Chordomas are a rare form of primary bone tumors arising from clivus, vertebra, and sacrum. Although it usually occurs in adults, children can be affected too. Multidisciplinary treatment is required and is particularly challenging because the chordoma's proximity to critical structures creates a high risk for significant adverse events. Standard procedure consists of extensive surgery followed by high-dose radiation therapy in excess of 70 Gy. Proton beam therapy has become one of the standard procedures to achieve high, local intensity while maximally sparing normal tissue in adults and children. Results achieved so far are promising and are superior to what has been achieved with surgery alone or conventional radiation therapy. When compared with modern photon radiation techniques, such as intensity-modulated radiation therapy, proton beam therapy may be of particular interest for children to provide high conformality while reducing the irradiated volume and therefore potentially minimizing the risk for secondary cancer induction. The role of chemotherapy remains to be defined.
Chordomas (CHs) are rare, primary bone tumors that originate from remnants of the notochord. During the embryologic period, the notochord is replaced by the bony and cartilaginous structures of the axial skeleton. However, remnants can be entrapped by bone, particularly in the clivus, spine, and sacrum . CHs account for 1% to 4% of all bone malignancies . Although CHs are considered low grade histologically, the locally aggressive behavior and the potential to disseminate make this entity difficult for oncologic management. CHs are supposed to be generally slow-growing tumors and are radioresistant . The tumor sites along the brainstem, spinal cord, and cauda make local treatment, such as extensive surgery and high-dose radiation therapy, particularly challenging . Therefore, the predominant pattern of failure is local recurrence . The standard treatment for CHs is complete surgery. However, very few patients can be cured by surgery alone, as in about 50% of the patients some residual disease has to be left behind . Proton beam therapy (PT) has been proven to deliver high doses of therapy safely, even at critical sites. PT is now an important technique in postoperative radiation therapy for CHs in adults and children worldwide, and its feasibility and efficacy have been proven [7, 8]. Despite all efforts and improvements in surgical and radio-oncologic treatments, results of therapy for CHs in children remain dissatisfying. The Surveillance, Epidemiology, and End Results (SEER) program from the National Cancer Institute reports overall survival rates of only 69% after 5 years and 41% after 10 years, respectively . Therefore, we are still looking for improvements in the clinical care of CHs today. In children, who are particularly vulnerable to radiation injury, the difference between safety and sufficient local-dose intensity is extremely small.
Epidemiology and Clinical presentation
The SEER data from a population-based study suggest an incidence of CHs of 0.08 per 100 000, with a predominance in men and a peak incidence at the age of 50 to 60 years . CHs rarely affect children with less than about 5% of all CHs arising in patients younger than 40 years. CHs represent only 0.1% to 0.2% of all cranial malignancies in childhood . The tumor sites seem to be almost equally distributed between the base of the skull and the mobile spine. Even though they generally arise in the midline, more-lateral CHs may develop, especially in the parasellar region or petrous bone.
Because CHs are locally aggressive and often invasive lesions, patients usually present with symptoms originating from local pressure being site specific rather than tumor specific. Typical tumor sites are the clivus, vertebra, and the sacrococcygeal bone. In most children, the tumor arises in the skull base. These cranial CHs often arise from the clival body. The patient may present with headaches and diplopia because of unilateral or bilateral abducens nerve palsy [3, 10]. A CH of the clivus may extend into the nasopharynx, resulting in nasal obstruction, epistaxis, or dysphagia. In clival tumors with superior extension, endocrinopathies or compression of the chiasm and visual impairment may be observed. Inferior clival tumors may compress the brainstem or involve the foramen magnum, which can induce caudal cranial nerve dysfunctions or life-threatening emergencies. CHs of the mobile spine and sacrum can present with pain or radiculopathy related to the respective level at which they occur. Bladder and bowel dysfunction can happen [11, 12]. Cervical tumors usually grow extradurally, but they can extend intradurally. Even some exclusively intradural tumors have been reported. A patient with a CH rarely presents with dissemination. However, during autopsy, metastases were found in up to 40% of cases, and in children, the risk of dissemination may be even greater . Coffin and colleagues  identified metastases in 7 of 12 children (58%) with CHs. Therefore, the authors considered CHs more aggressive in children than they are in adults. Borba et al  described age-specific differences in the incidence of metastases, with dissemination in 57.9% of patients younger than 5 years, but in only 8.5% of children older than 5 years.
The chondrosarcomas (CSs) behave quite similar to the CHs. Sometimes, distinguishing CSs from CHs is challenging when looking at clinical, radiologic, and histopathology features only. CSs are malignant cartilaginous tumors, predominantly arising from the trunk skeleton. A CS shows local aggressiveness and has a high risk for recurrence. The treatment concept is similar to that for CHs, requiring challenging surgical procedures and high-dose radiation therapy . Many of the available studies investigated both CHs and CSs. The CSs may have a slightly more-favorable outcome than CHs do. Although this article primarily focuses on CHs, reference must be made to results from both CH and CS treatments.
For children, whether a prognosis of CH and CS is less favorable, is debatable [8, 15]. Some authors have even observed particularly advantageous results after combined surgical and radiotherapeutic approaches in children [17, 18]. Especially in the very young, extremely aggressive and atypical or dedifferentiated types can sometimes occur that are difficult to manage (see Figure 1a and b) [10, 15]. Figure 1a and b represent an extraordinarily dedifferentiated CH of the clivus that is compressing the brainstem and cervical myelon of a 3-year old child. Several surgeries were performed, which did not achieve sufficient tumor removal. Even though histopathologic findings suggested the tumor had a low proliferation rate, residual tumor volume increased 3-fold in a short time. Curative radiation therapy was deemed infeasible because of the vicinity of the residue to central nervous system structures and, therefore, aggressive chemotherapy was started.
CHs have been described since 1856 by Rudolf Virchow . Macroscopically, a CH appears as a soft, grayish mass, with a smooth or lobulated surface . Microscopically, they are characterized by large, polygonal cells with abundant eosinophilic cytoplasm or vacuolated physaliphorous cells filed with intracytoplasmatic mucin . The tumor is arranged in lobuli. Typically, CHs are subclassified into conventional (classic), chondroid, and dedifferentiated types. The dedifferentiated type is a highly malignant form, predominantly seen in the sacrococcygeal area and is known to be associated with high mortality, particularly in young patients . Immunohistologic markers can be useful in distinguishing CHs from CSs. In contrast to the CSs, CHs cells stain positive for cytokeratin and epithelial membrane antigens [1, 20, 22]. Also, CHs stain positive for vimentin and S100 protein .
Imaging and Workup
The first step in a CH workup is a complete history and a physical examination. Cranial magnetic resonance imaging (MRI) and computed tomography (CT) as well as a chest x-ray and an abdominal ultrasound are performed when the patient is preparing for surgery. A CT scan can better illustrate bony structures, whereas the MRI better visualizes the tumor and its relation to the adjacent soft structures and the organs at risk. The tumor can present as hypodense, hyperdense, or isodense in the CT scan. A contrast CT scan can show the various extents of any enhancement . Intratumoral calcifications may reflect bone sequestra . On T1-weighted MRI images, the tumor is usually of low or intermediate intensity. On T2-weighted MRI images, CHs typically show hyperintensity . Contrast enhancement in MRIs with gadolinium may be mild to strong. Fat suppression may help a clinician recognize the tumor borders. By radiologic features alone, CHs cannot be distinguished from CSs. An MRI or conventional angiography may help in understanding the collateral circulation. Before tumor resection, a biopsy or fine-needle aspiration may be considered to establish a pathologic diagnosis. Even if the risk for dissemination is low, an MRI of the craniospinal axis is recommended before postoperative radiation therapy to exclude deposits or bilateral CHs. For optimal planning, some centers use an additional myelography for the best information about the spinal cord and the tumor geometry. To diagnose and quantify adverse events after surgery and radiation therapy, we generally recommend performing baseline evaluations of organs potentially at risk (Table 1). Because of the proximity to the base of the skull, tumors to the optic nerves, cochlea, and pituitary/hypothalamus, it is particularly important to evaluate the endocrine, visual, and auditory functions before starting any locally aggressive therapy, such as irradiation [27, 28].
No general agreement exists regarding whether staging should follow the American Joint Committee on Cancer system, according to TNM structure (tumor size, lymph node involvement, and metastases). Particularly because of the relatively low incidence of lymph node involvement and distant metastases and because operability is often the most important prognostic factor, TNM-based staging may not be appropriate.
Because of the complexity of this entity, any treatment approach needs to be handled by a multidisciplinary team of experts . In principle, the 2 cornerstones of tumor treatment are surgery, usually followed by postoperative high-dose radiation therapy. With this combined approach, the prognosis for patients with CHs has improved significantly over time. In contrast, the role of chemotherapy is still unproven. However, experimental approaches, primarily for dedifferentiated and disseminated disease, have been reported anecdotally.
Sacral and Spinal Lesions
Today, the treatment of choice for sacral and spinal lesions—in cases of both CH and CS—is a wide, en bloc resection, first established in 1978 . The extent of the resection was positively associated with better overall and disease-free survival [6, 31]. Not violating the capsule and ensuring wide surgical margins seem to be crucial because of a significantly greater risk for recurrence after violations of the tumor margins . In addition, the issue of potential tumor seeding from contaminated surgical pathways has been highlighted. Several studies have demonstrated the importance of wide resections, or even gross total resections, which may be better, for any site, whether spinal, sacral, or cranial [32–35]. For upper sacroiliac lesions, a posterior-transperineal approach with reconstructive efforts may be advantageous. For some lower lesions, combined anterior and posterior surgical pathways are needed. A sacrectomy with the sparing of the S2 may be able to preserve bowel and bladder function in about 50% of patients, which is even more likely if the S3 is spared as well [30, 36].
For clival CHs, various techniques have been established, depending on the tumor site, tumor extent, and the surgeon's preference. All decisions should be made individually on a case-by-case basis by a surgeon experienced with base-of-skull surgeries. The surgical pathway may vary and be anterior, anterolateral, lateral, or posterolateral. Operative approaches described [37, 38] include transsphenoidal, transmaxillary, transnasal, high anterior cervical retropharyngeal, and transoral. Recently, endoscopic endonasal techniques have been used to access the clivus . Cerebrospinal fluid leakage needs to be avoided, and the use of flaps can be considered for repair after dura violation. Complete resection is desired whenever feasible without risking major neurologic impairments. In subtotal resection, radiation therapy should follow the surgery. Especially in moderate, postoperative tumor residue, the combined modality can lead to long-term tumor control [8, 40]. For radiation therapy, tumor control can be achieved by elaborating some space between the tumor and the most relevant organs at risk (ie, brainstem, spinal chord, chiasm). With PT, steep dose gradients can be achieved. Therefore, even an additional space of 5 mm between the target and the brainstem can lead to lowering the dose to the brainstem by up to 20% (Figure 2a). It should be noted that PT can successfully limit the dose load to the brainstem, despite geometric proximity (Figure 2b).
CHs and CSs are typically localized in proximity to critical structures, such as cranial nerves, the brainstem, the spinal cord, the optic pathway, arteries, brain parenchyma, and the pelvis. Complete resection often remains elusive for many patients despite all the advancements in microscopic and image-guided surgical procedures. Therefore, adjuvant radiation therapy has been conducted for decades to improve the prognosis. Ridenour et al  demonstrated improved outcome in young patients with combined surgery and postoperative radiation therapy compared with those who had surgery alone (77% versus 40% survival). Unfortunately, CHs are considered radioresistant at dose levels of 45 to 60 Gy [1, 10, 16]. In contrast, for dose-escalation levels in excess of 60 Gy, tumor response has been achieved [16, 41, 42]. However, because of the vicinity of CHs to critical organs at risk, dose escalation comes with risks, and dose coverage will often have to be compromised. Therefore, especially modern conformal techniques and high precision have been investigated to broaden the therapeutic window. Some groups no longer recommend conventional radiation therapy . With stereotactic techniques and radiosurgery, steep gradients outside the tumor were achieved, allowing high dose levels but sufficient sparing of critical structures. However, only small series have so far been evaluated, but they have shown tumor responses in up to 80% of the patients. The mean tumor volume was relatively small (4.6–9.7 mL), and total dose ranged from 17 to 36 Gy in a single fraction. Therefore, stereotactic techniques and radiosurgery may be beneficial for small residual disease or recurrent tumors [43–45].
Charged particle therapy was evaluated and has now become an important technique for postoperative management in pediatric and adult patients with CHs. Particles, as carbon ions or protons, offer an advantage over photon-based radiation therapy in dose selectivity. They are characterized by a steep-dose falloff distal to the target and, consequently, smaller doses to the surrounding tissue. Typical doses for PT ranged from 64 to 79 Gy (radiobiologic equivalent [RBE] dose) [8, 46, 47]. With carbon ions, similar results were achieved with different fractionation regimens, but there were various uncertainties about the radiobiologic effects . Especially for children, there are some general concerns about secondary particle induction and an increased risk for secondary neoplasms when using heavy ions. There is only one report on a few adolescents and young adults , so carbon ions will need to be further evaluated and compared with PT. Heavy ions may serve as an alternative to PT in some cases.
Generally, CHs are considered insensitive to chemotherapy . However, in preclinical and clinical setting, a response of CHs to various drugs, such as anthracycline, cisplatin, and alkylating agents, has been reported [51, 52]. In some case studies, the role of chemotherapy was highlighted in residual disease or recurrence . One case study even reported complete response to chemotherapy alone . Therefore, especially in pediatric CHs, where the proportion of dedifferentiated and atypical types is high and prognosis, because of an inoperable or disseminated tumor, is extremely poor, chemotherapy may be used as an additional modality to increase local intensity or target systemic disease. Recently, molecular profiling of CHs has been performed. Receptor inhibitors, such as imatinib, sunitinib, or cetuximab, have been tested and patients have shown some response [33, 55–57]. In the future, additional molecular pathways will be targeted, and the role of targeted therapies will be further elucidated.
Special Aspects of Proton Beam Therapy in Children
The most promising conformal photon radiation techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy, are often unable to optimally spare the organs at risk around the tumor. That is especially true for high-radiation doses to the target when a large low-dose volume is not desirable because it carries significant risk, particularly in the pediatric cohort. In children, any treatment with an ionizing dose will impose a risk of secondary malignancies . In fact, protons have a well-defined range of penetration and well-localized energy deposition at the end of the beam path, called the Bragg peak, leading to improved dose distributions and permitting dose escalation with the target and sparing the normal tissue around the tumor. With PT, there is no exit dose within a few millimeters distal to the tumor, leading to significant reduction in irradiated volume when compared with photon irradiation . Therefore, protons achieve similar conformality when compared with IMRT but carry a lower risk for secondary malignancy induction . Because of its peculiar physical properties, PT has been already shown to achieve high local control rates in pediatric CHs and CSs as well as reducing the incidence and severity of late side effects . Recently, data on secondary malignant neoplasms (SMNs) was published by the Massachusetts General Hospital (Boston, MA, USA) group; the 10-year cumulative incidence rate of second cancers was 5.4% for proton patients and 8.6% for photon patients. There was no gender-specific increased risk for SMN . Taking into account the mean age of the cohort (59 years) and the fact that the proton group did not have solely proton beams but a combination with photon beams, we consider the difference even greater when looking at protons-only in children. A study on retinoblastomas, with a median follow-up of 6.9 years, demonstrated that photon therapy was associated with significantly higher cumulative incidence for in-field malignancies of 14% after 10 years. In contrast, after PT, no incidence of in-field malignancies was seen. When looking at all SMNs, incidences were 14% and 5%, respectively . With regard to late sequelae other than SMN, the price of survival is significant after treating CNS disease in children facing several health conditions in about 80% of the survivors . Therefore, to potentially decrease adverse events on hearing, neurocognition, and quality of life, PT is of special interest for children [64, 65].
Effect of Beam Delivery Modality
Because PT is regarded as achieving high conformality with reduced risk for SMN induction, possible differences in beam delivery technologies can be studied. Currently, PT technology has increased rapidly, and there are now 3 delivery techniques: the standard method, called passively scattered (PS), the uniform scanning (US), and the most-modern pencil beam scanning (PBS). So far, most clinical studies have used the PS technique, and only a few pediatric patients have received PT with PBS , compared to the standard PS technique [8, 10, 17, 66]. The main advantages of PS PT in conformality and dose distribution are the faster speed in overall dose delivery and each field having a homogenous, nearly simultaneous dose distribution. An additional advantage is the steep, lateral dose gradients because of the use of individual collimators (see Figure 2a). In the PBS technique, individual fields are composed of multiple spots, and only the sum of all spots and fields result into the desired plan. Intensity modulation (IMPT) can be achieved by using spot scanning techniques and may be advantageous, particularly when looking at difficult geometries like the base of skull or spinal lesions  (see Figure 3). With PBS and IMPT, conformality may be improved . However, there are concerns about robustness when looking at IMPT plans, especially in the area of heterogeneous densities. On the other hand, with PS, patching fields may be necessary to achieve optimal sparing of the organs at risks, which may lead to significant uncertainties in the match lines . For SMN induction, PBS offers the proton beam delivery technique with the least secondary particles such as neutrons . When children are involved, that may be a relevant advantage because secondary particles usually increase the potential risk for SMN when compared with active delivery techniques . However, data from Chung et al  did not reveal any increased incidence of SMN in the proton group. None of the children in their cohort developed any secondary cancer.
Dose and Volume Concept for Proton Beam Therapy
For CHs and CSs in children and young adults, total doses of 65.3 to 78 Gy (RBE) were reported in the presented series, with daily fraction doses of 1.8 to 2.0 Gy (RBE) [8, 17, 18, 66] (see Tables 2 and 3). The dose to the clinical target volume (CTV) was 50 Gy (RBE) and the dose to the gross tumor volume was 65 to 74 Gy (RBE). Usually, proton centers administer slightly lower doses ranging from 65 to 70 Gy (RBE) for CSs [8, 46, 61, 70, 71] and higher doses to the CHs, often exceeding 74 Gy (RBE). The CTV is usually defined to encompass the gross tumor volume (containing any tumor enhancement in CT or MRI) plus an additional margin of 5 to 6 mm, respecting natural barriers [8, 17]. Hug et al  recommended that the CTV should cover, at minimum, the tumor bed, representing the initial, preoperative tumor extension. Generally, it was not recommended that the CTV encompass the surgical access routes, even if it may have been taken into account on an individual basis. Rutz et al  reported including surgical implants into the CTV.
Clinical Results of Proton Beam Therapy in Children in Detail
Today, many dosimetric studies on a variety of pediatric tumors have demonstrated the superiority of PT compared with external beam photon techniques. including IMRT, in reducing the dose delivered to normal tissues . In the case of pediatric patients with CHs and CSs, there are only few clinical studies involving only a few patients. Patient characteristics and treatment characteristics are listed in Table 2 and Table 3, respectively. Excellent local control (LC), overall survival (OS), and late toxicity rates have been evaluated in all pediatric CHs and CS studies, and are reported in Table 4. Other outcomes are reported in Table 5. The studies revealed better OS and reduced incidence of late side effects when compared with adults, which may reflect the efficiency of proton beam irradiation in this particular population age. However, follow-up times were still limited. Benk et al  treated 18 pediatric patients with CHs with a combination of photons and protons obtaining LC and OS at 5 years of 63% and 68%, respectively, after a median follow-up of 72 months. Low rates (11%) of high-grade (G3–G4) treatment toxicity were reported (1 patient with a brain necrosis and 1 with muscle fibrosis). In the Hug et al  study, 10 patients (77%), aged 1 to 19 years, had CHs and 3 (23%) had CSs . Seven patients (54%) received a combination of photons and protons, and 6 patients (46%) received protons only. After mean follow-up of 40 months, 5-year LC and OS were 60% and 100% for both groups, respectively. The incidence of high-grade toxicity was low (8%), and only 1 patient developed brain parenchyma necrosis. Hoch et al  reported on 5-year OS rates after a mean follow-up of 86.5 months in 73 pediatric patients with CHs in the skull base. Late morbidity was not evaluated in that study. Habrand et al  treated almost all children (29 of 30; 97%) with combined photon and proton radiation therapy using PS proton technique, and 1 patient was treated with protons. The 5-year OS and progression-free survival rates were 81% and 77% for patients with CHs (n = 27; 90%), and 100% and 100% for patients with CSs (n = 3; 10%), respectively. Only 1 patient experienced grade 3 auditory toxicity after PT. At the Paul Scherrer Institute (PSI), 26 patients (19 CHs [73%], 7 CSs [27%]) received PT with the PBS technique. Excellent 5-year LC and OS rates were reported of 81% and 89% for CHs and 80% and 75% for CSs, respectively . Rutz et al  reported on even more-favorable LC rates in children and adolescents with CHs or CSs after surgery and PT. All patients were alive at last follow-up (median, 36 months). Acute toxicity was moderate with skin reactions at grade 1 to 3 and focal alopecia at grade 1. Tolerance of PT treatment was excellent, with no patient developing higher-grade treatment-related toxicity . In none of the studies was radiation-related secondary cancer reported.
Despite the finding that CHs and CSs may have more-aggressive behavior in young children , most pediatric CHs at the base of the skull (conventional or chondroid variants) when treated with postoperative protons had a better OS than adults did with similar tumors . The OS after a mean follow-up of 7.25 years was 81% in children, and the 5-year OS was 55% in adults, respectively. Treatment results may be somewhat better in CSs than in CHs, but that will need to be confirmed [8, 17].
The effect of tumor site is still under debate. Benk et al  reported that tumors originating in the cervical spine resulted in statistically significantly inferior survival rates compared with those located in the skull base. However, Habrand et al  as well as Rombi et al  found no effect by cervical spine location.
CH is an extremely rare disease in children. The best therapeutic approaches should be managed by specialists to ensure optimal results. Standard treatment usually consists of a maximal, but safely achievable, resection followed by high-dose radiation therapy. PT is now considered as an important modality for radiation therapy in CH. Especially in children, PT offers a significant advantage over IMRT when looking at the high local control and survival rates while minimizing the risk of late side effects and SMN. The different proton beam delivery techniques need to be individually chosen when balancing benefits and drawbacks of each modality. The role of chemotherapy is not yet well established, but it may be worth further investigated, especially when looking at atypical and disseminated CHs in early childhood.
ADDITIONAL INFORMATION AND DECLARATIONS
Acknowledgments: The authors would like to thank the Paul Scherrer Institute and Anna-Lena Steffen (WPE) for their contribution.
Conflict of Interest Disclosure: The authors have no conflicts of interest to disclose.