Evidence-Based Optimization of Post-Treatment Surveillance for Skull Base Chordomas Based on Local and Distant Disease Progression

Evidence-Based Optimization of Post-Treatment Surveillance for Skull Base Chordomas Based on... Abstract BACKGROUND There are no guidelines regarding post-treatment surveillance specific to skull base chordomas. OBJECTIVE To determine an optimal imaging surveillance schedule to detect both local and distant metastatic skull base chordoma recurrences. METHODS A retrospective review of 91 patients who underwent treatment for skull base chordoma between 1993 and 2017 was conducted. Time to and location of local and distant recurrence(s) were cataloged. Existing chordoma surveillance recommendations (National Comprehensive Cancer Network [NCCN], London and South East Sarcoma Network [LSESN], European Society for Medical Oncology [ESMO], Chordoma Global Consensus Group [CGCG]) were applied to our cohort to compare the number of recurrent patients and months of undiagnosed tumor growth between surveillances. These findings were used to inform the creation of a revised imaging surveillance protocol (MD Anderson Cancer Center Chordoma Imaging Protocol [MDACC-CIP]), presented here. RESULTS Thirty-four patients with 79 local/systemic recurrences met inclusion criteria. Mean age at diagnosis and follow-up time were 45 yr and 79 mo, respectively. The MDACC-CIP imaging protocol significantly reduced the time to diagnosis of recurrence compared with the LSESN and CGCG/ESMO imaging protocols for surveillance of local disease with a cumulative/average of 576/16.9 (LSESN), 336/9.8 (CGCG), and 170/5.0 (MDACC-CIP) months of undetected growth, respectively. The NCCN and MDACC-CIP guidelines for distant metastatic surveillance identified a cumulative/average of 65/6.5 and 51/5.1 mo of undetected growth, respectively, and were not significantly different. CONCLUSION The MDACC-CIP for skull base chordoma accounts for recurrence trends unique to this disease, including a higher rate of leptomeningeal spread than sacrococcygeal primaries, resulting in improved sensitivity and prompt diagnosis. Chordoma, Recurrence, Surveillance, Guidelines, Malignancy, Skull Base, Cancer ABBREVIATIONS ABBREVIATIONS CGCG Chordoma Global Consensus Group CT computed tomography ESMO European Society for Medical Oncology IRB institutional review board KM Kaplan-Meier LMD leptomeningeal disease LSESN London and South East Sarcoma Network MDACC-CIP MD Anderson Cancer Center Chordoma Imaging Protocol MRI magnetic resonance imaging NCCN National Comprehensive Cancer Network OS overall survival PFS progression-free survival XRT radiation therapy Chordomas are bony malignancies with a behavioral spectrum that can span from indolent local disease to locally aggressive growth and at times to distant metastatic spread.1,2 Despite advances in surgical strategies, charged particle radiation therapy, and attempts at targeted therapy options, it represents a challenging disease to treat with reported 5-yr progression-free survival (PFS) of 45% to 81%, 5-yr overall survival (OS) rates of 55% to 67%, and 10-yr OS rates of 32% to 61%.3-8 Ultimately, this disease is characterized by local recurrence and/or distant metastases with disease progression as the primary cause of death in patients when it occurs.2 Consequently, there is a need for the timely diagnosis of both local and distant disease progression. To date, several groups have published surveillance recommendations for chordoma including the National Comprehensive Cancer Network (NCCN),9 the London and South East Sarcoma Network (LSESN),10 and the European Society for Medical Oncology (ESMO)/Chordoma Global Consensus Group (CGCG).11,12 Unfortunately, there are several common and notable limitations to these guidelines such as a lack of skull base specific recommendations, variation in local surveillance screening intervals, and a paucity of specifics regarding examination for metastatic disease. No single guideline to date provides a comprehensive set of recommendations for all forms of local and distant disease that can be seen after initial treatment of skull base chordomas. Given the differences in clinical behavior, and underlying biology of spinal chordomas, there is a need for treatment recommendations specific to the skull base population.13 In the current study, we compared the efficacy of current screening recommendations through the retrospective application of each algorithm to our cohort of patients with recurrent disease with the goal of developing a revised imaging surveillance protocol for timely diagnosis of local and systemic progression (Table 1). METHODS Between 1993 and 2017, 91 newly diagnosed skull base chordomas have undergone initial definitive treatment at our institution. A retrospective chart review of all patients with recurrent disease was performed. The study was conducted under an institutional review board (IRB)-approved protocol in compliance with regulations set by our institution with regard to the study of human subjects; patient consent was deemed not to be required by the IRB due to the study design. Review of the prospectively accrued Brain and Spine Tumor Registry Database identified 34 patients with recurrent disease meeting inclusion criteria. Electronic medical records and medical imaging were reviewed to identify patient demographics, follow-up times, PFS and OS, treatment specifics, surgical outcomes, histologic subtype, and surveillance trends for the study cohort and recurrence data. Local progression was defined as progressive disease along the skull base, and distant metastasis was defined as progressive disease at sites separate from the skull base. OS was calculated from the time of the index surgery to the time of death. PFS was identified as the interval from surgery to first recurrence, or, in the case of any subsequent recurrences, from the date of treatment for the recurrence to the date of the next radiographically identified progression. The chordoma screening protocols put forth by the LSESN, CGCG/ESMO, and NCCN were reviewed in detail (Table 1). Each algorithm was then applied to the clinical course of each patient within our cohort who suffered at least 1 recurrence. The number of recurrences that developed between recommended screening intervals was recorded and then averaged out for each screening protocol to allow for comparison. Next, the intervals between date of known recurrence and time to detection of the recurrence via the recommended screening interval imaging were recorded for each patient and then compared amongst screening protocols. These numbers were totaled and averaged for comparison. In the current study, only the local screening recommendations for the LSESN and CGCG/ESMO were used given that the LSESN has limited systemic recommendations for pulmonary disease alone and the CGCG/ESMO makes no systemic disease screening suggestions. By contrast, the NCCN recommendations for systemic surveillance are more exhaustive and were therefore used for analysis in the current study. The NCCN guidelines for local disease surveillance do not allow for quantitative analysis and were therefore excluded. After review of the data generated from the application of the established protocols to our cohort, a revised imaging screening protocol entitled “MD Anderson Cancer Center Chordoma Imaging Protocol” (MDACC-CIP) was developed to reduce time from recurrence to diagnosis and improve diagnostic accuracy via additional imaging modalities. The proposed MDACC-CIP protocol involves a magnetic resonance imaging (MRI) skull base every 3 mo for the first year following surgery, every 6 mo for years 2 to 4, then yearly thereafter. For systemic disease, which most commonly occurs in the lungs, spine, and along the leptomeninges, the MDACC-CIP employs the use of computed tomography (CT) chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Additionally, the MDACC-CIP proposal is restarted once a patient is treated for progression at any site. This algorithm was applied in the same fashion to our cohort, and results were then compared to previously established guidelines for comparison. Statistical analysis was conducted with SPSS (SPSS for Windows, IBM Inc, Armonk, New York) and Graph Pad (Graphpad Software Inc, La Jolla, California). Pearson chi-square and Fisher's exact tests were used to compare categorical variables whereas a 2-tailed Student's t-test was employed for continuous variables. Kaplan-Meier (KM) survival analysis was used to generate OS and PFS data for the entire cohort. A P-value < .05 was considered significant for all analyses. TABLE 1. Previously Published Surveillance Guidelines and Currently Proposed Recommendation Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI CGCG: Chordoma Global Consensus Group, ESMO: European Society for Medical Oncology, LSESN: London and South East Sarcoma Network, NCCN: National Comprehensive Cancer Network, MDACC-CIP: M.D. Anderson Chordoma Imaging Protocol. aAfter development of recurrence, the recommendation is for the surveillance protocol to be restarted similar to completion of initial treatment. View Large TABLE 1. Previously Published Surveillance Guidelines and Currently Proposed Recommendation Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI CGCG: Chordoma Global Consensus Group, ESMO: European Society for Medical Oncology, LSESN: London and South East Sarcoma Network, NCCN: National Comprehensive Cancer Network, MDACC-CIP: M.D. Anderson Chordoma Imaging Protocol. aAfter development of recurrence, the recommendation is for the surveillance protocol to be restarted similar to completion of initial treatment. View Large RESULTS Patient Demographics and Treatment Specifics Patient demographics, disease status at presentation, and specifics of treatment prior to presentation to MDACC are presented in Table 2. Histologic subtype for 34 patients experiencing recurrent disease was as follows: chondroid (n = 20), conventional (n = 12), and de-differentiated (n = 2; Figure 1). Mean follow-up time was 79 mo (range 2-260 mo). KM OS and PFS curves for the entire cohort are shown in Figure 2. Median OS and PFS were 159 and 47 mo, respectively. Treatment specifics in newly diagnosed patients and then in the management of local and systemic progression are shown in Table 2 FIGURE 1. View largeDownload slide Breakdown of recurrences by histologic subtype for entire cohort (n = 91). FIGURE 1. View largeDownload slide Breakdown of recurrences by histologic subtype for entire cohort (n = 91). FIGURE 2. View largeDownload slide Kaplan–Meier survival curves for entire cohort (n = 91). A, OS; B, PFS. FIGURE 2. View largeDownload slide Kaplan–Meier survival curves for entire cohort (n = 91). A, OS; B, PFS. TABLE 2. Demographics and Treatments for All Newly Diagnosed Patients Treated Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) LMD, leptomeningeal disease; XRT, radiation therapy. View Large TABLE 2. Demographics and Treatments for All Newly Diagnosed Patients Treated Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) LMD, leptomeningeal disease; XRT, radiation therapy. View Large Patterns and Time Course of Progression Patterns of recurrence and their time course are shown in Table 3. Following initial treatment, the first recurrence took place within the first 5, 5 to 10, and >10 yr in 55%, 10%, and 35% of patients, respectively. Median time to the first local and metastatic recurrence was 13.5 and 51, respectively, with the earliest metastatic sites being observed in the spine, lungs, and skin. Mean time to recurrences 2 to 6 are listed in Table 3, while exact time of diagnosis of all local and metastatic recurrences is plotted in bar graph form in Figure 3. As demonstrated in Figure 4, early recurrence was more often marked by local spread with an increasing amount of distant metastatic disease seen later in the disease course. The probability of developing a second recurrence following the first and each subsequent recurrence thereafter is depicted in line plot form in Figure 5. FIGURE 3. View largeDownload slide Bar graph of local (A) and distant (B) recurrences by month from completion of initial treatment (n = 34). FIGURE 3. View largeDownload slide Bar graph of local (A) and distant (B) recurrences by month from completion of initial treatment (n = 34). FIGURE 4. View largeDownload slide Pattern of recurrence trend over time (n = 34). FIGURE 4. View largeDownload slide Pattern of recurrence trend over time (n = 34). FIGURE 5. View largeDownload slide Probability of developing subsequent disease recurrence (based on cohort with recurrent disease, n = 34). FIGURE 5. View largeDownload slide Probability of developing subsequent disease recurrence (based on cohort with recurrent disease, n = 34). TABLE 3. Location and Time Course of Disease Progression Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) The following distant metastases were noted: spinal column metastases (5 patients), LMD (4 patients), pulmonary (2 patients), long bones (2 patients), parotid gland (1 patient), scalp (1 patient). View Large TABLE 3. Location and Time Course of Disease Progression Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) The following distant metastases were noted: spinal column metastases (5 patients), LMD (4 patients), pulmonary (2 patients), long bones (2 patients), parotid gland (1 patient), scalp (1 patient). View Large Diagnostic Effectiveness of Current Screening Recommendations vs MDACC-CIP Tables 4 and 5 outline the duration of undiagnosed time following the application of the local (LSESN, CGCG/ESMO, MDACC-CIP) and distant (NCCN, MDACC-CIP) surveillance protocols over a 15-yr follow-up period. As demonstrated, the MDACC-CIP protocol for local surveillance reduced the time to the diagnosis of local recurrent disease by approximately 66% as compared to the LSESN schedule (5.0 mo mean undiagnosed months vs 16.9, P < .05) and by 50% as compared to the CGCG/ESMO schedule (5.0 mo mean undiagnosed months vs 9.8, P < .05). For distant disease surveillance, the MDACC-CIP only slightly reduced undiagnosed disease as compared to the NCCN protocol. It is important to note, however, that the NCCN includes only CT imaging of the spine, whereas the MDACC-CIP utilizes MRI for spinal surveillance. Therefore, it is likely that the NCCN would have failed to diagnose the patients with spinal leptomeningeal disease (LMD) thus rendering the NCCN protocol inadequate as a comprehensive systemic surveillance tool. TABLE 4. Intersurveillance Recurrences and Months of Undiagnosed Recurrence Amongst Imaging Schedules Applied to the Cohort for 15 yr Post-Treatment Surveillance Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large TABLE 4. Intersurveillance Recurrences and Months of Undiagnosed Recurrence Amongst Imaging Schedules Applied to the Cohort for 15 yr Post-Treatment Surveillance Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large TABLE 5. Comparison of Published Screening Schedules to Our Proposed Revision for Disease Surveillance Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large TABLE 5. Comparison of Published Screening Schedules to Our Proposed Revision for Disease Surveillance Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large DISCUSSION To date, several regimens for post-treatment surveillance for chordomas have been published.13-16 Unfortunately, these recommendations are not specific to skull base chordomas and their unique clinical behavior relative to spinal pathology. Furthermore, while the published guidelines thoroughly address local disease surveillance, they are relatively limited in their scope with regards to detection of metastatic disease. Given the impact of patterns of progression on disease specific survival and on indications for different treatment modalities, we felt there is a need for effective treatment surveillance.2,14 Additionally, early detection of recurrence could open the possibility of non-surgical treatment options (ie, stereotactic radiosurgery) while avoiding the need for repeat surgical intervention where the risk/benefit profile may not be favorable.2,15,16 To our knowledge, this study represents the first to quantify the differences in current surveillance guidelines in order to identify areas where imaging frequency and modality might be improved specifically for skull base chordoma. Chordoma Recurrence Patterns At first recurrence following initial treatment, 32 of 34 patients (94%) developed local progression only while the remaining 2 patients presented with local progression and distant disease. Over the next 2 recurrences, the number of distant metastases increased. While every case of distant recurrence was preceded by an initial local recurrence, a few patients went on to develop distant metastases without further local progression. Patterns of distant metastasis in our cohort demonstrate that while most begin to occur around 4 to 5 yr postoperatively, there are cases occurring within the first year following treatment. Published rates of chordoma metastasis vary from 13 to 27% for skull base chordoma tumors.8,17,18 Patients in the current study, which includes 62 with primary skull base chordoma treated with surgery and radiation therapy in most cases, developed metastases 19% of the time. In keeping with other series, patients developed metastatic disease in similar locations: spine and lungs.1,18 In our cohort, LMD represented the second most common form of distant metastasis, occurring in 10% of patients who developed local progression or recurrence. This varies from other reported series, which are largely based on sacrococcygeal primary tumors wherein dural violation may have been less common and metastasis more likely via hematologic spread. Current Surveillance Protocols and the MDACC-CIP Based on the time course and decreasing interval with subsequent recurrences, we devised a more vigilant surveillance regimen for early local recurrence by increasing the number of skull base MRIs during years 1 to 4 after initial diagnosis and treatment for recurrence. Overall, the changes made in the MDACC-CIP for local disease resulted in a reduction of the total number of missed months of undiagnosed disease for the entire cohort over the first 15 yr from 576 (LSESN) and 336 (CGCG) to 170 and the average number of undiagnosed patients dropped from 16.6 (LSESN) and 9.6 (CGCG) to 4.9. While increasing the number of surveillance scans would impact the overall cost of care, it is important to consider that early detection of recurrence would open the door to treatment options such as stereotactic radiosurgery while avoiding the need for repeat surgical resection for bulky disease. This theoretically avoids the surgical costs and leaves the door open to presumably more cost-effective treatments. In the current study, metastasis occurred in approximately one-fifth of patients with an average metastasis-free survival following surgery +/– adjuvant radiation of 57 mo. Similarly, a recent study of 151 patients with skull base chordoma treated with surgery and adjuvant radiation demonstrated a 91% metastasis-free survival rate at 7 yr.17 Nevertheless, in our series, the range of metastatic onset occurred as early as 10 mo and as late as 131 mo following treatment with spread to multiple areas throughout the body. Therefore, pulmonary surveillance algorithms, which have been suggested for metastatic bone sarcoma,19 will not alone suffice for metastatic skull base chordoma. Likewise, CT with contrast, as suggested by the recent NCCN recommendations, is insufficient as a single modality for surveillance of epidural and LMD metastases, which are more prevalent in skull base chordoma. As such, the MDACC-CIP for metastatic disease includes the addition of a surveillance complete spine MRI, which can be done at the same time of the skull base MRI allowing for seamless integration into the protocol. Imaging Specifics for Skull Base Chordoma Surveillance Current recommendations for initial imaging and local surveillance include MRI T2 sequences in 3 axes (axial/sagittal/coronal) and T1 pre- and postfat saturation with thin slices (1-2 mm) through skull base.12 While gadolinium-enhanced sequences are a useful addition to the scanning regimen for chordoma, enhancement patterns are variable20,21 and less consistent than T2 sequences which commonly display a robust and inhomogeneous T2 hyperintense signal with internal septations.22 Of note, enhancement patterns in the postradiation setting can be particularly difficult to interpret. For the purposes of surgical planning, CT is obtained in 3 axes (axial/sagittal/coronal) with thin slices through the skull base, to delineate the extent of clival and extra-clival bony invasion by the tumor. For local surveillance in the post-treatment setting, CT is not very useful and is therefore not routinely performed12 and not recommended in the MDACC-CIP. For metastatic disease surveillance, the MDACC-CIP includes an MRI of the entire spine, with 3-axis T2- and gadolinium-enhanced sequences plus CT chest/abdomen/pelvis, with and without iodinated contrast. This combination, rather than whole body MRI and/or whole body CT, was chosen based on the location of the majority of skull base chordoma metastases (lungs and spine) in an effort to maximize yield while reducing cost and radiation exposure. For spinal metastases, MRI is paramount to other modalities for the evaluation of epidural extension and proximity to the spinal cord and nerve roots. Furthermore, MRI is also more specific for LMD than CT or metabolic nuclear studies. Given the risk of pulmonary, lymph node or other soft tissue metastases within the chest, abdomen and pelvis, targeted CT has been recommended for restaging. Limitations Age,5,23 histologic subtype,6,8,24 degree of resection,4,8,24,25 primary vs recurrent disease at operation,7,26,27 and adjuvant radiation timing and modality7 have all been shown to affect chordoma control rates and recurrence patterns. These factors could theoretically be the basis of tailored surveillance recommendations. Given the limited size of our patient cohort, we were unable to divide the group into subcohorts for separate analysis based on differences in these factors. In our cohort, there were fractions of patients who developed either early local progression, systemic metastases, and/or LMD despite optimal tumor and treatment related factors (ie, chondroid histology, gross total resection with margins, well designed radiation dosing, etc.). The low incidence of this disease is clearly a complicating factor and is highlighted by the fact that all major organizational guidelines (ie, NCCN, etc.) only provide generalized recommendations. Ultimately, the identification of correlative molecular markers predictive of clinical outcomes will aid in the development of tailored surveillance (and, potentially, therapeutic) recommendations. The development of more precise algorithms with decision trees accounting for differences in these factors are necessary but require large patient repositories with accurate histologic analysis, treatment plans, and follow-up data. Furthermore, the cost of increasing surveillance scans vs the improved cost-effectiveness of early disease detection has to be considered. Unfortunately, our study and available data were not able to factor this into the analysis. A prospective trial comparing skull base chordoma surveillance schedules would help validate the need for more intensive imaging surveillance in certain instances and provide insight into specific cohorts that require less frequent monitoring (ie, those with chondroid histology status post gross total resection with wide margins). CONCLUSION Despite advances in treatment, skull base chordoma continues to recur frequently and at irregular intervals in local and distant sites. LMD involvement is higher in this cohort, which must be accounted for in any surveillance protocol. In the current study, we propose a revised imaging surveillance protocol to account for these findings to improve the timely detection and treatment of recurrent disease. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Chambers PW , Schwinn CP . Chordoma: a clinicopathologic study of metastasis . Am J Clin Pathol . 1979 ; 72 ( 5 ): 765 - 776 . Google Scholar CrossRef Search ADS PubMed 2. Raza SM , Bell D , Freeman JL , Grosshans DR , Fuller GN , DeMonte F . Multimodality management of recurrent skull base chordomas: factors impacting tumor control and disease-specific survival . Oper Neurosurg . 2017 ; In Press . 3. Bohman LE , Koch M , Bailey RL , Alonso-Basanta M , Lee JY . Skull base chordoma and chondrosarcoma: influence of clinical and demographic factors on prognosis: a SEER analysis . World Neurosurg . 2014 ; 82 ( 5 ): 806 - 814 . Google Scholar CrossRef Search ADS PubMed 4. Di Maio S , Rostomily R , Sekhar LN . Current surgical outcomes for cranial base chordomas: cohort study of 95 patients . Neurosurgery . 2012 ; 70 ( 6 ): 1355 - 1360 ; discussion 1360 . Google Scholar CrossRef Search ADS PubMed 5. Jones PS , Aghi MK , Muzikansky A , Shih HA , Barker FG 2nd , Curry WT Jr . Outcomes and patterns of care in adult skull base chordomas from the Surveillance, Epidemiology, and End Results (SEER) database . J Clin Neurosci . 2014 ; 21 ( 9 ): 1490 - 1496 . Google Scholar CrossRef Search ADS PubMed 6. Ouyang T , Zhang N , Zhang Y et al. Clinical characteristics, immunohistochemistry, and outcomes of 77 patients with skull base chordomas . World Neurosurg . 2014 ; 81 ( 5-6 ): 790 - 797 . Google Scholar CrossRef Search ADS PubMed 7. Tzortzidis F , Elahi F , Wright D , Natarajan SK , Sekhar LN . Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas . Neurosurgery . 2006 ; 59 ( 2 ): 230 - 237 ; discussion 230-237 . Google Scholar CrossRef Search ADS PubMed 8. Wu Z , Zhang J , Zhang L et al. Prognostic factors for long-term outcome of patients with surgical resection of skull base chordomas-106 cases review in one institution . Neurosurg Rev . 2010 ; 33 ( 4 ): 451 - 456 . Google Scholar CrossRef Search ADS PubMed 9. Biermann JS , Chow W , Reed DR et al. NCCN guidelines insights: bone cancer, Version 2.2017 . J Natl Compr Canc Netw . 2017 ; 15 ( 2 ): 155 - 167 . Google Scholar CrossRef Search ADS PubMed 10. Gerrand C , Athanasou N , Brennan B et al. UK guidelines for the management of bone sarcomas . Clin Sarcoma Res . 2016 ; 6 ( 1 ): 7 . Google Scholar CrossRef Search ADS PubMed 11. Group ESESNW . Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol . 2014 ; 25 ( suppl 3 ): iii113 - iii123 . CrossRef Search ADS PubMed 12. Stacchiotti S , Sommer J Chordoma Global Consensus Group . Building a global consensus approach to chordoma: a position paper from the medical and patient community . Lancet Oncol . 2015 ; 16 ( 2 ): e71 - e83 . Google Scholar CrossRef Search ADS PubMed 13. Bell AH , DeMonte F , Raza SM et al. Transcriptome comparison identifies potential biomarkers of spine and skull base chordomas . Virchows Arch . 2018 ; 472 ( 3 ): 489 - 497 . Google Scholar CrossRef Search ADS PubMed 14. Stacchiotti S , Gronchi A , Fossati P et al. Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group . Ann Oncol . 2017 ; 28 ( 6 ): 1230 - 1242 . Google Scholar CrossRef Search ADS PubMed 15. Kano H , Iqbal FO , Sheehan J et al. Stereotactic radiosurgery for chordoma: a report from the North American Gamma Knife Consortium . Neurosurgery . 2011 ; 68 ( 2 ): 379 - 389 . Google Scholar CrossRef Search ADS PubMed 16. Sen C , Triana AI , Berglind N , Godbold J , Shrivastava RK . Clival chordomas: clinical management, results, and complications in 71 patients . J Neurosurg . 2010 ; 113 ( 5 ): 1059 - 1071 . Google Scholar CrossRef Search ADS PubMed 17. Weber DC , Malyapa R , Albertini F et al. Long term outcomes of patients with skull-base low-grade chondrosarcoma and chordoma patients treated with pencil beam scanning proton therapy . Radiother Oncol . 2016 ; 120 ( 1 ): 169 - 174 . Google Scholar CrossRef Search ADS PubMed 18. Yasuda M , Bresson D , Chibbaro S et al. Chordomas of the skull base and cervical spine: clinical outcomes associated with a multimodal surgical resection combined with proton-beam radiation in 40 patients . Neurosurg Rev . 2012 ; 35 ( 2 ): 171 - 183 ; discussion 182-183 . Google Scholar CrossRef Search ADS PubMed 19. Cipriano C , Griffin AM , Ferguson PC , Wunder JS . Developing an evidence-based followup schedule for bone sarcomas based on local recurrence and metastatic progression . Clin Orthop Relat Res . 2017 ; 475 ( 3 ): 830 - 838 . Google Scholar CrossRef Search ADS PubMed 20. Chang C , Chebib I , Torriani M , Bredella M . Osseous metastases of chordoma: imaging and clinical findings . Skeletal Radiol . 2017 ; 46 ( 3 ): 351 - 358 . Google Scholar CrossRef Search ADS PubMed 21. Walcott BP , Nahed BV , Mohyeldin A , Coumans JV , Kahle KT , Ferreira MJ . Chordoma: current concepts, management, and future directions . Lancet Oncol . 2012 ; 13 ( 2 ): e69 - e76 . Google Scholar CrossRef Search ADS PubMed 22. Soo MY . Chordoma: review of clinicoradiological features and factors affecting survival . Australas Radiol . 2001 ; 45 ( 4 ): 427 - 434 . Google Scholar CrossRef Search ADS PubMed 23. Hoch BL , Nielsen GP , Liebsch NJ , Rosenberg AE . Base of skull chordomas in children and adolescents: a clinicopathologic study of 73 cases . Am J Surg Pathol . 2006 ; 30 ( 7 ): 811 - 818 . Google Scholar CrossRef Search ADS PubMed 24. Wang L , Tian K , Wang K et al. Factors for tumor progression in patients with skull base chordoma . Cancer Med . 2016 ; 5 ( 9 ): 2368 - 2377 . Google Scholar CrossRef Search ADS PubMed 25. Samii A , Gerganov VM , Herold C et al. Chordomas of the skull base: surgical management and outcome . J Neurosurg . 2007 ; 107 ( 2 ): 319 - 324 . Google Scholar CrossRef Search ADS PubMed 26. Gay E , Sekhar LN , Rubinstein E et al. Chordomas and chondrosarcomas of the cranial base: results and follow-up of 60 patients . Neurosurgery . 1995 ; 36 ( 5 ): 887 - 897 ; discussion 896-897 . Google Scholar CrossRef Search ADS PubMed 27. George B , Bresson D , Bouazza S et al. Les chordomes . Neurochirurgie . 2014 ; 60 ( 3 ): 63 - 140 . Google Scholar CrossRef Search ADS PubMed Operative Neurosurgery Speaks! Audio abstracts available for this article at www.operativeneurosurgery-online.com. COMMENTS The authors have provided important data on the clinical course of 34 patients who had recurrent clival chordomas who they treated between 1993 and 2017. As expected, this is a small number. However, they have drawn our attention to the need for standardization of the monitoring for patients with clival chordoma for local recurrence as well as distant spread. Close and systematic monitoring of these patients for many years is essential in order to detect recurrences and metastases early so that treatment options are available in a timely manner. Interestingly, despite the close monitoring of their entire cohort of 91 patients, the numbers of overall and progression-free survival are similar to other reported contemporary series. It should also be noted that time to recurrence keeps getting shorter with each episode of recurrence thus needing more frequent imaging after each recurrence. They have reported a larger number of recurrences in the “chondroid chordoma” group. We have also had a similar experience thus indicating that these are not necessarily a better subset of chordomas. Whether the cost-benefit analysis supports that the MDACC-CIP should be a “standard” time line of imaging studies will need to be seen based on future reports from other investigators. Chandranath Sen New York, New York In this paper, the authors have proposed a set of guidelines for monitoring patients with chordoma, after treatment. I believe that this protocol needs to be modified. In patients with new onset of tumors, the goal of treatment should be total or near total resection, followed by Proton Beam or Carbon Ion radiation (rarely, Radiosurgery). In patients with recurrent tumors, repeat surgery, re-irradiation, and protocol-based chemotherapy are all considerations. Although I agree with an MRI scan 3 months after the initial treatment, subsequent imaging should be decided by the presence of residual tumor, pathological subtype, or molecular markers. If recurrence is detected, the surgeon should also have some treatment to offer the patient. WE need to be cautious about recommending frequent imaging follow up for a rare disease, which will raise the level of anxiety in the patient, the cost of medical care, and the ease of being able to get health insurance in the USA. Laligam N. Sekhar Seattle, Washington We read this manuscript with a lot of enthusiasm. In our practice we do not necessarily follow a rigid protocol when following up patients with clival chordomas. It is clear that while some patients have a very benign course, others have what I would describe as fulminant disease. Once that progression is established during the initial, short surveillance period, the protocol can be adjusted. In terms of local disease, we agree on obtaining a brain MRI with and without contrast 3 months after surgery and proton beam therapy. When a total resection is confirmed and pathology does not point to a more aggressive subtype of chordoma, such as “chondroid” type, obtaining follow-up imaging 6 months later seems appropriate. Conversely, when dealing with possible residuals or aggressive subtype of chordoma, another follow up MRI 3 months later seems prudent. This manuscript calls the attention to the potential of distant disease. We are likely to revise our current practice to incorporate more frequent investigations for metastatic disease as suggested by the authors. Daniel M. Prevedello Ricardo L. Carrau Columbus, Ohio The authors have provided a very detailed analysis of the timing and patterns of recurrence (local and/or distant) for patients that underwent treatment for skull base chordomas in an effort to develop a refined, higher yield strategy of follow-up with surveillance brain, spine, and body imaging. This adds significantly to our understanding of the patterns of recurrent disease for the challenging condition of skull-base chordomas. The authors propose a more extensive imaging routine that identifies recurrent disease more quickly than other more general screening protocols. Whether this method improves outcomes, or whether the costs of such extensive imaging can be justified remains to be determined. Michael Chicoine St. Louis, Missouri Operative Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Hailiang Tang, MD Department of Neurosurgery Huashan Hospital Fudan University Shanghai, China Chinese: Hailiang Tang, MD Department of Neurosurgery Huashan Hospital Fudan University Shanghai, China Close English: Garni Barkhoudarian, MD Brain Tumor Center and Pituitary Disorders Program John Wayne Cancer Institute Santa Monica, California English: Garni Barkhoudarian, MD Brain Tumor Center and Pituitary Disorders Program John Wayne Cancer Institute Santa Monica, California Close French: Johan Pallud, MD, PhD Department of Neurosurgery Medical School of Paris Descartes University Paris, France French: Johan Pallud, MD, PhD Department of Neurosurgery Medical School of Paris Descartes University Paris, France Close Russian: Mikhail Gelfenbeyn, MD, PhD Department of Neurological Surgery University of Washington Seattle, Washington Russian: Mikhail Gelfenbeyn, MD, PhD Department of Neurological Surgery University of Washington Seattle, Washington Close Italian: Francesco Acerbi, MD, PhD Department of Neurosurgery Fondazione IRCCS Istituto Neurologico C. Besta Milano Milano, Italy Italian: Francesco Acerbi, MD, PhD Department of Neurosurgery Fondazione IRCCS Istituto Neurologico C. Besta Milano Milano, Italy Close Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Close Korean: Hye Ran Park, MD Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Korean: Hye Ran Park, MD Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Close Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Close Spanish: Ariel M. Kaen, MD, PhD Department of Neurosurgery Hospital Virgen del Rocío Sevilla, Spain Spanish: Ariel M. Kaen, MD, PhD Department of Neurosurgery Hospital Virgen del Rocío Sevilla, Spain Close Copyright © 2018 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Operative Neurosurgery Oxford University Press

Evidence-Based Optimization of Post-Treatment Surveillance for Skull Base Chordomas Based on Local and Distant Disease Progression

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Congress of Neurological Surgeons
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Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
2332-4252
eISSN
2332-4260
D.O.I.
10.1093/ons/opy073
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See Article on Publisher Site

Abstract

Abstract BACKGROUND There are no guidelines regarding post-treatment surveillance specific to skull base chordomas. OBJECTIVE To determine an optimal imaging surveillance schedule to detect both local and distant metastatic skull base chordoma recurrences. METHODS A retrospective review of 91 patients who underwent treatment for skull base chordoma between 1993 and 2017 was conducted. Time to and location of local and distant recurrence(s) were cataloged. Existing chordoma surveillance recommendations (National Comprehensive Cancer Network [NCCN], London and South East Sarcoma Network [LSESN], European Society for Medical Oncology [ESMO], Chordoma Global Consensus Group [CGCG]) were applied to our cohort to compare the number of recurrent patients and months of undiagnosed tumor growth between surveillances. These findings were used to inform the creation of a revised imaging surveillance protocol (MD Anderson Cancer Center Chordoma Imaging Protocol [MDACC-CIP]), presented here. RESULTS Thirty-four patients with 79 local/systemic recurrences met inclusion criteria. Mean age at diagnosis and follow-up time were 45 yr and 79 mo, respectively. The MDACC-CIP imaging protocol significantly reduced the time to diagnosis of recurrence compared with the LSESN and CGCG/ESMO imaging protocols for surveillance of local disease with a cumulative/average of 576/16.9 (LSESN), 336/9.8 (CGCG), and 170/5.0 (MDACC-CIP) months of undetected growth, respectively. The NCCN and MDACC-CIP guidelines for distant metastatic surveillance identified a cumulative/average of 65/6.5 and 51/5.1 mo of undetected growth, respectively, and were not significantly different. CONCLUSION The MDACC-CIP for skull base chordoma accounts for recurrence trends unique to this disease, including a higher rate of leptomeningeal spread than sacrococcygeal primaries, resulting in improved sensitivity and prompt diagnosis. Chordoma, Recurrence, Surveillance, Guidelines, Malignancy, Skull Base, Cancer ABBREVIATIONS ABBREVIATIONS CGCG Chordoma Global Consensus Group CT computed tomography ESMO European Society for Medical Oncology IRB institutional review board KM Kaplan-Meier LMD leptomeningeal disease LSESN London and South East Sarcoma Network MDACC-CIP MD Anderson Cancer Center Chordoma Imaging Protocol MRI magnetic resonance imaging NCCN National Comprehensive Cancer Network OS overall survival PFS progression-free survival XRT radiation therapy Chordomas are bony malignancies with a behavioral spectrum that can span from indolent local disease to locally aggressive growth and at times to distant metastatic spread.1,2 Despite advances in surgical strategies, charged particle radiation therapy, and attempts at targeted therapy options, it represents a challenging disease to treat with reported 5-yr progression-free survival (PFS) of 45% to 81%, 5-yr overall survival (OS) rates of 55% to 67%, and 10-yr OS rates of 32% to 61%.3-8 Ultimately, this disease is characterized by local recurrence and/or distant metastases with disease progression as the primary cause of death in patients when it occurs.2 Consequently, there is a need for the timely diagnosis of both local and distant disease progression. To date, several groups have published surveillance recommendations for chordoma including the National Comprehensive Cancer Network (NCCN),9 the London and South East Sarcoma Network (LSESN),10 and the European Society for Medical Oncology (ESMO)/Chordoma Global Consensus Group (CGCG).11,12 Unfortunately, there are several common and notable limitations to these guidelines such as a lack of skull base specific recommendations, variation in local surveillance screening intervals, and a paucity of specifics regarding examination for metastatic disease. No single guideline to date provides a comprehensive set of recommendations for all forms of local and distant disease that can be seen after initial treatment of skull base chordomas. Given the differences in clinical behavior, and underlying biology of spinal chordomas, there is a need for treatment recommendations specific to the skull base population.13 In the current study, we compared the efficacy of current screening recommendations through the retrospective application of each algorithm to our cohort of patients with recurrent disease with the goal of developing a revised imaging surveillance protocol for timely diagnosis of local and systemic progression (Table 1). METHODS Between 1993 and 2017, 91 newly diagnosed skull base chordomas have undergone initial definitive treatment at our institution. A retrospective chart review of all patients with recurrent disease was performed. The study was conducted under an institutional review board (IRB)-approved protocol in compliance with regulations set by our institution with regard to the study of human subjects; patient consent was deemed not to be required by the IRB due to the study design. Review of the prospectively accrued Brain and Spine Tumor Registry Database identified 34 patients with recurrent disease meeting inclusion criteria. Electronic medical records and medical imaging were reviewed to identify patient demographics, follow-up times, PFS and OS, treatment specifics, surgical outcomes, histologic subtype, and surveillance trends for the study cohort and recurrence data. Local progression was defined as progressive disease along the skull base, and distant metastasis was defined as progressive disease at sites separate from the skull base. OS was calculated from the time of the index surgery to the time of death. PFS was identified as the interval from surgery to first recurrence, or, in the case of any subsequent recurrences, from the date of treatment for the recurrence to the date of the next radiographically identified progression. The chordoma screening protocols put forth by the LSESN, CGCG/ESMO, and NCCN were reviewed in detail (Table 1). Each algorithm was then applied to the clinical course of each patient within our cohort who suffered at least 1 recurrence. The number of recurrences that developed between recommended screening intervals was recorded and then averaged out for each screening protocol to allow for comparison. Next, the intervals between date of known recurrence and time to detection of the recurrence via the recommended screening interval imaging were recorded for each patient and then compared amongst screening protocols. These numbers were totaled and averaged for comparison. In the current study, only the local screening recommendations for the LSESN and CGCG/ESMO were used given that the LSESN has limited systemic recommendations for pulmonary disease alone and the CGCG/ESMO makes no systemic disease screening suggestions. By contrast, the NCCN recommendations for systemic surveillance are more exhaustive and were therefore used for analysis in the current study. The NCCN guidelines for local disease surveillance do not allow for quantitative analysis and were therefore excluded. After review of the data generated from the application of the established protocols to our cohort, a revised imaging screening protocol entitled “MD Anderson Cancer Center Chordoma Imaging Protocol” (MDACC-CIP) was developed to reduce time from recurrence to diagnosis and improve diagnostic accuracy via additional imaging modalities. The proposed MDACC-CIP protocol involves a magnetic resonance imaging (MRI) skull base every 3 mo for the first year following surgery, every 6 mo for years 2 to 4, then yearly thereafter. For systemic disease, which most commonly occurs in the lungs, spine, and along the leptomeninges, the MDACC-CIP employs the use of computed tomography (CT) chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Additionally, the MDACC-CIP proposal is restarted once a patient is treated for progression at any site. This algorithm was applied in the same fashion to our cohort, and results were then compared to previously established guidelines for comparison. Statistical analysis was conducted with SPSS (SPSS for Windows, IBM Inc, Armonk, New York) and Graph Pad (Graphpad Software Inc, La Jolla, California). Pearson chi-square and Fisher's exact tests were used to compare categorical variables whereas a 2-tailed Student's t-test was employed for continuous variables. Kaplan-Meier (KM) survival analysis was used to generate OS and PFS data for the entire cohort. A P-value < .05 was considered significant for all analyses. TABLE 1. Previously Published Surveillance Guidelines and Currently Proposed Recommendation Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI CGCG: Chordoma Global Consensus Group, ESMO: European Society for Medical Oncology, LSESN: London and South East Sarcoma Network, NCCN: National Comprehensive Cancer Network, MDACC-CIP: M.D. Anderson Chordoma Imaging Protocol. aAfter development of recurrence, the recommendation is for the surveillance protocol to be restarted similar to completion of initial treatment. View Large TABLE 1. Previously Published Surveillance Guidelines and Currently Proposed Recommendation Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI Source Local Distant LSESN 201618 Year 1: q6 month MRI Pulmonary surveillance only: Years 2-10: annual MRI Years 1-2: CXR q 3-6 mo >10 yr: q5 year MRI Years 3-5: CXR q6 months Years 6-10: CXR annually CGCG/ESMO 201520 Years 1-5: q6 month MRI, No recommendations made Years 6-15: annual MRI NCCN 201717 X-ray, CT +/– MRI (both with contrast) of the surgical site as clinically indicated CT chest: q6 months × 5 yr then annually thereafter CT abdomen and pelvis: annually MDACC-CIP 2017a Year 1: q3 month MRI CT chest/abdomen/pelvis with and without contrast and MRI spine with and without gadolinium every 6 mo for the first year then annually thereafter. Years 2-4: q6 month MRI >5 yr: annually MRI CGCG: Chordoma Global Consensus Group, ESMO: European Society for Medical Oncology, LSESN: London and South East Sarcoma Network, NCCN: National Comprehensive Cancer Network, MDACC-CIP: M.D. Anderson Chordoma Imaging Protocol. aAfter development of recurrence, the recommendation is for the surveillance protocol to be restarted similar to completion of initial treatment. View Large RESULTS Patient Demographics and Treatment Specifics Patient demographics, disease status at presentation, and specifics of treatment prior to presentation to MDACC are presented in Table 2. Histologic subtype for 34 patients experiencing recurrent disease was as follows: chondroid (n = 20), conventional (n = 12), and de-differentiated (n = 2; Figure 1). Mean follow-up time was 79 mo (range 2-260 mo). KM OS and PFS curves for the entire cohort are shown in Figure 2. Median OS and PFS were 159 and 47 mo, respectively. Treatment specifics in newly diagnosed patients and then in the management of local and systemic progression are shown in Table 2 FIGURE 1. View largeDownload slide Breakdown of recurrences by histologic subtype for entire cohort (n = 91). FIGURE 1. View largeDownload slide Breakdown of recurrences by histologic subtype for entire cohort (n = 91). FIGURE 2. View largeDownload slide Kaplan–Meier survival curves for entire cohort (n = 91). A, OS; B, PFS. FIGURE 2. View largeDownload slide Kaplan–Meier survival curves for entire cohort (n = 91). A, OS; B, PFS. TABLE 2. Demographics and Treatments for All Newly Diagnosed Patients Treated Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) LMD, leptomeningeal disease; XRT, radiation therapy. View Large TABLE 2. Demographics and Treatments for All Newly Diagnosed Patients Treated Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) Presenting Characteristic N (%) Gender  Male 37 (41)  Female 54 (59) Age 44.6 yr (Mean) Presenting Karnofsky Performance Score 90 (Median) Previous Treatment  Previous Biopsy +/– XRT 17  Prior Surgery +/– XRT 14 Treatment at Initial Diagnosis  Surgery + XRT 42 Treatment at Recurrent Disease  Local Progression 37   Surgery 5 (13.5)   Chemotherapy 5 (13.5)   Radiation Therapy 8 (22)   Surgery, Chemotherapy, Radiation Therapy 1 (3)   Surgery, Chemotherapy 2 (5)   Surgery, Radiation Therapy 8 (22)   Chemotherapy, Radiation Therapy 3 (8)   No Treatment 5 (13.5)  Distant Metastases (Systemic) 13   Surgery 3 (23)   Chemotherapy 4 (31)   Radiation Therapy 1 (7.7)   Surgery, Chemotherapy 1 (7.7)   Chemotherapy, Radiation Therapy 4 (31)  Distant Metastases (LMD) 7   Chemotherapy 1 (14.2)   Palliative Surgery, Chemotherapy 3 (42.8)   Chemotherapy, Radiation Therapy 2 (28.6)   No Treatment 1 (14.2) LMD, leptomeningeal disease; XRT, radiation therapy. View Large Patterns and Time Course of Progression Patterns of recurrence and their time course are shown in Table 3. Following initial treatment, the first recurrence took place within the first 5, 5 to 10, and >10 yr in 55%, 10%, and 35% of patients, respectively. Median time to the first local and metastatic recurrence was 13.5 and 51, respectively, with the earliest metastatic sites being observed in the spine, lungs, and skin. Mean time to recurrences 2 to 6 are listed in Table 3, while exact time of diagnosis of all local and metastatic recurrences is plotted in bar graph form in Figure 3. As demonstrated in Figure 4, early recurrence was more often marked by local spread with an increasing amount of distant metastatic disease seen later in the disease course. The probability of developing a second recurrence following the first and each subsequent recurrence thereafter is depicted in line plot form in Figure 5. FIGURE 3. View largeDownload slide Bar graph of local (A) and distant (B) recurrences by month from completion of initial treatment (n = 34). FIGURE 3. View largeDownload slide Bar graph of local (A) and distant (B) recurrences by month from completion of initial treatment (n = 34). FIGURE 4. View largeDownload slide Pattern of recurrence trend over time (n = 34). FIGURE 4. View largeDownload slide Pattern of recurrence trend over time (n = 34). FIGURE 5. View largeDownload slide Probability of developing subsequent disease recurrence (based on cohort with recurrent disease, n = 34). FIGURE 5. View largeDownload slide Probability of developing subsequent disease recurrence (based on cohort with recurrent disease, n = 34). TABLE 3. Location and Time Course of Disease Progression Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) The following distant metastases were noted: spinal column metastases (5 patients), LMD (4 patients), pulmonary (2 patients), long bones (2 patients), parotid gland (1 patient), scalp (1 patient). View Large TABLE 3. Location and Time Course of Disease Progression Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) Occurrence Patients Mean Time to Progression from Initial Diagnosis (mo) Mean Time to Progression From Last Recurrence (mo) Recurrence Location N (%) First Recurrence 34 27 Local: 32 (94) Distant: 0 (0) Local + Distant: 2 (6) Second Recurrence 19 56 32 Local: 14 (74) Distant: 3 (16) Local + Distant: 2 (10) Third Recurrence 12 80 20 Local: 7 (58) Distant: 3 (25) Local + Distant: 2 (17) Fourth Recurrence 9 93 12 Local: 5 (56) Distant: 1 (11) Local + Distant: 3 (33) Fifth Recurrence 4 100 17 Local: 2 (50) Distant: 0 Local + Distant: 2 (50) Sixth Recurrence 2 107 6 Local: 1 (50) Distant: 0 (0) Local + Distant: 1 (50) The following distant metastases were noted: spinal column metastases (5 patients), LMD (4 patients), pulmonary (2 patients), long bones (2 patients), parotid gland (1 patient), scalp (1 patient). View Large Diagnostic Effectiveness of Current Screening Recommendations vs MDACC-CIP Tables 4 and 5 outline the duration of undiagnosed time following the application of the local (LSESN, CGCG/ESMO, MDACC-CIP) and distant (NCCN, MDACC-CIP) surveillance protocols over a 15-yr follow-up period. As demonstrated, the MDACC-CIP protocol for local surveillance reduced the time to the diagnosis of local recurrent disease by approximately 66% as compared to the LSESN schedule (5.0 mo mean undiagnosed months vs 16.9, P < .05) and by 50% as compared to the CGCG/ESMO schedule (5.0 mo mean undiagnosed months vs 9.8, P < .05). For distant disease surveillance, the MDACC-CIP only slightly reduced undiagnosed disease as compared to the NCCN protocol. It is important to note, however, that the NCCN includes only CT imaging of the spine, whereas the MDACC-CIP utilizes MRI for spinal surveillance. Therefore, it is likely that the NCCN would have failed to diagnose the patients with spinal leptomeningeal disease (LMD) thus rendering the NCCN protocol inadequate as a comprehensive systemic surveillance tool. TABLE 4. Intersurveillance Recurrences and Months of Undiagnosed Recurrence Amongst Imaging Schedules Applied to the Cohort for 15 yr Post-Treatment Surveillance Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large TABLE 4. Intersurveillance Recurrences and Months of Undiagnosed Recurrence Amongst Imaging Schedules Applied to the Cohort for 15 yr Post-Treatment Surveillance Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 Surveillance Site Organization Total Months of Undiagnosed Recurrence for Entire Cohort Average Months of Undiagnosed Recurrence Per Patient Surveillance Method and Quantity Local MDACC-CIP 170 170/34 = 5.0 MRI Brain: 455 CGCG 336 336/34 = 9.8 MRI Brain: 286 LSESN 576 576/34 = 16.9 MRI Brain: 196 Distant MDACC-CIP 51 51/10 = 5.1 CT chest/abd/pelv: 122 MRI spine: 122 NCCNa 65 65/10 = 6.5 CT chest: 104 CT abd/pelv: 64 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large TABLE 5. Comparison of Published Screening Schedules to Our Proposed Revision for Disease Surveillance Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large TABLE 5. Comparison of Published Screening Schedules to Our Proposed Revision for Disease Surveillance Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 Surveillance Site Surveillance Schedules Average Months of Undiagnosed Recurrence Per Patient P-value Local MDACC-CIP vs CGCG 5.0 vs 9.8 .013 MDACC-CIP vs LSESN 5.0 vs 16.9 .003 Distant MDACC-CIP Vs NCCNa 5.1 vs 6.5 .364 aNote that NCCN Distant Surveillance Recommendations would have missed all instances of LMD and cervical MRI spinal metastases based on recommended imaging modalities and target anatomic sites. View Large DISCUSSION To date, several regimens for post-treatment surveillance for chordomas have been published.13-16 Unfortunately, these recommendations are not specific to skull base chordomas and their unique clinical behavior relative to spinal pathology. Furthermore, while the published guidelines thoroughly address local disease surveillance, they are relatively limited in their scope with regards to detection of metastatic disease. Given the impact of patterns of progression on disease specific survival and on indications for different treatment modalities, we felt there is a need for effective treatment surveillance.2,14 Additionally, early detection of recurrence could open the possibility of non-surgical treatment options (ie, stereotactic radiosurgery) while avoiding the need for repeat surgical intervention where the risk/benefit profile may not be favorable.2,15,16 To our knowledge, this study represents the first to quantify the differences in current surveillance guidelines in order to identify areas where imaging frequency and modality might be improved specifically for skull base chordoma. Chordoma Recurrence Patterns At first recurrence following initial treatment, 32 of 34 patients (94%) developed local progression only while the remaining 2 patients presented with local progression and distant disease. Over the next 2 recurrences, the number of distant metastases increased. While every case of distant recurrence was preceded by an initial local recurrence, a few patients went on to develop distant metastases without further local progression. Patterns of distant metastasis in our cohort demonstrate that while most begin to occur around 4 to 5 yr postoperatively, there are cases occurring within the first year following treatment. Published rates of chordoma metastasis vary from 13 to 27% for skull base chordoma tumors.8,17,18 Patients in the current study, which includes 62 with primary skull base chordoma treated with surgery and radiation therapy in most cases, developed metastases 19% of the time. In keeping with other series, patients developed metastatic disease in similar locations: spine and lungs.1,18 In our cohort, LMD represented the second most common form of distant metastasis, occurring in 10% of patients who developed local progression or recurrence. This varies from other reported series, which are largely based on sacrococcygeal primary tumors wherein dural violation may have been less common and metastasis more likely via hematologic spread. Current Surveillance Protocols and the MDACC-CIP Based on the time course and decreasing interval with subsequent recurrences, we devised a more vigilant surveillance regimen for early local recurrence by increasing the number of skull base MRIs during years 1 to 4 after initial diagnosis and treatment for recurrence. Overall, the changes made in the MDACC-CIP for local disease resulted in a reduction of the total number of missed months of undiagnosed disease for the entire cohort over the first 15 yr from 576 (LSESN) and 336 (CGCG) to 170 and the average number of undiagnosed patients dropped from 16.6 (LSESN) and 9.6 (CGCG) to 4.9. While increasing the number of surveillance scans would impact the overall cost of care, it is important to consider that early detection of recurrence would open the door to treatment options such as stereotactic radiosurgery while avoiding the need for repeat surgical resection for bulky disease. This theoretically avoids the surgical costs and leaves the door open to presumably more cost-effective treatments. In the current study, metastasis occurred in approximately one-fifth of patients with an average metastasis-free survival following surgery +/– adjuvant radiation of 57 mo. Similarly, a recent study of 151 patients with skull base chordoma treated with surgery and adjuvant radiation demonstrated a 91% metastasis-free survival rate at 7 yr.17 Nevertheless, in our series, the range of metastatic onset occurred as early as 10 mo and as late as 131 mo following treatment with spread to multiple areas throughout the body. Therefore, pulmonary surveillance algorithms, which have been suggested for metastatic bone sarcoma,19 will not alone suffice for metastatic skull base chordoma. Likewise, CT with contrast, as suggested by the recent NCCN recommendations, is insufficient as a single modality for surveillance of epidural and LMD metastases, which are more prevalent in skull base chordoma. As such, the MDACC-CIP for metastatic disease includes the addition of a surveillance complete spine MRI, which can be done at the same time of the skull base MRI allowing for seamless integration into the protocol. Imaging Specifics for Skull Base Chordoma Surveillance Current recommendations for initial imaging and local surveillance include MRI T2 sequences in 3 axes (axial/sagittal/coronal) and T1 pre- and postfat saturation with thin slices (1-2 mm) through skull base.12 While gadolinium-enhanced sequences are a useful addition to the scanning regimen for chordoma, enhancement patterns are variable20,21 and less consistent than T2 sequences which commonly display a robust and inhomogeneous T2 hyperintense signal with internal septations.22 Of note, enhancement patterns in the postradiation setting can be particularly difficult to interpret. For the purposes of surgical planning, CT is obtained in 3 axes (axial/sagittal/coronal) with thin slices through the skull base, to delineate the extent of clival and extra-clival bony invasion by the tumor. For local surveillance in the post-treatment setting, CT is not very useful and is therefore not routinely performed12 and not recommended in the MDACC-CIP. For metastatic disease surveillance, the MDACC-CIP includes an MRI of the entire spine, with 3-axis T2- and gadolinium-enhanced sequences plus CT chest/abdomen/pelvis, with and without iodinated contrast. This combination, rather than whole body MRI and/or whole body CT, was chosen based on the location of the majority of skull base chordoma metastases (lungs and spine) in an effort to maximize yield while reducing cost and radiation exposure. For spinal metastases, MRI is paramount to other modalities for the evaluation of epidural extension and proximity to the spinal cord and nerve roots. Furthermore, MRI is also more specific for LMD than CT or metabolic nuclear studies. Given the risk of pulmonary, lymph node or other soft tissue metastases within the chest, abdomen and pelvis, targeted CT has been recommended for restaging. Limitations Age,5,23 histologic subtype,6,8,24 degree of resection,4,8,24,25 primary vs recurrent disease at operation,7,26,27 and adjuvant radiation timing and modality7 have all been shown to affect chordoma control rates and recurrence patterns. These factors could theoretically be the basis of tailored surveillance recommendations. Given the limited size of our patient cohort, we were unable to divide the group into subcohorts for separate analysis based on differences in these factors. In our cohort, there were fractions of patients who developed either early local progression, systemic metastases, and/or LMD despite optimal tumor and treatment related factors (ie, chondroid histology, gross total resection with margins, well designed radiation dosing, etc.). The low incidence of this disease is clearly a complicating factor and is highlighted by the fact that all major organizational guidelines (ie, NCCN, etc.) only provide generalized recommendations. Ultimately, the identification of correlative molecular markers predictive of clinical outcomes will aid in the development of tailored surveillance (and, potentially, therapeutic) recommendations. The development of more precise algorithms with decision trees accounting for differences in these factors are necessary but require large patient repositories with accurate histologic analysis, treatment plans, and follow-up data. Furthermore, the cost of increasing surveillance scans vs the improved cost-effectiveness of early disease detection has to be considered. Unfortunately, our study and available data were not able to factor this into the analysis. A prospective trial comparing skull base chordoma surveillance schedules would help validate the need for more intensive imaging surveillance in certain instances and provide insight into specific cohorts that require less frequent monitoring (ie, those with chondroid histology status post gross total resection with wide margins). CONCLUSION Despite advances in treatment, skull base chordoma continues to recur frequently and at irregular intervals in local and distant sites. LMD involvement is higher in this cohort, which must be accounted for in any surveillance protocol. In the current study, we propose a revised imaging surveillance protocol to account for these findings to improve the timely detection and treatment of recurrent disease. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Chambers PW , Schwinn CP . Chordoma: a clinicopathologic study of metastasis . Am J Clin Pathol . 1979 ; 72 ( 5 ): 765 - 776 . Google Scholar CrossRef Search ADS PubMed 2. Raza SM , Bell D , Freeman JL , Grosshans DR , Fuller GN , DeMonte F . Multimodality management of recurrent skull base chordomas: factors impacting tumor control and disease-specific survival . Oper Neurosurg . 2017 ; In Press . 3. 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Audio abstracts available for this article at www.operativeneurosurgery-online.com. COMMENTS The authors have provided important data on the clinical course of 34 patients who had recurrent clival chordomas who they treated between 1993 and 2017. As expected, this is a small number. However, they have drawn our attention to the need for standardization of the monitoring for patients with clival chordoma for local recurrence as well as distant spread. Close and systematic monitoring of these patients for many years is essential in order to detect recurrences and metastases early so that treatment options are available in a timely manner. Interestingly, despite the close monitoring of their entire cohort of 91 patients, the numbers of overall and progression-free survival are similar to other reported contemporary series. It should also be noted that time to recurrence keeps getting shorter with each episode of recurrence thus needing more frequent imaging after each recurrence. They have reported a larger number of recurrences in the “chondroid chordoma” group. We have also had a similar experience thus indicating that these are not necessarily a better subset of chordomas. Whether the cost-benefit analysis supports that the MDACC-CIP should be a “standard” time line of imaging studies will need to be seen based on future reports from other investigators. Chandranath Sen New York, New York In this paper, the authors have proposed a set of guidelines for monitoring patients with chordoma, after treatment. I believe that this protocol needs to be modified. In patients with new onset of tumors, the goal of treatment should be total or near total resection, followed by Proton Beam or Carbon Ion radiation (rarely, Radiosurgery). In patients with recurrent tumors, repeat surgery, re-irradiation, and protocol-based chemotherapy are all considerations. Although I agree with an MRI scan 3 months after the initial treatment, subsequent imaging should be decided by the presence of residual tumor, pathological subtype, or molecular markers. If recurrence is detected, the surgeon should also have some treatment to offer the patient. WE need to be cautious about recommending frequent imaging follow up for a rare disease, which will raise the level of anxiety in the patient, the cost of medical care, and the ease of being able to get health insurance in the USA. Laligam N. Sekhar Seattle, Washington We read this manuscript with a lot of enthusiasm. In our practice we do not necessarily follow a rigid protocol when following up patients with clival chordomas. It is clear that while some patients have a very benign course, others have what I would describe as fulminant disease. Once that progression is established during the initial, short surveillance period, the protocol can be adjusted. In terms of local disease, we agree on obtaining a brain MRI with and without contrast 3 months after surgery and proton beam therapy. When a total resection is confirmed and pathology does not point to a more aggressive subtype of chordoma, such as “chondroid” type, obtaining follow-up imaging 6 months later seems appropriate. Conversely, when dealing with possible residuals or aggressive subtype of chordoma, another follow up MRI 3 months later seems prudent. This manuscript calls the attention to the potential of distant disease. We are likely to revise our current practice to incorporate more frequent investigations for metastatic disease as suggested by the authors. Daniel M. Prevedello Ricardo L. Carrau Columbus, Ohio The authors have provided a very detailed analysis of the timing and patterns of recurrence (local and/or distant) for patients that underwent treatment for skull base chordomas in an effort to develop a refined, higher yield strategy of follow-up with surveillance brain, spine, and body imaging. This adds significantly to our understanding of the patterns of recurrent disease for the challenging condition of skull-base chordomas. The authors propose a more extensive imaging routine that identifies recurrent disease more quickly than other more general screening protocols. Whether this method improves outcomes, or whether the costs of such extensive imaging can be justified remains to be determined. Michael Chicoine St. Louis, Missouri Operative Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Hailiang Tang, MD Department of Neurosurgery Huashan Hospital Fudan University Shanghai, China Chinese: Hailiang Tang, MD Department of Neurosurgery Huashan Hospital Fudan University Shanghai, China Close English: Garni Barkhoudarian, MD Brain Tumor Center and Pituitary Disorders Program John Wayne Cancer Institute Santa Monica, California English: Garni Barkhoudarian, MD Brain Tumor Center and Pituitary Disorders Program John Wayne Cancer Institute Santa Monica, California Close French: Johan Pallud, MD, PhD Department of Neurosurgery Medical School of Paris Descartes University Paris, France French: Johan Pallud, MD, PhD Department of Neurosurgery Medical School of Paris Descartes University Paris, France Close Russian: Mikhail Gelfenbeyn, MD, PhD Department of Neurological Surgery University of Washington Seattle, Washington Russian: Mikhail Gelfenbeyn, MD, PhD Department of Neurological Surgery University of Washington Seattle, Washington Close Italian: Francesco Acerbi, MD, PhD Department of Neurosurgery Fondazione IRCCS Istituto Neurologico C. Besta Milano Milano, Italy Italian: Francesco Acerbi, MD, PhD Department of Neurosurgery Fondazione IRCCS Istituto Neurologico C. Besta Milano Milano, Italy Close Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Japanese: Jun Muto, MD, PhD Department of Neurosurgery Keio University School of Medicine Tokyo, Japan Close Korean: Hye Ran Park, MD Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Korean: Hye Ran Park, MD Department of Neurosurgery Soonchunhyang University Seoul Hospital Seoul, Republic of Korea Close Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Portuguese: Hugo Leonardo Doria-Netto Department of Micro-Neurosurgery CNC-Centro de Neurociasncia Sao Paulo, Brazil Close Spanish: Ariel M. Kaen, MD, PhD Department of Neurosurgery Hospital Virgen del Rocío Sevilla, Spain Spanish: Ariel M. Kaen, MD, PhD Department of Neurosurgery Hospital Virgen del Rocío Sevilla, Spain Close Copyright © 2018 by the Congress of Neurological Surgeons

Journal

Operative NeurosurgeryOxford University Press

Published: Apr 18, 2018

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