Radiol med DOI 10.1007/s11547-013-0345-0
RADIOTHERAPY
Proton beam radiotherapy: report of the first ten patients treated at the ‘‘Centro Nazionale di Adroterapia Oncologica (CNAO)’’ for skull base and spine tumours Roberto Orecchia • Viviana Vitolo • Maria Rosaria Fiore • Piero Fossati • Alberto Iannalfi • Barbara Vischioni • Anurita Srivastava • Jeffrey Tuan • Mario Ciocca • Silvia Molinelli • Alfredo Mirandola • Gloria Vilches • Andrea Mairani • Barbara Tagaste • Marco Riboldi • Giulia Fontana • Guido Baroni • Sandro Rossi • Marco Krengli Received: 17 September 2012 / Accepted: 20 February 2013 Ó Italian Society of Medical Radiology 2013
Abstract Purpose The Italian National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO), equipped with a proton and ion synchrotron, started clinical activity in September 2011. The clinical and technical characteristics of the first ten proton beam radiotherapy treatments are reported. Materials and methods Ten patients, six males and four females (age range 27–73 years, median 55.5), were treated with proton beam radiotherapy. After one to two surgical procedures, seven patients received a histological diagnosis of chordoma (of the skull base in three cases, the cervical spine in one case and the sacrum in three cases)
R. Orecchia (&) V. Vitolo M. R. Fiore P. Fossati A. Iannalfi B. Vischioni A. Srivastava J. Tuan M. Ciocca S. Molinelli A. Mirandola G. Vilches A. Mairani B. Tagaste M. Riboldi G. Fontana G. Baroni S. Rossi M. Krengli Fondazione CNAO, Strada Privata Campeggi, 27100 Pavia, Italy e-mail:
[email protected] R. Orecchia P. Fossati European Institute of Oncology, Milan, Italy A. Srivastava Medanta Cancer Institute, Medanta the Medicity, Sector 38, Gurgaon, India J. Tuan National Cancer Centre Singapore, Singapore, Singapore M. Riboldi G. Baroni Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milan, Italy M. Krengli Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
and three of low-grade chondrosarcoma (skull base). Prescribed doses were 74 GyE for chordoma and 70 GyE for chondrosarcoma at 2 GyE/fraction delivered 5 days per week. Results Treatment was well tolerated without toxicityrelated interruptions. The maximal acute toxicity was grade 2, with oropharyngeal mucositis, nausea and vomiting for the skull base tumours, and grade 2 dermatitis for the sacral tumours. After 6–12 months of follow-up, no patient developed tumour progression. Conclusions The analysis of the first ten patients treated with proton therapy at CNAO showed that this treatment was feasible and safe. Currently, patient accrual into these as well as other approved protocols is continuing, and a longer follow-up period is needed to assess tumour control and late toxicity. Keywords Proton therapy Skull base Spine Chordoma Chondrosarcoma Hadrontherapy
Introduction The Italian National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO) was established in 2001 by the Italian Ministry of Health, and a project was launched to realise a centre designed for the use of charged particles for cancer treatment. Construction of the facility was completed in February 2010 and proton beam became available in October 2010. The facility is equipped with a synchrotron to accelerate protons and ions and with three treatment rooms, two with fixed horizontal and one with both horizontal and vertical beam lines. After relevant commissioning tests, clinical activity started with protons in September 2011 and with carbon ions in November 2012.
123
Radiol med
We report the results of the first ten patients affected by skull base and spine chordoma and chondrosarcoma who have completed proton beam radiotherapy, with an emphasis on the clinical and technical characteristics of the treatment.
inclusion into the approved protocols for proton therapy. Each patient received in-depth information regarding the potentially expected outcome and side effects and gave their informed consent. Treatment planning and delivery
Materials and methods Patient population To start clinical activity, prospective trials for proton beam radiotherapy were designed for established indications as per existing literature and included skull base and spine chordoma and chondrosarcoma and intracranial meningioma. These trials were approved by the institutional ethics committee of CNAO and authorised by the Ministry of Health. They were conducted in agreement with the criteria of the Helsinki Declaration. We report on the first ten patients, with a minimum of 6 months follow-up, treated in phase II trials for skull base and spine chordoma and chondrosarcoma of grade I–II. The main patients’ characteristics are shown in Table 1. Clinical symptoms and signs were dependent on the site of the disease and included headache, cranial nerve deficits, visual and auditory and hypothalamus–pituitary dysfunction in patients with intracranial lesions, and mobility problems and bowel or bladder incontinence for patients with spine tumour locations. Five out of ten patients were referred after the first surgical operation, 3/10 were referred after having been reoperated either for gross residual disease or for tumour relapse, and 2/10, deemed unresectable at the time of diagnosis, were referred for proton therapy after undergoing biopsy for diagnostic purposes. No patient had received prior radiotherapy. All patients underwent complete clinical and radiological assessment including review of any previous examinations, imaging studies, surgical procedures and pathology reports before a decision was taken as to the eligibility for
Treatment planning mandated a simulation noncontrast computed tomography (CT) scan (SOMATOM Sensation Open, Siemens, Germany) with customised immobilisation in the treatment position (Fig. 1). The CT scan was performed with a slice and interslice thickness of 2 mm. Magnetic resonance imaging (MRI) with a 3.0 T unit (Magnetom Verio, Siemens, Germany) was also performed in the same position as the simulation CT, using the same immobilisation device. The sequences obtained were contrast and noncontrast T1, T2 images along with fat suppression, FLAIR (fluid-attenuated inversion recovery), STIR (short tau inversion recovery) and ADC (apparent diffusion coefficient) sequences. Both CT and MRI datasets were transferred via the DICOM protocol to the treatment planning system (TPS) (Syngo VB10, Siemens, Germany) for image fusion prior to segmentation. The structures delineated were gross tumour volume (GTV), clinical target volume (CTV), both low dose and high dose, planning target volume (PTV) both low and high dose, and organs at risk (OARs). The OARs differed depending on
Table 1 Patients’ characteristics Parameters
Numbers
Age Mean ± standard deviation, range
54 ± 17.7, (27–73) years
Gender Males:females
6:4
Histology and location of chordoma Skull base/cervical spine
3/1
Sacrum
3
Chondrosarcoma (grade I–II) Skull base
123
3
Fig. 1 Setup verification in a patient with skull base chordoma before treatment delivery
Radiol med
tumour location and included brainstem, temporal lobes, pituitary, optic chiasm, optic nerves, eyes, cochlea, spinal cord, parotid glands, pharyngeal sphincters, larynx for the skull base region, and rectal wall, sacral nerves, spinal cord, kidneys and small bowel for the spine location; the skin was delineated as an OAR in all cases. CTV to PTV expansion was 2 mm for skull base and 4 mm for spine tumours, figures that were obtained after accurate in-house estimation of the patient setup. The high-dose CTV values for skull base and spine tumour locations are reported in Table 2. Doses were measured in Gray equivalent (GyE) considering a relative biological effectiveness value of 1.1 compared to that of photons. The prescribed doses as per protocol were 74 GyE for chordoma and 70 GyE for chondrosarcoma at 2 GyE per fraction delivered 5 days per week. Treatment was given by single beam optimisation (SBO) and intensity-modulated proton therapy (IMPT) in two phases delivered with different technical modalities. In the first phase, the prescribed dose was 54 GyE at 2 GyE per fraction, and SBO was used in four cases and IMPT in six cases. In the second phase, the prescribed dose was 20 GyE for chordoma and 16 GyE for chondrosarcoma at 2 GyE per fraction, and SBO was used in two cases and IMPT in seven cases. The number of beams used during each treatment phase varied from two to three (Fig. 2). A three-component system was employed for ensuring reproducibility of the patient setup position: a couch
enabling six degrees of freedom, the patient positioning system (PPS) (Schaer Engineering AG, Switzerland), an inroom radiographic patient position verification system (Schaer Engineering AG, Switzerland) and a real-time infrared optical tracking device (VeriSuite, MEDCOM, Germany) custom designed and developed at CNAO [1]. With this system, the patient position can be reproduced within an accuracy of \1 mm. The position is verified also by using the in-room X-ray imaging system prior to the delivery of each beam.
Table 2 High-dose clinical target volume (CTV)
Results
Location
High-dose CTV Mean ± standard deviation (cc)
High-dose CTV range (cc)
Skull base and cervical spine (N = 7)
43.42 ± 38.05
6.69–123.49
Sacrum (N = 3)
902.65 ± 709.51
52.06–2,311.61
Toxicity and response assessment During the entire course of treatment, the patients were evaluated weekly by clinical checks to assess acute toxicity. Toxicity was scored as per CTCAE v4.0. Post-treatment follow-up visits were scheduled at 3-monthly intervals when all investigations including MRI were repeated to assess late toxicity as well. Tumour response was assessed at least 6 months after treatment completion and was defined according to the protocols as complete response (CR) in the case of complete disappearance of the tumour lesion, partial response (PR) in the case of reduction in volume [65 % of the initial volume, progressive disease (PD) when the increase in volume is [73 % of the initial volume and stable disease (SD) when volume changes are between PR and PD.
Treatment was well tolerated by all patients and there were no treatment interruptions due to toxicity. The maximal acute toxicities recorded are listed in Table 3 and consisted of grade 2 oropharyngeal mucositis and nausea and vomiting for skull base tumours, and grade 2 dermatitis for sacral tumours. All toxicities were self-limited and patients
Fig. 2 Relative dose distribution on axial, sagittal and coronal computed tomography (CT) slices depicting planning target volume and healthy structures in a case of skull base chordoma
123
Radiol med Table 3 Maximal acute toxicities during treatment None
Grade 1
Grade 2
Grade 3
Skull base/cervical spine (N = 7) Dermatitis
2
5
0
0
Alopecia
5
2
0
0
Oropharyngeal mucositis
4
2
1
0
Headache
2
5
0
0
Nausea
6
0
1
0
Vomiting
6
0
1
0
Dysphagia
6
1
0
0
Sacrum (N = 3) Dermatitis
0
0
3
0
Proctitis Dysuria
3 3
0 0
0 0
0 0
fully recovered within a few weeks after treatment completion. After a minimum and maximum follow-up interval of 6 and 12 months, all but one patient (9/10) showed SD at MRI studies. One case of skull base chordoma was classified as PR, showing a reduction in the three axes, X, Y and Z, from 56, 43 and 66 to 50, 23 and 33 mm, respectively, after 9 months’ follow-up (Fig. 3).
Discussion Chordoma and chondrosarcoma of the skull base and spine are rare malignant neoplasms that are challenging to treat. Chordoma arises from the remnants of the notochord and is typically a slow-growing but sometimes also aggressive tumour with a tendency to recur locally [2, 3]. Genetic changes were found in chordoma and their role in diagnosis and prognosis is still under investigation [4]. As for chondrosarcoma, the usual histological subtypes are Fig. 3 Pre-treatment (left) and 9 months after post-treatment (right) T2-weighted magnetic resonance imaging (MRI) in sagittal view showing partial response in a case of skull base chordoma (same case as in Fig. 2)
123
conventional and mesenchymal, which are further classified as grades I–III based on the differentiation [14]. Grades I–II (low-grade) are quite indolent and tend to recur locally, while grade III is more aggressive with a high metastatic potential [2, 3]. Complete surgical resection offers the best chance of control, but is rarely achievable due to the proximity of nearby critical structures which risk irreversible damage in the case of aggressive resection. Consequently, in most cases gross or microscopic residual disease is the norm, which translates into high recurrence rates. In our series, only partial resection could be achieved in skull base cases, even though repeat resection was attempted in two out of seven cases. Combining surgery with radiation has improved the local control rates in literature studies. These tumours are considered to be relatively radioresistant and a minimum useful photon dose is considered to be 60–65 Gy, or even higher, especially in series where charged particle irradiation was used [2, 3, 5–7]. Historically, photon doses between 50 and 60 Gy resulted in local control rates ranging from 17 to 23 % [7]. Recurrence rates as high as 70–100 % have been recorded for even small lesions at such dose levels [8–10]. In part, these high local recurrence rates in older literature series could be attributed to limitations of imaging for target identification, but even contemporary series reported poor control rates with conventional radiation at dose levels of 50–64 Gy [11]. Debus et al. [12], in a study of patient outcome after stereotactic fractionated photon radiotherapy used to treat skull base chordoma and low-grade chondrosarcoma with doses of 66.6 Gy (for chordoma) and 64.9 Gy (for chondrosarcoma), reported 5-year local control rates of 50 and 100 %, respectively. Analysis of predictors for local failure after proton beam radiotherapy by Terahara et al. [13] included the presence of low-dose regions, typically in close proximity to doselimiting critical structures in the case of incomplete surgery. A study by Noel et al. [14] reported that proton doses
Radiol med
\56 GyE to GTV correlate with a higher risk of local failures. These findings emphasise the importance of avoiding low-dose regions within the target volume. This can be achieved by combining adequate surgical resection with protons which can offer a better dose distribution compared to photons. When performing surgery on sacral tumours, care has to be taken to preserve the sacral nerves and cauda equina. Chordomas are slow-growing tumours which can reach considerable dimensions in the pelvis before the symptoms appear and the diagnosis can be obtained. Literature studies have shown that proton therapy can be successfully used even in the case of large macroscopic disease without prior radical surgery [15]. In our set of patients, surgery was rejected at the time of diagnosis in two cases, as the expected morbidity of a radical resection outweighed the benefits. Additionally, in these cases, proton therapy offered a chance to preserve bladder and bowel function while controlling tumour progression. In terms of dose distribution, protons have an edge over photons due to the inherent radiation physics, although radiobiologically they do not differ greatly from photons, having a radiobiological effective value of 1.1 as compared to 1 of photons. The characterising feature is the energy deposition in the patient tissues located in the Bragg peak that can be opportunely spread out, thereby sparing most of the traversed and the deeper located tissues. This high spatial selectivity enables better sparing of the healthy tissues [16, 17] and can result in delivery of 10–20 % higher doses to the tumour as compared to conventional radiotherapy [12, 18]. It has also been reported that protons deliver 1.5–3 times lower integral dose outside the target volume as compared to X-rays [19]. Protons can be delivered as either a passive scattered beam or an active spot-scanning technique. Active beam scanning produces a focused pencil beam that can be deflected laterally by magnets to scan the target. This way, the high-dose region is limited to the target alone and, unlike the passive scattering systems, there is no extra dose deposition proximal to the target itself [20]. In the given set of patients, a combination of both SBO and IMPT techniques was used in most cases. Consequent to the superior dose conformation, sparing of normal tissues was possible to a higher extent as compared to conventional radiotherapy, which translated into a low incidence of acute side effects reported in this set of patients, with maximal toxicities being Bgrade 2 overall. It should be emphasised that, apart from dermatitis, more common in cases of sacral lesions approaching the skin surface, a major proportion of patients had no toxicity at all during the course of treatment. After a minimum of 6 months’ follow-up, 9/10 patients had SD and 1/10 was labelled as having PR as per the
protocol. These are slow responding tumours and may persist as such for many years. The usual policy is to keep them under observation and perform sequential MRI for follow-up. After radiotherapy, no dramatic shrinkage of the tumour is expected to be seen on imaging studies. Accordingly, the general consensus is to define ‘‘tumour control’’ as a state of no clinical or radiological signs of tumour progression. Late toxicity was assessed in all patients, although the follow-up was limited to 6–12 months; two patients were scored as having grade 2 toxicity as per CTCAE v 4.0. One patient with sacral chordoma had episodic rectal bleeding persisting for 3–4 weeks that resolved spontaneously, and the other patient, who had skull base chordoma, had an expected hypothalamic–pituitary failure and is currently on hormone replacement therapy. Early toxicity and preliminary findings of late side effects are in the range of the other literature reports [2, 7, 14]. Conclusion The analysis of the first ten patients treated with spotscanning proton therapy at CNAO showed that this treatment was feasible and could be delivered safely with mild toxicity. Currently, patient accrual into these as well as other approved protocols is continuing and a longer followup is needed to assess definitive local tumour control rate and late toxicity. Acknowledgments The authors would like to acknowledge the President, the Technical and Scientific Committee, the Advisory Board, the General Secretary, the Office of Communications, the Department of Safety Prevention and Environment Service, the Department of Legal Affairs and Human Resources, the Department of Radioprotection, the Office of Quality, the Accelerator Department, the Department of Infrastructure, the Department of Administration and Finance, the Radiation Technologist Unit and the nursing staff for their contribution towards making it possible to initiate clinical activity at CNAO. Conflict of interest Roberto Orecchia, V. Vitolo, M.R. Fiore, P. Fossati, A. Iannalfi, B. Vischioni, A. Srivastava, J. Tuan, M. Ciocca, S. Molinelli, A. Mirandola, G. Vilches, A. Mairani, B. Tagaste, M. Riboldi, G. Fontana, G. Baroni, S. Rossi and M. Krengli declare no conflict of interest.
References 1. Fattori G, Riboldi M, Desplanques M et al (2012) Automated fiducial localization in CT images based on surface processing and geometrical prior knowledge for radiotherapy applications. IEEE Trans Biomed 59:2191–2199 2. Hug EB, Loredo LN, Slater JD et al (1999) Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg 91:432–439 3. Munzenrider JE, Liebsch NJ (1999) Proton therapy for tumors of the skull base. Strahlenther Onkol 175(Suppl 2):57–63
123
Radiol med 4. Vujovic S, Henderson S, Presneau N et al (2006) Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 209:157–165 5. Schulz-Ertner D, Nikoghosyan A, Thilmann C et al (2004) Results of carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Phys 58:631–640 6. Weber DC, Rutz HP, Pedroni ES et al (2005) Results of spot scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience. Int J Radiat Oncol Biol Phys 63:401–409 7. Ares C, Hug EB, Lomax AJ et al (2009) Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol Biol Phys 75:1111–1118 8. Saxton JP (1981) Chordoma. Int J Radiat Oncol Biol Phys 7:913–915 9. Rich TA, Schiller A, Suit HD, Mankin HJ (1981) Clinical and pathological review of 48 cases of chordomas. Cancer 56:182–187 10. Catton C, O’Sullivan B, Bell R et al (1996) Chordoma: long term follow-up after radical photon irradiation. Radiother Oncol 41:67–72 11. Zorlu F, Gurkaynak M, Yildiz F et al (2000) Conventional external radiotherapy in the management of clivus chordomas with overt residual disease. Neurol Sci 21:203–207 12. Debus J, Schulz-Ertner D, Schad L et al (2000) Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys 47:591–596
123
13. Terahara A, Niemierko A, Goitein M (1999) Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma. Int J Radiat Oncol Biol Phys 45:351–358 14. Noe¨l G, Feuvret L, Ferrand R et al (2004) Radiotherapeutic factors in the management of cervical-basal chordomas and chondrosarcomas. Neurosurgery 55:1252–1260 15. Park L, DeLaney TF, Liebsch NJ et al (2006) Sacral chordomas: impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor. Int J Radiat Oncol Biol Phys 65:1514–1521 16. Orecchia R, Zurlo A, Loasses A et al (1998) Particle beam therapy (hadrontherapy): basis for interest and clinical experience. Eur J Cancer 34:459–468 17. Jereczek-Fossa BA, Krengli M, Orecchia R (2006) Particle beam radiotherapy for head and neck tumors: radiobiological basis and clinical experience. Head Neck 28:750–760 18. Goitein M (2010) Trials and tribulations in charged particle radiotherapy. Radiother Oncol 95:23–31 19. Lomax AJ, Bortfeld T, Goitein G et al (1999) A treatment planning inter-comparison of protons and intensity-modulated photon therapy. Radiother Oncol 51:257–271 20. Jakel O (2009) Medical physics aspects of particle therapy. Radiat Prot Dosimetry 137:156–166
