search Google Scholar
    • Export Citation
  • 21

    Hsieh PCGalia GLSciubba DMBydon AMarco RARhines L: En-bloc excision of chordomas in the cervical spine: review of 5 consecutive cases with over 4-year follow-up. Spine (Phila Pa 1976) 36:E158115872011

    • Search Google Scholar
    • Export Citation
  • 22

    Hsieh PCXu RSciubba DMMcGirt MJNelson CWitham TF: Long-term clinical outcomes following en bloc resections for sacral chordomas and chondrosarcomas: a series of twenty consecutive patients. Spine (Phila Pa 1976) 34:223322392009

    • Search Google Scholar
    • Export Citation
  • 23

    Hsu KYZucherman JFMortensen NJohnston JOGartland J: Follow-up evaluation of resected lumbar vertebral chordoma over 11 years: a case report. Spine (Phila Pa 1976) 25:253725402000

    • Search Google Scholar
    • Export Citation
  • 24

    Hsu WKosztowski TAZaidi HAGokaslan ZLWolinsky JP: Image-guided, endoscopic, transcervical resection of cervical chordoma. Technical note. J Neurosurg Spine 12:4314352010

    • Search Google Scholar
    • Export Citation
  • 25

    Huang WCao DMa JYang XXiao JZheng W: Solitary plasmacytoma of cervical spine: treatment and prognosis in patients with neurological lesions and spinal instability. Spine (Phila Pa 1976) 35:E278E2842010

    • Search Google Scholar
    • Export Citation
  • 26

    Kelley SPAshford RURao ASDickson RA: Primary bone tumours of the spine: a 42-year survey from the Leeds Regional Bone Tumour Registry. Eur Spine J 16:4054092007

    • Search Google Scholar
    • Export Citation
  • 27

    Leitner YShabat SBoriani LBoriani S: En bloc resection of a C4 chordoma: surgical technique. Eur Spine J 16:223822422007

  • 28

    McMaster MLGoldstein AMBromley CMIshibe NParry DM: Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12:1112001

    • Search Google Scholar
    • Export Citation
  • 29

    Rhines LDFourney DRSiadati ASuk IGokaslan ZL: En bloc resection of multilevel cervical chordoma with C-2 involvement. Case report and description of operative technique. J Neurosurg Spine 2:1992052005

    • Search Google Scholar
    • Export Citation
  • 30

    Sciubba DMChi JHRhines LDGokaslan ZL: Chordoma of the spinal column. Neurosurg Clin N Am 19:5152008

  • 31

    Štulík JKozák JŠebesta PVyskočil TKryl JKlezl Z: Total spondylectomy of C2: report of three cases and review of the literature. J Spinal Disord Tech 23:e53e582010

    • Search Google Scholar
    • Export Citation
  • 32

    Suchomel PBuchvald PBarsa PFroehlich RChoutka OKrejzar Z: Single-stage total C-2 intralesional spondylectomy for chordoma with three-column reconstruction. Technical note. J Neurosurg Spine 6:6116182007

    • Search Google Scholar
    • Export Citation
  • 33

    Sundaresan NSteinberger AAMoore FSachdev VPKrol GHough L: Indications and results of combined anteriorposterior approaches for spine tumor surgery. J Neurosurg 85:4384461996

    • Search Google Scholar
    • Export Citation
  • 34

    Vassal FDumas BNuti C: Margin-free, en bloc resection of a multilevel cervical chordoma with C-2 involvement: case report with 2-year follow-up and description of operative technique. Br J Neurosurg 26:9299312012

    • Search Google Scholar
    • Export Citation
  • 35

    York JEKaczaraj AAbi-Said DFuller GNSkibber JMJanjan NA: Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery 44:74801999

    • Search Google Scholar
    • Export Citation

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 297 297 20
PDF Downloads 198 198 15
EPUB Downloads 0 0 0

PubMed

Google Scholar