Survival and treatment of cranial and spinal cord chordomas: a population-based study

95% CI=1.734-3.297, p<0.001) were independent prognostic factors for OS; the age (HR=0.335, 95% CI=0.151-0.743, p=0.007), histological type (HR=4.600, 95% CI=2.356-8.983, p=<0.001), GTR (HR=0.284, 95% CI=0.178-0.453, p<0.001) radiation (HR=1.406, 95% CI=1.060-1.866, p=0.018), chemotherapy (HR=2.023, 95% CI=1.222-3.351, p=0.006), and tumor extension (HR=3.381, 95% CI=2.237-5.109, p<0.001) were independent prognostic factors for CSS.


Introduction
Chordomas are rare, slow-growing malignant tumors and are commonly seen between 60 and 70 years, accounting for 1-4% of all primary malignant bone tumors; they typically arise from the embryonic cells of the primitive notochord. [7] In the year of 1857, chordoma was rst described by Virchow [19], the dedifferentiated chordoma was rst described by Debernardi in 1913 [23], and then Heffel nger rstly reported chondroid chordoma in 1973. [10] Surgery has been well established in the initial treatment of chordomas [28], but surgery alone may be insu cient and impossible for long-term local control [29]. And treatment regime varies among patients, with controversial or no accepted criteria. [8] Besides treatment, it is necessary to combine variables such as age, sex and tumor characteristic to further predict the longterm outcome of patients.
However, limited studies constructed a detailed prediction model used to perform individualized survival estimation for patients with cranial and spinal cord chordomas. Therefore, we aimed to evaluate the clinical behavior, the extent of resection, and adjuvant radiation as well as chemotherapy, as they related to survival in cranial and spinal cord chordomas; and developed nomograms for reliable estimation of 3-, 5-, and 10-year survival.
Overall survival (OS) was measured from the date of random assignment to the date of death (all reasons); cancer speci c survival (CSS) was measured from the date of random assignment to the date of death (only related cancers).

Statistical analysis
Patients were excluded from univariate and multivariate analysis if survival time was 0 (n=41), unknown surgery information (n=26), and unavailable tumor extension information (n=242). The missing data regarding tumor size was more than 20% of sample size, so we did not explore the association between size and survival in this study.
When appropriate, categorical data was analyzed using Pearson chi-square or Fisher's examination and student t test. Survival analysis was conducted using the Cox proportional hazards model. The nomograms were established to estimate 3-, 5-and 10-year CSS and OS rates. To verify the prediction accuracy, we calculated concordance index (C-index), and time-independent receiver operating characteristic curve (ROC) with the area under the curve value. In addition, decisive curve analysis was used to determine the 3-, 5-, and 10-year survival rates. P<0.05 was considered statistically signi cant. All data were analyzed using R version. 3.6.3, and extensive packages with "survival", "survminer", "rms", "decisive", and "foreign" were used.
Surprisingly, patients who received surgery and radiotherapy showed a worse survival compared with those who received surgery alone (HR=1.406, 95%CI=1.060-1.866; p=0.018); plus, patients who received surgery and chemotherapy showed a decreased survival compared with those who received surgery alone (HR=2.203, 95% CI=1.222-3.351; p=0.006). ( Figure 2B) Discussion Chordomas, with locally aggressive behavior and poor prognosis, are thought to arise from embryo notochordal remnants of the neuraxis, predominantly in the skull base, vertebral column, and sacrococcygeal area. [12,21] No wonder that clinical management of chordoma is usually challenging for its locally invasive growth pattern. Using the patient data from the SEER database, we constructed a nomogram that indicated survival was associated with many factors. The C-index and the graphical calibration method suggested that nomogram exhibited a good predictive ability.
Univariate analysis revealed that year of diagnosis was a predictor of survival, but further multivariate analysis was not further performed as different follow-up time was a point.
Our result showed that age group (20-39 years) was a favorable factor for both CSS and OS in the patients with spinal cord tumor. Younger age, with a tendency to aggressive clinical behavior, has been described as an adverse factor for poor survival, which is consistent with our nding, on multivariate analysis, that patients under 20 had a worse survival. [5,21] The histological variants are classi ed into 3 groups: classical (conventional), chondroid, and dedifferentiated. [9] While patients diagnosed with chordoma NOS have better outcome, those in a mix group with chondroid chordoma and dedifferentiated chordoma had a poor survival in our study.
This current study demonstrated that surgery played an important role in the treatment of patients of chordomas. Also, this outcome added support to previous literature suggesting a better survival related to aggressive treatment. [24,15,11,25,1] Extent of resection was the most important factor in prediction survival, with only 75.9% (cranial group) and 75.3% (spinal cord group) actuarial 10 year CSS rate for GTR, with 71.8% (cranial group) and 65.1% (spinal cord group) actuarial 10-year CSS rate for non-GTR. One retrospective study, with 31 pediatric chordomas, showed 90% survival in 10 patients with GTR, compared with only 29% OS rate at 10 years after subtotal resection. [17] but, in terms of a high risk commonly seen in the skull base and local invasion of tumor, GTR might be not possible and neurological preservation should be took notice of.
Interestingly, the addition of radiotherapy showed the signi cantly poor CSS in patients with spinal cord chordoma. Recently, Lee et al and Jawad, using the data from the SEER database, showed similar results that adjuvant radiation was associated with worse survival outcomes. [14,13] These results seemed to contributed to the relation between the use of radiotherapy and disappointing survival. Indeed, radiotherapy alone, in a large number of people, led to a poor prognosis, to some degree, which caused an unbelievable nding that surgery with radiation was related to worse survival compared with surgery alone. Moreover, there was no identi ed treatment dose or objective quality assessment in this retrospective study. Radiotherapy was traditionally recommended in the form of hypofractionated proton beam or photo beam with at least 74 Gy for patients with chordoma. [2] Y et al. described a series of 282 patients with sacral and spinal chordoma, but signi cantly increased OS was not observed in patients who underwent radiation with a median dose of 58 Gy; [27] while Schuli-Ertner reported that radiation dose more than 60 CGE was a favorable factor for local control; [20] these results suggested high dose radiation could improve survival. In addition, radiation sequence might be a key factor of survival: preoperative radiation+surgery+radiotherapy vs. surgery+radiotherapy. [26,18] Last, patients with poor condition (regional or distant metastasis) were more likely to receive radiation. Maybe that the extension of this tumor counteracted the role the radiation in survival.
In particular, there was a paucity of studies regarding the association between chemotherapy and survival. The routine use of chemotherapy in addition to surgery is controversial because although pervious report advocated that chemotherapy could increase survival [16], others suspected this nding. [4,22] In this current study, no difference in survival was observed between surgery alone and surgery with chemotherapy for cranial chordoma; to our surprise, patients with surgery and chemotherapy had a worse survival compared with those with surgery alone for spinal cord chordoma. It is important to realize that the rate of radiotherapy receipt was pretty low, in 2.4% of patients with cranial chordoma and in 5.2 of patients with spinal cord chordoma, respectively.
Considering its malignancy [3,6], with local recurrence and distant metastasis, it is imperative to need evidence from a randomized trial supporting the addition of chemotherapy.

Conclusion
Poor prognosis is mainly due to regional or distant progression. Initial aggressive treatment is necessary for patients with chordoma and we have better to make an attempt to achieve GTR with minimally morbid surgical approach. Notably, radiotherapy or chemotherapy in addition to surgery did not reduce the hazard risk of cranial chordoma. On the other hand, adjuvant radio-or chemo-therapy imparted a mortality risk increase in patients with spinal cord chordoma. Considered that inherent and retrospective nature of the SEER database, unfortunately, we failed to propose a standard treatment paradigm of these tumors. But a prospective randomized clinical trials to evaluate the role of adjuvant therapies survival could be performed based on our ndings.

Declarations Funding None
Con ict of interest We declare that there is no con ict of interest.
Ethical approval This study was approved by the Institutional Review Board.
Informed consent The informed consents were available for all patients.    Supplementary Files