Original article Strahlenther Onkol 2014 · 190:686–691 DOI 10.1007/s00066-014-0608-2 Received: 14 December 2013 Accepted: 18 December 2013 Published online: 25 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Matthias Uhl1 · Thomas Welzel1 · Jan Oelmann1 · Gregor Habl1 · Henrik Hauswald1 · Alexandra Jensen1 · Malte Ellerbrock2 · Jürgen Debus1 · Klaus Herfarth1 1Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany 2Heidelberg Ion Therapy Center (HIT), Heidelberg, Germany
Active raster scanning with carbon ions Reirradiation in patients with recurrent skull base chordomas and chondrosarcomas
Chordomas and chondrosarcomas are rare tumors. Chordomas arise from remnants of the notochord and chondrosarcomas from remnants of the cartilage. Both are categorized as malignant bone tumors. The prevalence of chordoma is 0.08/100,000 in the USA. The mean age at diagnosis for chordoma is 49 years and for chondrosarcoma 40 years. Involvement of the skull base can be found in approximately 35 % of chordomas and in 5–12 % of chondrosarcomas [1, 2]. Metastatic disease is very rare in chordoma and chondrosarcoma of the skull base. Therefore, sufficient local control is the most important factor. A microscopically complete resection of chordomas and chondrosarcomas of the skull base is rarely possible due to the structures of the skull base, and even then there remains a high risk of local recurrence [3]. An optimal functionconserving tumor surgery followed by radiotherapy with particle beam therapy is the treatment option of choice. In radiation therapy of chordoma, there is a dose– effect relationship. Applied doses of less than 60 Gy in conventional fractionation lead to inadequate local control [4]. Total doses up to 80 GyE can be administered with protons or a proton–photon combination (RBE 1.1 for protons) [5, 6]. A recent summary of the literature shows a 5to 0-year local control rate of 69.2/54 % in chordomas and of 75–99/98 % in chondrosarcomas of the skull base after particle therapy. The survival rate at 5/10 years was 79.8/54 % for chordomas and 99–
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100/99 % for chondrosarcomas [7, 8]. The rate of side effects is also similar to previously published results. Thus, high-dose radiotherapy with protons offers excellent opportunities for long-term local control rates and survival times. A recent study on the use of carbon ions for the treatment of skull base chordoma reported excellent tumor control rates of 70 % at 5 years [4]. The local control in chondrosarcoma of the skull base was 96.2 % after 3 years [9]. Randomized studies will evaluate the use of carbon ions compared with protons [10, 11]. As shown by various studies, there are a number of patients with relapse of skull base chordomas and chondrosarcomas. A second course of irradiation was avoided in the past because of the inability to spare organs at risk adjacent to the tumor site. Recently, there are more and more reports about reirradiation in various tumor entities [12–14]. Especially in the skull base region, reirradiation with conventional techniques would pose a great risk of severe side effects [15]. New high conformal techniques like intensity modulated radiotherapy (IMRT) and stereotactic treatment [16] offer a steep dose gradient with the opportunity of a second treatment in the skull base region. Due to their unique physical and biological properties, particles are favored for (re)irradiation of the skull base. Especially with carbon ions, a high biological effective dose deposition in the tumor is possible with sparing of the adjacent sensitive structures. The value of this rela-
tive biological effectiveness (RBE) is between 3 and 5 depending on different factors [17]. Our department started patient treatment in November 2009 and to date has treated more than 1,500 patients with protons or carbon ions, including approximately 300 patients with skull base chordoma and chondrosarcoma. In 25 patients with relapsed chordoma and chondrosarcoma, we performed reirradiation with carbon ions.
Patients and methods Between January 2010 and October 2012, we used reirradiation with carbon ions to treat 25 patients in an individual attempt for cure. The patients were irradiated for the recurrence of skull base chondrosarcoma (n = 5) or skull base chordoma (n = 20). Patients with tumor relapse on repeat magnetic resonance imaging (MRI) and/or with histological confirmation after surgery were selected for treatment (. Fig. 1a, b). Of the patients, 24 had at least one (1–6) partial resection in the past. Only one patient had not undergone any surgical intervention. The patients’ characteristics are summarized in . Table 1. All patients were immobilized individually using scotch cast (n = 6) or thermoplastic (n = 19) head masks. The planning examinations contained a computed tomography (CT) scan with 3 mm slice thickness and a contrast-enhanced MRI scan for 3D image correlation. The clinical target volume (CTV) for reirradi-
Fig. 1 9 a T2-STIR magnetic resonance imaging (MRI) of clival chordoma postIMRT (72.5 Gy, 2009); b T1 contrast-enhanced MRI showing extensive chordoma recurrence (2012); c dose distribution of reirradiation with 51 GyE C12 (2012)
ation included the visible tumor on MRI with an approximately 3-mm safety margin. The planning target volume (PTV) included the CTV with a 3-mm margin. The definition of the PTV considered adjacent organs at risk and prior radiation dose to avoid exceeding tissue tolerance (e.g., brain stem, optic nerve, optic chiasm, etc.). The prescribed doses depended on the prior radiation dose and interval between the treatments. The median prescribed dose was 51 GyE (45–60 GyE). For all patients, we kept the cumulative maximum dose of the brain stem at below 60 GyE. To calculate the cumulative maximum dose, we used the specific alpha/beta ratio of the organs at risk and summarized the ED2 doses (equivalent dose in 2 Gy fraction dose). If there was an interval of more than 1 year between radiation treatments, a recovery capacity of maximum 40 % for the brain stem and spinal cord was assumed. If the optic nerve or chiasm was involved in the tumor, we discussed the possible risks of visual loss with the patients after treatment planning. All patients received only carbon ion therapy. The therapy was delivered via active beam application using the raster scanning method. Inverse planning was done using Siemens TPS® equipment including biological optimization tools. The prescribed dose was given in five to six fractions per week in a single
dose of 3 GyE carbon ions. Daily image guidance was realized using orthogonal x-rays in treatment position. Corrections were made using a robotic table with six degrees of freedom. Follow-up MRI examinations were carried out 8 weeks after completion of reirradiation. Further follow-up was done every 3 months in the first year, every 6 months in the second year, and every 6–12 months from the third year after treatment. Local progression-free survival (LPFS) was evaluated using the Kaplan–Meier method; toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.4.03). The patients were requested to undergo ophthalmologic and endocrinological examinations in regular intervals.
Results Reirradiation with carbon ions could be performed on all 25 patients without interruption. Of the patients, 23 had been previously treated with irradiation once, and two patients twice. Fourteen of the patients had undergone particle therapy (C12/H1) in the past, with a median dose of 60 GyE (42–72 GyE); 11 of them had photon therapy with a median dose of 66 Gy (details are shown in . Tables 2 and 3). The median applied total dose of reirradiation with carbon ions was 51 GyE
(range: 45–60 GyE) in five to six fractions of 3 GyE per week (. Fig. 1c). This corresponds to a median equivalent dose of 63.8 GyE (range: 56.2–75 GyE) calculated for a fraction dose of 2 Gy (ED2 Gy) and an alpha/beta ratio of 2. The median interval between the last treatment and the current reirradiation was 7.0 years (2– 31 years). The median follow-up time was 14 months (2–30). The median planning treatment volume (PTV) was 133 ml (30– 363 ml). During follow-up, one relapse occurred in a patient with chondrosarcoma, the other five cases of relapse occurred in patients with chordoma. Using the Kaplan–Meier method, the 2-year LPFS probability was 79.3 %. A PTV volume of less than 100 ml or a total dose of up to 51 GyE was nonsignificantly associated with a higher local control rate (. Fig. 2). The observed acute toxicity was low. One patient developed grade 2 mucositis during therapy. Three patients had hypacusis due to a new onset of temporary middle ear effusion (CTC grade 2). Five patients developed an asymptomatic temporal lobe reaction after treatment without the need for surgical intervention (grade 1). Only one patient had a grade 3 osteoradionecrosis in the treatment area 1 month after irradiation, which required surgery. The cumulative dose in this patient was 111 GyE C12 (3 GyE SD), which corresponds approximately to ED2 Gy of Strahlentherapie und Onkologie 7 · 2014
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Abstract · Zusammenfassung Strahlenther Onkol 2014 · 190:686–691 DOI 10.1007/s00066-014-0608-2 © Springer-Verlag Berlin Heidelberg 2014 M. Uhl · T. Welzel · J. Oelmann · G. Habl · H. Hauswald · A. Jensen · M. Ellerbrock · J. Debus · K. Herfarth
Active raster scanning with carbon ions. Reirradiation in patients with recurrent skull base chordomas and chondrosarcomas Abstract Purpose. To evaluate the safety and efficacy of reirradiation with carbon ions in patients with relapse of skull base chordoma and chondrosarcoma. Patients and methods. Reirradiation with carbon ions was performed on 25 patients with locally recurrent skull base chordoma (n = 20) or chondrosarcoma (n = 5). The median time between the last radiation exposure and the reirradiation with carbon ions was 7 years. In the past, 23 patients had been irradiated once, two patients twice. Reirradiation was delivered using the active raster scanning method. The total median dose was 51.0 GyE carbon ions in a weekly regimen of
five to six fractions of 3 GyE. Local progression-free survival (LPFS) was evaluated using the Kaplan–Meier method; toxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03). Results. The treatment could be finished in all patients without interruption. In 80 % of patients, symptom control was achieved after therapy. The 2-year-LPFS probability was 79.3 %. A PTV volume of 51 GyE was associated with a superior local control rate. The therapy was associated with low acute toxicity. One patient developed grade 2 mucositis during therapy. Furthermore, 12 % of patients had tym-
panic effusion with mild hypacusis (grade 2), while 20 % developed an asymptomatic temporal lobe reaction after treatment (grade 1). Only one patient showed a grade 3 osteoradionecrosis. Conclusion. Reirradiation with carbon ions is a safe and effective method in patients with relapsed chordoma and chondrosarcoma of the skull base. Keywords Reirradiation · Chordoma · Chondrosarcoma · Skull base · Carbon ion
Kohlenstoffionen in aktiver Strahlapplikation. Re-Bestrahlung von Patienten mit Rezidiv eines Chordoms oder Chondrosarkoms der Schädelbasis Zusammenfassung Zielsetzung. Evaluierung der Sicherheit und Wirksamkeit einer Re-Bestrahlung mittels Kohlenstoffionen bei Patienten mit Lokalrezidiv eines Chordoms und Chondrosarkoms der Schädelbasis. Material und Methoden. Bei 25 Patienten mit einem Lokalrezidiv eines Chordoms (n = 20) oder Chondrosarkoms (n = 5) der Schädelbasis erfolgte eine Re-Bestrahlung mittels Kohlenstoffionen. Die mediane Zeit zwischen letzter Bestrahlung und Re-Bestrahlung mit Kohlenstoffionen betrug 7 Jahre. Hierbei hatten 23 Patienten eine Bestrahlung und 2 Patienten zwei Bestrahlungen in der Vergangenheit erhalten. Die Re-Bestrahlung mit Kohlenstoffionen in aktiver Strahlapplikation erfolgte mit einer medianen Gesamtdosis von 51 GyE in einer wöchentlichen Fraktio-
138.8 Gy. In 84 % (21/25) of patients, the tumor-associated symptoms were stable or had decreased after therapy. A dedicated collection of cranial nerve status before and after treatment and other side effects are listed in . Table 4.
Discussion In the past, reirradiation of the skull base was avoided because of the feared side effects due to its proximity to critical or-
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nierung von 5–6 × 3 GyE. Das lokal progressionsfreie Überleben (LPFS) wurde mit Hilfe der Kaplan-Meier-Methode bestimmt. Zur Toxizitätsbestimmung wurden die Kriterien des NCI CTCAE v.4.03 (National Cancer Institute „Common Terminology Criteria for Adverse Events“ Version 4.03) herangezogen. Ergebnisse. Die Therapie konnte bei allen Patienten ohne Unterbrechung durchgeführt werden. Bei 80 % der Patienten konnte durch die Behandlung eine Kontrolle der Symptome erreicht werden. Das lokal progressionsfreie Überleben nach 2 Jahren betrug 79,3 %. Patienten mit einem Planungszielvolumen (PTV) von 51 GyE wiesen eine bessere lokale Kontrolle auf. Die Therapie war mit einer niedrigen Akuttoxizität verbunden.
gans. The data of the present study from a small group of patients indicate that reirradiation with heavy ions in the case of tumor recurrence in the skull base is possible without major side effects. Less serious side effects like middle ear effusion, which appeared in three of our patients, also occur after the first irradiation of nasopharyngeal or skull base tumors and can be effectively treated using different techniques such as tympanic drainage [18]. The side effects concerning the
Ein Patient hatte während der Behandlung eine Mukositis °II. Bei 12 % der Patienten zeigte sich ein Paukenerguss mit leichter Hypakusis (CTC°II). Eine asymptomatische Temporallappenreaktion wurde bei 20 % der Patienten nach Therapie im MRT nachgewiesen (CTC°I). Ein Patient entwickelte eine Osteoradionekrose (CTC°III). Schlussfolgerung. Die Re-Bestrahlung von Patienten mit Lokalrezidiv eines Chordoms und Chondrosarkoms der Schädelbasis stellt eine sichere und effektive Methode dar. Schlüsselwörter Re-Bestrahlung · Partikeltherapie · Chordom · Chondrosarkom · Schädelbasis · Kohlenstoffionen
cranial nerves were lower than expected due to the high cumulative doses in our patients. Two of three patients with increasing trigeminal paresthesia and one of two patients with increasing nervus abducens injury (double vision) showed recurrent tumor growth as the reason for the increase in symptoms. Only two patients had an impairment of cranial nerve function without tumor relapse. One patient developed increasing double vision (n. abducens) and another patient n. hy-
Table 1 Patient characteristics
Table 2 Technique and dose of prior
Characteristic Age (years) Median Range Sex (n) Male Female Histology Chordoma Chondrosarcoma Surgery
radiation treatment
Value
Technique Photon (n = 2; hypofractionated) Photon (n = 9; normofractionated) Proton (n = 2; normofractionated) Carbon ion (n = 12; hypofractionated)
50 39–76 17 8 20 5 24
Median dose (range) 3 × 7 Gy (80 % isodose) 5 × 5 Gy (80 % isodose) 66 Gy (38–72.5 Gy) 68.4 GyE; 72 GyE 60 GyE (42–60 GyE)
GyE Gray equivalent
Table 3 Two patients with third radiation treatment Pat. no. 1 2
Diagnosis Chordoma Chondrosarcoma
1st RT course 60 GyE C12 (2001) 62.3 Gy photons (1979)
2nd RT course 42 GyE C12 (2006) 46.5 Gy photons (1980)
3rd RT course 51 GyE C12 51 GyE C12
RT radiation therapy, GyE Gray equivalent, C12 carbon ion
Table 4 Cranial nerve status/side effects before and after treatment Cranial nerve paresis/ side effect Nn. olfactorii N. opticus N. oculomotorius/ trochlearis N. trigeminus N. abducens N. facialis N. vestibulocochlearis N. glossopharyngeus N. vagus N. hypoglossus Loss of taste Middle ear effusion Pituitary deficiency Hemiplegia Focal epilepsy Chronic cephalgia Osteoradionecrosis Temporal lobe reaction
Baseline (n)
Improvement (n)
Impairment (n)
New (n)
3 8 4
– 1 –
– – –
– – –
11 12 4 10 5 4 8 5 2 4 1 1 5 – –
1 1 – – – – – – – – – – 1 – –
3 2 – – – – 1 – – – – – – – –
– – – – – – – – 3 – – – – 1 5
poglossus paresis and n. trigeminus paresthesia. Demizu et al. [19] reported a dosedependent neuropathy of the optic nerve after particle therapy. Univariate analysis showed a significant increase in blindness after the application of a maximum dose of 65 GyE on the optic nerve. The time of visual loss after treatment was highly variable [19]. Urie et al. [20] described a complication rate for the cranial nerves of 1 % at 60 GyE and 5 % at 70 GyE after proton therapy. Over 50 % of the in-
juries occurred within the first 24 months after treatment but none after 60 months [20]. Indeed, other data show a significant increase of nerve palsy in long-term follow-up after definitive photon irradiation in patients with nasopharyngeal cancer. An increase of nerve palsy by 10 % every 5 years up to a cumulative incidence of 45 % after 20 years was found. Here, the fibrosis is considered as a possible reason for cranial nerve palsy [21]. One reason for the low side effects in our series could
be that most of the patients had had a complete paralysis of some cranial nerves before reirradiation, due to previous treatments (surgery and/or Irradiation) or due to tumor infiltration. This is reflected in the baseline of the cranial nerve paresis in . Table 4 For example, four of the eight patients with optic nerve injury had had complete unilateral blindness before, such that a re-dose exposure could not lead to further impairment. Also, reirradiation was only performed if the cumulative dose for a functioning optic nerve had not exceeded the tolerance dose. Due to the difficult delineation of other cranial nerves and the lack of recording the applied dose in the previous treatment, the tolerance dose in these nerves could not be maintained reliably. However, the observation period in our patients was a median of 14 months, which is relatively short and may not reflect the potential fibrosis induced by the long-term effects to the cranial nerves. Despite the physical advantage of ions, the dose could not be completely avoided in the temporal lobe. In five patients a temporal lobe reaction occurred after reirradiation. The temporal lobe reaction was defined as visible contrast medium enhancement on T1weighted postgadolinium MRI within the volume affected by high dose. One explanation for the contrast enhancement is a blood–brain barrier breakdown after irradiation. These areas can be reversible or a precursor of radiation necrosis [22]. One patient developed temporal bone osteoradionecrosis, which needed surgery. Schlampp et al. [22] described a dose-dependent incidence of temporal lobe reaction after heavy-ion therapy in patients with skull base chordomas and chondrosarcomas. The calculated maximum tolerance dose to the temporal lobe for 5 and 50 % probabilities of temporal lobe reaction was 68.8 GyE and 87.3 GyE, respectively [22]. A temporal lobe reaction seems to correlate with the volume included in high-dose regions [22, 23]. The median cumulative applied tumor dose in our patients was 121.2 GyE (ED2 Gy 134 GyE). To avoid myelopathy [24] or brain stem necrosis, tolerance doses were respected as published by several groups before. According to the QUANTEC criteria, the entire brain stem may be treatStrahlentherapie und Onkologie 7 · 2014
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1.0
1.0
0.8
0.8
TD>51GyE. n=4
0.6
PTV>100ml. n=14
0.4
Probability
Probability
Original article
TD≤51GyE. n=21 0.4 0.2
0.2 0.0
0.6
n.s.
0.0
0.00 5.00 10.00 15.00 20.00 25.00 30.00
0.00 5.00 10.00 15.00 20.00 25.00 30.00
a
months
n.s.
b
months
Fig. 2 8 Local control probability (Kaplan–Meier) in patients a with PTV 100 ml (green) and b with TD ≤ 51 GyE (blue) or TD > 51 GyE (green)
ed with up to 54 Gy. Smaller volumes can be treated to a maximum dose of 59 Gy. The risk of injury seems to increase significantly at doses greater than 64 Gy [25, 26]. An excellent preservation of these structures is possible due to the physical properties of heavy ions with a very steep dose gradient. There is not much difference in terms of the severity and frequency of side effects in our series compared with the rates reported in the literature after first treatment. The risk–benefit ratio of irradiation of the skull base is, according to our data, clearly in favor of the benefits, with a 2-year local control rate of 79.5 %. Four patients with renewed recurrence already showed progressive disease at the first MRI follow-up after reirradiation. Reirradiation appears to have had no effect on the tumor in these patients. A particularly aggressive biology of the tumor has to be considered in these cases.
Conclusion Reirradiation of recurrent skull base chordomas and chondrosarcomas using carbon ions is safe. In some patients, the treatment could not prevent tumor growth. Further investigations will discover the cause of early relapse or nonresponse to therapy. Currently, there are further biological studies as a supplementary program in prospective trials for patients in primary treatment.
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Corresponding address Dr. med. M. Uhl M.D. Department of Radiation Oncology University of Heidelberg Im Neuenheimer Feld 400 69120 Heidelberg [email protected]
Compliance with ethical guidelines Conflict of interest. M. Uhl, T. Wenzel, J. Oelmann, G. Habl, H. Hauswald, A. Jensen, M. Ellerbrock, J. Debus, and K. Herfarth state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.
References 1. McMaster ML, Goldstein AM, Bromley CM et al (2001) Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Cause Control 12:1–11 2. Lee SY, Lim YC, Song MH et al (2005) Chondrosarcoma of the head and neck. Yonsei Med J 46:228– 232 3. Samii A, Gerganov VM, Herold C et al (2007) Chordomas of the skull base: surgical management and outcome. J Neurosurg 107:319–324 4. Schulz-Ertner D, Karger CP, Feuerhake A et al (2007) Effectiveness of carbon ion radiotherapy in the treatment of skull-base chordomas. Int J Radiat Oncol Biol Phys 68:449–457 5. Terahara A, Niemierko A, Goitein M et al (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
6. Munzenrider JE, Liebsch NJ (1999) Proton therapy for tumors of the skull base. Strahlenther Onkol 175:57–63 7. Amichetti M, Amelio D, Cianchetti M et al (2010) A systematic review of proton therapy in the treatment of chondrosarcoma of the skull base. Neurosurg Rev 33:155–165 8. Amichetti M, Cianchetti M, Amelio D et al (2009) Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev 32:403– 416 9. Schulz-Ertner D, Nikoghosyan A, Hof H et al (2007) Carbon ion radiotherapy of skull base chondrosarcomas. Int J Radiat Oncol Biol Phys 67:171–177 10. Nikoghosyan AV, Karapanagiotou-Schenkel I, Munter MW et al (2010) Randomised trial of proton vs. carbon ion radiation therapy in patients with chordoma of the skull base, clinical phase III study HIT-1-Study. BMC Cancer 10:607 11. Nikoghosyan AV, Rauch G, Munter MW et al (2010) Randomised trial of proton vs. carbon ion radiation therapy in patients with low and intermediate grade chondrosarcoma of the skull base, clinical phase III study. BMC Cancer 10:606 12. Vormittag L, Lemaire C, Radonjic D et al (2012) Reirradiation combined with capecitabine in locally recurrent squamous cell carcinoma of the head and neck. A prospective phase II trial. Strahlenther Onkol 188:235–242 13. Mizumoto M, Okumura T, Ishikawa E et al (2013) Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Technical considerations based on experience at a single institution. Strahlenther Onkol 189:656–663 14. Niyazi M, Söhn M, Schwarz SB et al (2012) Radiation treatment parameters for re- irradiation of malignant glioma. Strahlenther Onkol 188:328– 333 15. Rong X, Tang Y, Chen M et al (2012) Radiation-induced cranial neuropathy in patients with nasopharyngeal carcinoma. A follow-up study. Strahlenther Onkol 188:282–286 16. Kocher M, Treuer H, Hoevels M et al (2013) Endocrine and visual function after fractionated stereotactic radiotherapy of perioptic tumors. Strahlenther Onkol 189:137–141 17. Grun R, Friedrich T, Elsasser T et al (2012) Impact of enhancements in the local effect model (LEM) on the predicted RBE-weighted target dose distribution in carbon ion therapy. Phys Med Biol 57:7261– 7274 18. Kuo CL, Wang MC, Chu CH et al (2012) New therapeutic strategy for treating otitis media with effusion in postirradiated nasopharyngeal carcinoma patients. J Chin Med Assoc 75:329–334 19. Demizu Y, Murakami M, Miyawaki D et al (2009) Analysis of Vision loss caused by radiation-induced optic neuropathy after particle therapy for headand-neck and skull-base tumors adjacent to optic nerves. Int J Radiat Oncol Biol Phys 75:1487–1492 20. Urie MM, Fullerton B, Tatsuzaki H et al (1992) A dose response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy. Int J Radiat Oncol Biol Phys 23:27–39 21. Kong L, Lu JJ, Liss AL et al (2011) Radiation-induced cranial nerve palsy: a cross-sectional study of nasopharyngeal cancer patients after definitive radiotherapy. Int J Radiat Oncol Biol Phys 79:1421– 1427 22. Schlampp I, Karger CP, Jakel O et al (2011) Temporal lobe reactions after radiotherapy with carbon ions: incidence and estimation of the relative biological effectiveness by the local effect model. Int J Radiat Oncol Biol Phys 80:815–823
23. Pehlivan B, Ares C, Lomax AJ et al (2012) Temporal lobe toxicity analysis after proton radiation therapy for skull base tumors. Int J Radiat Oncol Biol Phys 83:1432–1440 24. Mul VE, de Jong JM, Murrer LH et al (2012) Lhermitte sign and myelopathy after irradiation of the cervical spinal cord in radiotherapy treatment of head and neck cancer. Strahlenther Onkol 188:71– 76 25. Mayo C, Yorke E, Merchant TE (2010) Radiation associated brainstem injury. Int J Radiat Oncol Biol Phys 76:S36–S41 26. Debus J, Hug EB, Liebsch NJ, et al (1997) Brainstem tolerance to conformal radiotherapy of skull base tumors. Int J Radiat Oncol Biol Phys 39:967–975
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Matthias Uhl1 · Thomas Welzel1 · Jan Oelmann1 · Gregor Habl1 · Henrik Hauswald1 · Alexandra Jensen1 · Malte Ellerbrock2 · Jürgen Debus1 · Klaus Herfarth1 1Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany 2Heidelberg Ion Therapy Center (HIT), Heidelberg, Germany
Active raster scanning with carbon ions Reirradiation in patients with recurrent skull base chordomas and chondrosarcomas
Chordomas and chondrosarcomas are rare tumors. Chordomas arise from remnants of the notochord and chondrosarcomas from remnants of the cartilage. Both are categorized as malignant bone tumors. The prevalence of chordoma is 0.08/100,000 in the USA. The mean age at diagnosis for chordoma is 49 years and for chondrosarcoma 40 years. Involvement of the skull base can be found in approximately 35 % of chordomas and in 5–12 % of chondrosarcomas [1, 2]. Metastatic disease is very rare in chordoma and chondrosarcoma of the skull base. Therefore, sufficient local control is the most important factor. A microscopically complete resection of chordomas and chondrosarcomas of the skull base is rarely possible due to the structures of the skull base, and even then there remains a high risk of local recurrence [3]. An optimal functionconserving tumor surgery followed by radiotherapy with particle beam therapy is the treatment option of choice. In radiation therapy of chordoma, there is a dose– effect relationship. Applied doses of less than 60 Gy in conventional fractionation lead to inadequate local control [4]. Total doses up to 80 GyE can be administered with protons or a proton–photon combination (RBE 1.1 for protons) [5, 6]. A recent summary of the literature shows a 5to 0-year local control rate of 69.2/54 % in chordomas and of 75–99/98 % in chondrosarcomas of the skull base after particle therapy. The survival rate at 5/10 years was 79.8/54 % for chordomas and 99–
686 | Strahlentherapie und Onkologie 7 · 2014
100/99 % for chondrosarcomas [7, 8]. The rate of side effects is also similar to previously published results. Thus, high-dose radiotherapy with protons offers excellent opportunities for long-term local control rates and survival times. A recent study on the use of carbon ions for the treatment of skull base chordoma reported excellent tumor control rates of 70 % at 5 years [4]. The local control in chondrosarcoma of the skull base was 96.2 % after 3 years [9]. Randomized studies will evaluate the use of carbon ions compared with protons [10, 11]. As shown by various studies, there are a number of patients with relapse of skull base chordomas and chondrosarcomas. A second course of irradiation was avoided in the past because of the inability to spare organs at risk adjacent to the tumor site. Recently, there are more and more reports about reirradiation in various tumor entities [12–14]. Especially in the skull base region, reirradiation with conventional techniques would pose a great risk of severe side effects [15]. New high conformal techniques like intensity modulated radiotherapy (IMRT) and stereotactic treatment [16] offer a steep dose gradient with the opportunity of a second treatment in the skull base region. Due to their unique physical and biological properties, particles are favored for (re)irradiation of the skull base. Especially with carbon ions, a high biological effective dose deposition in the tumor is possible with sparing of the adjacent sensitive structures. The value of this rela-
tive biological effectiveness (RBE) is between 3 and 5 depending on different factors [17]. Our department started patient treatment in November 2009 and to date has treated more than 1,500 patients with protons or carbon ions, including approximately 300 patients with skull base chordoma and chondrosarcoma. In 25 patients with relapsed chordoma and chondrosarcoma, we performed reirradiation with carbon ions.
Patients and methods Between January 2010 and October 2012, we used reirradiation with carbon ions to treat 25 patients in an individual attempt for cure. The patients were irradiated for the recurrence of skull base chondrosarcoma (n = 5) or skull base chordoma (n = 20). Patients with tumor relapse on repeat magnetic resonance imaging (MRI) and/or with histological confirmation after surgery were selected for treatment (. Fig. 1a, b). Of the patients, 24 had at least one (1–6) partial resection in the past. Only one patient had not undergone any surgical intervention. The patients’ characteristics are summarized in . Table 1. All patients were immobilized individually using scotch cast (n = 6) or thermoplastic (n = 19) head masks. The planning examinations contained a computed tomography (CT) scan with 3 mm slice thickness and a contrast-enhanced MRI scan for 3D image correlation. The clinical target volume (CTV) for reirradi-
Fig. 1 9 a T2-STIR magnetic resonance imaging (MRI) of clival chordoma postIMRT (72.5 Gy, 2009); b T1 contrast-enhanced MRI showing extensive chordoma recurrence (2012); c dose distribution of reirradiation with 51 GyE C12 (2012)
ation included the visible tumor on MRI with an approximately 3-mm safety margin. The planning target volume (PTV) included the CTV with a 3-mm margin. The definition of the PTV considered adjacent organs at risk and prior radiation dose to avoid exceeding tissue tolerance (e.g., brain stem, optic nerve, optic chiasm, etc.). The prescribed doses depended on the prior radiation dose and interval between the treatments. The median prescribed dose was 51 GyE (45–60 GyE). For all patients, we kept the cumulative maximum dose of the brain stem at below 60 GyE. To calculate the cumulative maximum dose, we used the specific alpha/beta ratio of the organs at risk and summarized the ED2 doses (equivalent dose in 2 Gy fraction dose). If there was an interval of more than 1 year between radiation treatments, a recovery capacity of maximum 40 % for the brain stem and spinal cord was assumed. If the optic nerve or chiasm was involved in the tumor, we discussed the possible risks of visual loss with the patients after treatment planning. All patients received only carbon ion therapy. The therapy was delivered via active beam application using the raster scanning method. Inverse planning was done using Siemens TPS® equipment including biological optimization tools. The prescribed dose was given in five to six fractions per week in a single
dose of 3 GyE carbon ions. Daily image guidance was realized using orthogonal x-rays in treatment position. Corrections were made using a robotic table with six degrees of freedom. Follow-up MRI examinations were carried out 8 weeks after completion of reirradiation. Further follow-up was done every 3 months in the first year, every 6 months in the second year, and every 6–12 months from the third year after treatment. Local progression-free survival (LPFS) was evaluated using the Kaplan–Meier method; toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.4.03). The patients were requested to undergo ophthalmologic and endocrinological examinations in regular intervals.
Results Reirradiation with carbon ions could be performed on all 25 patients without interruption. Of the patients, 23 had been previously treated with irradiation once, and two patients twice. Fourteen of the patients had undergone particle therapy (C12/H1) in the past, with a median dose of 60 GyE (42–72 GyE); 11 of them had photon therapy with a median dose of 66 Gy (details are shown in . Tables 2 and 3). The median applied total dose of reirradiation with carbon ions was 51 GyE
(range: 45–60 GyE) in five to six fractions of 3 GyE per week (. Fig. 1c). This corresponds to a median equivalent dose of 63.8 GyE (range: 56.2–75 GyE) calculated for a fraction dose of 2 Gy (ED2 Gy) and an alpha/beta ratio of 2. The median interval between the last treatment and the current reirradiation was 7.0 years (2– 31 years). The median follow-up time was 14 months (2–30). The median planning treatment volume (PTV) was 133 ml (30– 363 ml). During follow-up, one relapse occurred in a patient with chondrosarcoma, the other five cases of relapse occurred in patients with chordoma. Using the Kaplan–Meier method, the 2-year LPFS probability was 79.3 %. A PTV volume of less than 100 ml or a total dose of up to 51 GyE was nonsignificantly associated with a higher local control rate (. Fig. 2). The observed acute toxicity was low. One patient developed grade 2 mucositis during therapy. Three patients had hypacusis due to a new onset of temporary middle ear effusion (CTC grade 2). Five patients developed an asymptomatic temporal lobe reaction after treatment without the need for surgical intervention (grade 1). Only one patient had a grade 3 osteoradionecrosis in the treatment area 1 month after irradiation, which required surgery. The cumulative dose in this patient was 111 GyE C12 (3 GyE SD), which corresponds approximately to ED2 Gy of Strahlentherapie und Onkologie 7 · 2014
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Abstract · Zusammenfassung Strahlenther Onkol 2014 · 190:686–691 DOI 10.1007/s00066-014-0608-2 © Springer-Verlag Berlin Heidelberg 2014 M. Uhl · T. Welzel · J. Oelmann · G. Habl · H. Hauswald · A. Jensen · M. Ellerbrock · J. Debus · K. Herfarth
Active raster scanning with carbon ions. Reirradiation in patients with recurrent skull base chordomas and chondrosarcomas Abstract Purpose. To evaluate the safety and efficacy of reirradiation with carbon ions in patients with relapse of skull base chordoma and chondrosarcoma. Patients and methods. Reirradiation with carbon ions was performed on 25 patients with locally recurrent skull base chordoma (n = 20) or chondrosarcoma (n = 5). The median time between the last radiation exposure and the reirradiation with carbon ions was 7 years. In the past, 23 patients had been irradiated once, two patients twice. Reirradiation was delivered using the active raster scanning method. The total median dose was 51.0 GyE carbon ions in a weekly regimen of
five to six fractions of 3 GyE. Local progression-free survival (LPFS) was evaluated using the Kaplan–Meier method; toxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03). Results. The treatment could be finished in all patients without interruption. In 80 % of patients, symptom control was achieved after therapy. The 2-year-LPFS probability was 79.3 %. A PTV volume of 51 GyE was associated with a superior local control rate. The therapy was associated with low acute toxicity. One patient developed grade 2 mucositis during therapy. Furthermore, 12 % of patients had tym-
panic effusion with mild hypacusis (grade 2), while 20 % developed an asymptomatic temporal lobe reaction after treatment (grade 1). Only one patient showed a grade 3 osteoradionecrosis. Conclusion. Reirradiation with carbon ions is a safe and effective method in patients with relapsed chordoma and chondrosarcoma of the skull base. Keywords Reirradiation · Chordoma · Chondrosarcoma · Skull base · Carbon ion
Kohlenstoffionen in aktiver Strahlapplikation. Re-Bestrahlung von Patienten mit Rezidiv eines Chordoms oder Chondrosarkoms der Schädelbasis Zusammenfassung Zielsetzung. Evaluierung der Sicherheit und Wirksamkeit einer Re-Bestrahlung mittels Kohlenstoffionen bei Patienten mit Lokalrezidiv eines Chordoms und Chondrosarkoms der Schädelbasis. Material und Methoden. Bei 25 Patienten mit einem Lokalrezidiv eines Chordoms (n = 20) oder Chondrosarkoms (n = 5) der Schädelbasis erfolgte eine Re-Bestrahlung mittels Kohlenstoffionen. Die mediane Zeit zwischen letzter Bestrahlung und Re-Bestrahlung mit Kohlenstoffionen betrug 7 Jahre. Hierbei hatten 23 Patienten eine Bestrahlung und 2 Patienten zwei Bestrahlungen in der Vergangenheit erhalten. Die Re-Bestrahlung mit Kohlenstoffionen in aktiver Strahlapplikation erfolgte mit einer medianen Gesamtdosis von 51 GyE in einer wöchentlichen Fraktio-
138.8 Gy. In 84 % (21/25) of patients, the tumor-associated symptoms were stable or had decreased after therapy. A dedicated collection of cranial nerve status before and after treatment and other side effects are listed in . Table 4.
Discussion In the past, reirradiation of the skull base was avoided because of the feared side effects due to its proximity to critical or-
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nierung von 5–6 × 3 GyE. Das lokal progressionsfreie Überleben (LPFS) wurde mit Hilfe der Kaplan-Meier-Methode bestimmt. Zur Toxizitätsbestimmung wurden die Kriterien des NCI CTCAE v.4.03 (National Cancer Institute „Common Terminology Criteria for Adverse Events“ Version 4.03) herangezogen. Ergebnisse. Die Therapie konnte bei allen Patienten ohne Unterbrechung durchgeführt werden. Bei 80 % der Patienten konnte durch die Behandlung eine Kontrolle der Symptome erreicht werden. Das lokal progressionsfreie Überleben nach 2 Jahren betrug 79,3 %. Patienten mit einem Planungszielvolumen (PTV) von 51 GyE wiesen eine bessere lokale Kontrolle auf. Die Therapie war mit einer niedrigen Akuttoxizität verbunden.
gans. The data of the present study from a small group of patients indicate that reirradiation with heavy ions in the case of tumor recurrence in the skull base is possible without major side effects. Less serious side effects like middle ear effusion, which appeared in three of our patients, also occur after the first irradiation of nasopharyngeal or skull base tumors and can be effectively treated using different techniques such as tympanic drainage [18]. The side effects concerning the
Ein Patient hatte während der Behandlung eine Mukositis °II. Bei 12 % der Patienten zeigte sich ein Paukenerguss mit leichter Hypakusis (CTC°II). Eine asymptomatische Temporallappenreaktion wurde bei 20 % der Patienten nach Therapie im MRT nachgewiesen (CTC°I). Ein Patient entwickelte eine Osteoradionekrose (CTC°III). Schlussfolgerung. Die Re-Bestrahlung von Patienten mit Lokalrezidiv eines Chordoms und Chondrosarkoms der Schädelbasis stellt eine sichere und effektive Methode dar. Schlüsselwörter Re-Bestrahlung · Partikeltherapie · Chordom · Chondrosarkom · Schädelbasis · Kohlenstoffionen
cranial nerves were lower than expected due to the high cumulative doses in our patients. Two of three patients with increasing trigeminal paresthesia and one of two patients with increasing nervus abducens injury (double vision) showed recurrent tumor growth as the reason for the increase in symptoms. Only two patients had an impairment of cranial nerve function without tumor relapse. One patient developed increasing double vision (n. abducens) and another patient n. hy-
Table 1 Patient characteristics
Table 2 Technique and dose of prior
Characteristic Age (years) Median Range Sex (n) Male Female Histology Chordoma Chondrosarcoma Surgery
radiation treatment
Value
Technique Photon (n = 2; hypofractionated) Photon (n = 9; normofractionated) Proton (n = 2; normofractionated) Carbon ion (n = 12; hypofractionated)
50 39–76 17 8 20 5 24
Median dose (range) 3 × 7 Gy (80 % isodose) 5 × 5 Gy (80 % isodose) 66 Gy (38–72.5 Gy) 68.4 GyE; 72 GyE 60 GyE (42–60 GyE)
GyE Gray equivalent
Table 3 Two patients with third radiation treatment Pat. no. 1 2
Diagnosis Chordoma Chondrosarcoma
1st RT course 60 GyE C12 (2001) 62.3 Gy photons (1979)
2nd RT course 42 GyE C12 (2006) 46.5 Gy photons (1980)
3rd RT course 51 GyE C12 51 GyE C12
RT radiation therapy, GyE Gray equivalent, C12 carbon ion
Table 4 Cranial nerve status/side effects before and after treatment Cranial nerve paresis/ side effect Nn. olfactorii N. opticus N. oculomotorius/ trochlearis N. trigeminus N. abducens N. facialis N. vestibulocochlearis N. glossopharyngeus N. vagus N. hypoglossus Loss of taste Middle ear effusion Pituitary deficiency Hemiplegia Focal epilepsy Chronic cephalgia Osteoradionecrosis Temporal lobe reaction
Baseline (n)
Improvement (n)
Impairment (n)
New (n)
3 8 4
– 1 –
– – –
– – –
11 12 4 10 5 4 8 5 2 4 1 1 5 – –
1 1 – – – – – – – – – – 1 – –
3 2 – – – – 1 – – – – – – – –
– – – – – – – – 3 – – – – 1 5
poglossus paresis and n. trigeminus paresthesia. Demizu et al. [19] reported a dosedependent neuropathy of the optic nerve after particle therapy. Univariate analysis showed a significant increase in blindness after the application of a maximum dose of 65 GyE on the optic nerve. The time of visual loss after treatment was highly variable [19]. Urie et al. [20] described a complication rate for the cranial nerves of 1 % at 60 GyE and 5 % at 70 GyE after proton therapy. Over 50 % of the in-
juries occurred within the first 24 months after treatment but none after 60 months [20]. Indeed, other data show a significant increase of nerve palsy in long-term follow-up after definitive photon irradiation in patients with nasopharyngeal cancer. An increase of nerve palsy by 10 % every 5 years up to a cumulative incidence of 45 % after 20 years was found. Here, the fibrosis is considered as a possible reason for cranial nerve palsy [21]. One reason for the low side effects in our series could
be that most of the patients had had a complete paralysis of some cranial nerves before reirradiation, due to previous treatments (surgery and/or Irradiation) or due to tumor infiltration. This is reflected in the baseline of the cranial nerve paresis in . Table 4 For example, four of the eight patients with optic nerve injury had had complete unilateral blindness before, such that a re-dose exposure could not lead to further impairment. Also, reirradiation was only performed if the cumulative dose for a functioning optic nerve had not exceeded the tolerance dose. Due to the difficult delineation of other cranial nerves and the lack of recording the applied dose in the previous treatment, the tolerance dose in these nerves could not be maintained reliably. However, the observation period in our patients was a median of 14 months, which is relatively short and may not reflect the potential fibrosis induced by the long-term effects to the cranial nerves. Despite the physical advantage of ions, the dose could not be completely avoided in the temporal lobe. In five patients a temporal lobe reaction occurred after reirradiation. The temporal lobe reaction was defined as visible contrast medium enhancement on T1weighted postgadolinium MRI within the volume affected by high dose. One explanation for the contrast enhancement is a blood–brain barrier breakdown after irradiation. These areas can be reversible or a precursor of radiation necrosis [22]. One patient developed temporal bone osteoradionecrosis, which needed surgery. Schlampp et al. [22] described a dose-dependent incidence of temporal lobe reaction after heavy-ion therapy in patients with skull base chordomas and chondrosarcomas. The calculated maximum tolerance dose to the temporal lobe for 5 and 50 % probabilities of temporal lobe reaction was 68.8 GyE and 87.3 GyE, respectively [22]. A temporal lobe reaction seems to correlate with the volume included in high-dose regions [22, 23]. The median cumulative applied tumor dose in our patients was 121.2 GyE (ED2 Gy 134 GyE). To avoid myelopathy [24] or brain stem necrosis, tolerance doses were respected as published by several groups before. According to the QUANTEC criteria, the entire brain stem may be treatStrahlentherapie und Onkologie 7 · 2014
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1.0
1.0
0.8
0.8
TD>51GyE. n=4
0.6
PTV>100ml. n=14
0.4
Probability
Probability
Original article
TD≤51GyE. n=21 0.4 0.2
0.2 0.0
0.6
n.s.
0.0
0.00 5.00 10.00 15.00 20.00 25.00 30.00
0.00 5.00 10.00 15.00 20.00 25.00 30.00
a
months
n.s.
b
months
Fig. 2 8 Local control probability (Kaplan–Meier) in patients a with PTV 100 ml (green) and b with TD ≤ 51 GyE (blue) or TD > 51 GyE (green)
ed with up to 54 Gy. Smaller volumes can be treated to a maximum dose of 59 Gy. The risk of injury seems to increase significantly at doses greater than 64 Gy [25, 26]. An excellent preservation of these structures is possible due to the physical properties of heavy ions with a very steep dose gradient. There is not much difference in terms of the severity and frequency of side effects in our series compared with the rates reported in the literature after first treatment. The risk–benefit ratio of irradiation of the skull base is, according to our data, clearly in favor of the benefits, with a 2-year local control rate of 79.5 %. Four patients with renewed recurrence already showed progressive disease at the first MRI follow-up after reirradiation. Reirradiation appears to have had no effect on the tumor in these patients. A particularly aggressive biology of the tumor has to be considered in these cases.
Conclusion Reirradiation of recurrent skull base chordomas and chondrosarcomas using carbon ions is safe. In some patients, the treatment could not prevent tumor growth. Further investigations will discover the cause of early relapse or nonresponse to therapy. Currently, there are further biological studies as a supplementary program in prospective trials for patients in primary treatment.
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Corresponding address Dr. med. M. Uhl M.D. Department of Radiation Oncology University of Heidelberg Im Neuenheimer Feld 400 69120 Heidelberg [email protected]
Compliance with ethical guidelines Conflict of interest. M. Uhl, T. Wenzel, J. Oelmann, G. Habl, H. Hauswald, A. Jensen, M. Ellerbrock, J. Debus, and K. Herfarth state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.
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