- Email: [email protected]
Spot-scanning proton therapy for malignant soft tissue tumors in childhood: First experiences at the Paul Scherrer Institute
Int. J. Radiation Oncology Biol. Phys., Vol. 67, No. 2, pp. 497–504, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2006.08.053
CLINICAL INVESTIGATION
Sarcoma
SPOT-SCANNING PROTON THERAPY FOR MALIGNANT SOFT TISSUE TUMORS IN CHILDHOOD: FIRST EXPERIENCES AT THE PAUL SCHERRER INSTITUTE BEATE TIMMERMANN, M.D.,* ANDREAS SCHUCK, M.D.,† FELIX NIGGLI, M.D.,‡ MARKUS WEISS, M.D.,§ ANTONY JONATHAN LOMAX, PH.D.,* EROS PEDRONI, PH.D.,* ADOLF CORAY, PH.D.,* MARTIN JERMANN, PH.D.,* HANS PETER RUTZ, M.D.,* AND GUDRUN GOITEIN, M.D.* *Division of Radiation Medicine, Proton Therapy, Paul Scherrer Institut, Villigen, Switzerland; †Department of Radiation Oncology, University of Münster, Münster, Germany; ‡Department of Paediatric Oncology, University Children’s Hospital, Zürich, Switzerland; §Department of Anaesthesia, University Children’s Hospital, Zürich, Switzerland Purpose: Radiotherapy plays a major role in the treatment strategy of childhood sarcomas. Consequences of treatment are likely to affect the survivor’s quality of life significantly. We investigated the feasibility of spot-scanning proton therapy (PT) for soft tissue tumors in childhood. Methods and Materials: Sixteen children with soft tissue sarcomas were included. Median age at PT was 3.3 years. In 10 children the tumor histology was embryonal rhabdomyosarcoma. All tumors were located in the head or neck, parameningeal, or paraspinal, or pelvic region. In the majority of children, the tumor was initially unresectable (Intergroup Rhabdomyosarcoma Study [IRS] Group III in 75%). In 50% of children the tumors exceeded 5 cm. Fourteen children had chemotherapy before and during PT. Median total dose of radiotherapy was 50 cobalt Gray equivalent (CGE). All 16 children were treated with spot-scanning proton therapy at the Paul Scherrer Institute, and in 3 children the PT was intensity-modulated (IMPT). Results: After median follow-up of 1.5 years, local control was achieved in 12 children. Four children failed locally, 1 at the border of the radiation field and 3 within the field. All 4 children died of tumor recurrence. All 4 showed unfavorable characteristic either of site or histopathology of the tumor. Acute toxicity was low, with Grade 3 or 4 side effects according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria occurring in the bone marrow only. Conclusions: Proton therapy was feasible and well tolerated. Early local control rates are comparable to those being achieved after conventional radiotherapy. For investigations on late effect, longer follow-up is needed. © 2007 Elsevier Inc. Sarcomas, Proton therapy, Irradiation, Treatment, Childhood.
sarcomas are treated with radiotherapy as compared with approximately 50% in the German and European Cooperative Childhood Soft Tissue Sarcoma trial (CWS) protocols and even less with approximately 30 – 40% in the International Society of Pediatric Oncology–Malignant Mesenchymal Tumor (SIOP-MMT) trials (5). Most commonly, radiotherapy is given by external beam photons, usually with three-dimensional conformal techniques. In the management of childhood tumors, special treatment techniques such as intensity-modulated radiotherapy (IMRT) and, in selected cases, brachytherapy or intraoperative electron treatment have also been introduced (6). Additionally, due to the unique characteristics of proton beam, an increasing proportion of children are treated with proton therapy (PT) (7). The selection of the appropriate mode of radiotherapy for
INTRODUCTION For patients with sarcomas, the treatment regimen includes a multidisciplinary strategy of combined surgery, chemotherapy, and radiotherapy depending specifically on tumor type, site of the primary tumor, and stage of disease (1, 2). In general, the strategy is individually adapted to achieve maximal chance for cure while trying to minimize the risk of late treatment sequelae. Radiotherapy plays a dominant role in those tumors, which cannot be surgically removed without leading to major impairment (2). However, the knowledge of severe late effects of radiotherapy has led to significant differences in treatment philosophies. For many years, European pediatric oncologists have attempted to avoid any irradiation by implementing intensive chemotherapy and second surgery (3, 4). It is estimated that in the American protocols approximately 70% of all children with Reprint requests to: Beate Timmermann, M.D., Division of Radiation Medicine, Paul Scherrer Institute, CH-5232 VilligenPSI, Villigen, Switzerland. Tel: (⫹41) 56-3103695; Fax: (⫹41) 56-3103515; E-mail: [email protected]
Conflict of interest: none. Received July 5, 2006, and in revised form Aug 18, 2006. Accepted for publication Aug 18, 2006. 497
498
I. J. Radiation Oncology
●
Biology
●
Physics
each individual child will be an important objective in the near future. Thus, more information about the spectrum of advantages as well as risks of the available radiotherapy techniques is needed. METHODS AND MATERIALS Since 1995, 262 patients have been treated with spot-scanning protons at the Paul Scherrer Institute. For principal patient selection, priority was given to pediatric patients and to diagnoses that require high cumulative doses for cure, i.e., chordoma and lowgrade chondrosarcoma. In 1997 the first child was treated. Herein we present an analysis on the subgroup of patients treated for soft tissue tumors in childhood. A signed informed consent was mandatory in all patients.
Patient selection Patients under 21 years of age with malignant soft tissue tumors in the region of head and neck, spine, and pelvis were included in this analysis. Since 2004 the decision for PT in children has been made by an interdisciplinary discussion of the reference radiotherapist of the German and European Cooperative Childhood Soft Tissue Sarcoma trial (CWS). Diagnoses were made by the institutional pathologist and in the majority of cases confirmed by a review pathologist. Patients were referred from several hospitals in different European countries.
Evaluation of disease In all children, initial images (magnetic resonance imaging or computed tomography scan) and pre-PT images were available. The staging was performed according to the specific protocol in which the respective child was treated. Retrospectively all patients were assigned to the respective Intergroup Rhabdomyosarcoma Study (IRS) group, according to the criteria of the IRS SurgicalPathologic Grouping Classification (8).
Evaluation of toxicity No prospective standardized evaluation of toxicity and quality of life was performed during the first years. Since 2003, radiationinduced acute and late toxicity was evaluated according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria for general status, bone marrow, skin, mucosa, salivary glands, pharynx/esophagus, larynx, lung, heart, upper gastrointestinal tract, bone, joints, central nervous system, spinal cord/peripheral nerves, ears, and eyes (9). The evaluation of toxicity was performed by the treating radiation oncologists. In patients treated before 2003, toxicity was scored retrospectively, according to RTOG/EORTC criteria. In 2004, a selfrating quality of life questionnaire for childhood cancer survivors (PEDQUOL) was introduced, completed by each patient and their parents and sent to the study center in Düsseldorf, Germany.
Pretreatment Surgery. In all children at least one biopsy was performed to ensure diagnosis. The extent of surgical procedure (complete or incomplete resection) was evaluated from the operation report and the postoperative imaging. Chemotherapy. Chemotherapy was administered according to the specific protocol in which the child was treated (Table 1). The
Volume 67, Number 2, 2007
Table 1. Applied treatment protocols and chemotherapeutic agents in the children receiving proton therapy Trial
Patients (n)
Agents
CWS2002
8
MMT-95 (3)
5
COG-D9803
1
No chemotherapy
2
Ifosfamide, actinomycin D, vincristine adriamycin* Ifosfamide, actinomycin D, vincristine, Epirubicin*, etoposide*, carboplatin* Vincristine, adriamycin, cyclophosphamide, topotecan† —
Abbreviations: CWS2002 ⫽ German and European Cooperative Childhood Soft Tissue Sarcoma trial; MMT-95 ⫽ Malignant Mesenchymal Tumor 1995 trial; COG-D9803 ⫽ Children’s Oncology Group Protocol-D9803. * For high-risk patients. † For experimental arm.
children were treated according to the MMT-95 protocol or CWS2002 protocol or Children’s Oncology Group (COG) protocol D9803. For some diagnoses no chemotherapy was recommended at all.
Proton beam therapy Immobilization aids were created individually for all patients to avoid patient motion and to achieve reproducible positioning of the patient. Patient positioning was checked before every fraction by generating one lateral and one frontal computed tomography scout view. Anatomic reference points were compared with the same points in the planning computed tomography. Planning computed tomography was the base for planning procedures in all patients. In case of setup deviation, the position of the patient was corrected by table movement. All patients were treated at the 360°-rotatable gantry at the Paul Scherrer Institute. The proton source at Paul Scherrer Institute is a sector cyclotron producing an intensive proton beam of 590 MeV. A small part is split from the main proton beam and degraded for medical application. The energy of the beam dedicated to medical application can be chosen between 85 and 270 MeV (mainly used are 138, 160, or 177 MeV, respectively). The energy of the beam can be chosen individually for each patient and for each field. Dose calculation for PT was calculated three-dimensionally using an algorithm developed at the Paul Scherrer Institute (PSI-Plan). It is based on a superposition of pencil beams, which are scanned within the target volume by a magnetic sweeper and table movements. To vary the depth of the Bragg peak, range shifters are shifted into the beam line. An optimization program calculates the necessary weighting of each Bragg peak to achieve a homogenous dose within the complete target volume (10, 11). Definition of target volume and dose as well as dose constraints for the organ at risks were derived from each protocol and individually adapted. A relative biologic effectiveness factor for protons of 1.1 relative to 60Co was employed (cobalt Gy equivalent ⫽ CGE ⫽ Proton Gy ⫻ 1.1). All plans were normalized to the mean dose of the planning target volume. Since 2004, intensity-modulated proton therapy (IMPT) has been administered at the Paul Scherrer Institute for selected patients, distributing several individually inhomogeneous fields in analogous manner to intensity modulation of photons (12). The source of high-energy protons at Paul Scherrer Institute is a research cyclotron predominately used for physics research. Con-
Spot-scanning proton therapy for soft tissue sarcoma in childhood
sequently, the beam is available for PT approximately 8 months a year, and then for only 4 days each week. Since 2004, documentation of radiation dose was performed according to the study on radiotherapy-associated late effects in childhood and adolescence (RISK) for all children and subsequently collected at the study center in Münster.
Sedation In children younger than 4 years of age, all planning and treatment procedures were performed in deep propofol sedation, because these children were too young for full cooperation and deliberate immobility. Sedations were performed by a team of pediatric anesthesiologists. Sedation was introduced with midazolam and propofol and maintained with continuous propofol infusion with spontaneous ventilation. Children were continuously monitored during and after sedation until they were again awake and able to walk.
Statistical considerations The data of children below 21 years of age with soft tissue tumors, as diagnosed by the institutional pathologists and treated at the Paul Scherrer Institute, served as the base for statistical evaluation. Evaluation of the extent of disease at diagnosis was performed by each treating center. Clinical data were collected and monitored by the Division of Radiation Medicine, Paul Scherrer Institute, Villigen, Switzerland. Documentation of radiotherapy was also performed at the Paul Scherrer Institute. The follow-up period was calculated from the date of biopsy to the last patient contact or last event. The length of survival was calculated from the date of first biopsy. Terminal events were defined as the date of death from any cause (overall survival) or date of progression or relapse (progression-free survival). For all patients alive without events, length of survival was censored for the statistical analysis at the last date of documented contact with the patient. Data for patients who died without evidence of progression were censored. Local disease control was defined as no evidence of recurrence or progression of the primary tumor. The Kaplan-Meier method was used to estimate overall survival. All analysis was performed by SPSS (version 13.0; SPSS Inc., Chicago, IL).
●
B. TIMMERMANN et al.
499
initial tumor size exceeded 5 cm in 8 children (50%). One child had metastases in lung and lymph nodes before PT. Pretreatment All children underwent at least one biopsy for histopathologic verification of the diagnosis. Postsurgical stages according to the IRS grouping system were Group I in 1 child (indication for radiotherapy was considered because of second local recurrence after third surgery), Group II in 2 children, Group III in 12, and Group IV in 1 child. Fourteen children received chemotherapy before and during PT; 12 were treated according to standardized treatment protocols (Table 1). In 2 children no chemotherapy was administered (malignant peripheral nerve sheath tumor, desmoid). Twelve children presented with macroscopical tumor residue when starting the PT. The interval between first diagnoses and PT was 2.4 to 18.6 months (median, 5.1 months). In 2 children the interval exceeded 10 months, both treated after local recurrence of disease. Proton beam therapy At the time of PT, the median age of the children was 3.7 years (range, 1.4 –14.1 years). In 9 children between the age of 1.4 and 4.2 years, all planning and treatment procedures were performed under deep sedation because of young age and insufficient cooperation. In 14 children, the PT was the only radiotherapy modality. In 2 children 10.0 and 10.8 CGE, respectively were added with photons for treatment completion after the proton beam period ended. The median total dose of PT was 50.0 CGE (range, 46 – 61.2). The median total duration of proton treatment was 42.5 days (range, 38 –50 days) giving 1.8 or 2.0 CGE per fraction, 4 times per week. The initial tumor volume was included for the clinical target volume in 15 children, and in 1 the tumor residue only was included. For the planning target volume, 15-mm safety margin was added (range, 10 –20 mm). However, to spare critical structures, it was necessary to compromise safety margin during treatment in some cases. In 7 children, the clinical target volume was restricted to the
RESULTS Patient population Between 1997 and 2005, 49 children and adolescents under the age of 21 years were treated at the Paul Scherrer Institute with PT for various diagnoses at various sites. We report on 16 of them treated for soft tissue tumors. These children were referred from 10 different hospitals in Germany, Switzerland, and The Netherlands. Age at time of first diagnosis ranged from 0.9 to 12.1 years (median, 3.3 years). Seven girls and 9 boys were included. Tumor histology was embryonal rhabdomyosarcoma in 10 patients and alveolar rhabdomyosarcoma, unclassified rhabdomyosarcoma, synovial sarcoma, undifferentiated sarcoma, malignant peripheral nerve sheath tumor, and desmoid tumor in 1 patient, respectively. The tumor site was parameningeal in 7, orbital in 4, paraspinal in 3, and head and neck and prostate in 1 patient, respectively. The
Fig. 1. Example of the dose distribution for “conventional” proton therapy of a parameningeal rhabdomyosarcoma in a 13-year-old girl. Thin green line: planning target volume.
500
I. J. Radiation Oncology
●
Biology
●
Physics
Volume 67, Number 2, 2007
collected. The patients’ characteristics and outcome are summarized in Table 3 (Table 3). Response In 12 children tumor residue was radiologically measurable before PT. Therefore, in 12 children response to PT could be evaluated. Results of the first imaging after PT were complete remission in 3, partial remission in 3, and stable disease in 6 patients. No progressive disease was observed during PT. Four children underwent a second surgery procedure to evaluate tumor residue after PT; in none of those was vital tumor tissue detected.
Fig. 2. Example of an intensity-modulated proton therapy plan with sparing of the lacrimal gland for a 12-year-old boy with an orbital rhabdomyosarcoma initially infiltrating the surrounding soft tissue.
residual tumor after 46 CGE (range, 36 –50). The volume of the planning target volume encompassed between 52.3 and 1224.4 cm3 (median, 234.8). Between one and three different treatment plans were calculated and irradiated per each child during PT (mean, 2.1) (Fig. 1). In 3 children PT was delivered with IMPT (in 2 for the entire treatment course, and in 1 in part of the series) (Fig. 2). Acute and late toxicity Acute side effects during treatment were mild (Table 2). Grade 3 or 4 toxicity occurred only for the bone marrow when parallel chemotherapy was applied. In 1 girl with a huge parameningeal tumor, severe lethargy occurred and resolved within 6 weeks after PT. Additionally, recurrent otitis and mastoiditis was observed and led to surgical intervention. In 2 children some reddening and swelling of the lower eyelid persisted for 8 weeks after orbital treatment. Five surviving children were observed for more than 1 year. For them information about late effects could be
Local control and survival After a median follow-up of 18.6 months (range, 4.3– 70.8 months), 12 of the 16 patients have maintained disease control (75%). Four children developed local failures. Local failures were observed in 50% of nonrhabdomyosarcoma-like tumors (2/4), but only in 16.7% of rhabdomyosarcoma-like tumors (2/12). Three recurrences were located within the radiation field and one at the field border. The failures occurred after 11.2, 11.7, 14.5, and 36.2 months (median time to recurrence, 13.4 months). Applied total doses for the children experiencing recurrences were 50.0, 50.4, 54.0, and 57.6 CGE. In the nonrhabdomyosarcoma group, both recurrences occurred in the patients receiving less than 60 CGE (50.4 and 54.0 CGE), whereas the nonrhabdomyosarcoma tumors receiving 60.0 and 61.2 CGE were both locally controlled. All 4 children who developed local recurrences died after a median time of 18.2 months. Estimated progression-free survival rates after 1 and 2 years were 81.8% and 71.6%, respectively. Estimated overall survival rates after 1 and 2 years were 90.9% and 69.3%, respectively (Figs. 3 and 4). DISCUSSION In soft tissue sarcoma, a multimodal approach is generally used, consisting of systemic and local treatment. For local treatment, a complete resection is preferred. However, complete surgery is frequently not possible
Table 2. Acute toxicity related to proton therapy Critical organ
Patients evaluable (n)
Grade 0
Grade I
Grade II
Grade III
Grade IV
Karnofsky Bone marrow Skin Mucosa GI tract GU tract CNS Eye Ear
16 13 16 13 3 2 13 12 12
13 — 1 2 3 2 13 5 11
3 1 11 5 — — — 5 1
— 5 4 6 — — — 2 —
— 4 — — — — — — —
— 3 — — — — — — —
Abbreviations: GI ⫽ gastrointestinal; GU ⫽ genitourinary; CNS ⫽ central nervous system.
Parameter/ Case
Age (years), gender
1 2 3
10.7, F 7.2, M 12.1, M
4
Interval to RT (mo)
RT dose (CGE)
Follow-up time (mo)
Time to LF (mo)
Synovial S RME Desmoid
Paraspinal Parameningeal Paraspinal
II IV I
3.4 3.8 14.6
50.4 57.6 60
70.8 16.6 51.9
36.2 11.7 —
9.2, F
MPNST
Paraspinal
II
5.4
61.2
35.2
—
5
10.8, M
RME
Parameningeal
III
3.4
54
32.4
—
6
1.4, M
RMA
Orbital
III
8.6
54
26.0
—
7 8 9 10 11 12 13 14 15 16
2.8, F 0.9, M 1.9, F 2.6, F 11.9, M 1.2, M 2.5, M 1.4, M 13.9, F 3.8, F
Undiff. S RME RMS.unclass RME RME RME RME RME RME RME
Parameningeal Prostate Parapharyngeal Parameningeal Orbital Orbital Parameningeal Orbital Parameningeal Parameningeal
III III III III III III III III III III
5.2 5.9 5.8 4.6 3.1 18.6 5.1 5.9 2.4 4.1
54 52 50 50 50 50 50 46 52 50
20.0 19.5 11.4 12.3 9.1 23.8 8.3 9.4 4.5 6.9
14.5 — 11.2 — — — — — — —
Outcome Dead Dead Alive, skin: hyperpigmentation! Neurology: normal Alive, skin: hyperpigmentation! Neurology: normal Alive, caries: hearing, vision, and neurology: normal Alive, mild myopia, orbital asymmetry! Dead Alive, no sequelae Dead Alive* Alive* Alive* Alive* Alive* Alive* Alive*
Abbreviations: RT ⫽ radiotherapy; IRS ⫽ Intergroup Rhabdomyosarcoma Study; CGE ⫽ cobalt Gray equivalent; LF ⫽ local failure; F/M ⫽ female/male; MPNST ⫽ malignant peripheral nerve sheath tumor; RME ⫽ embryonal rhabdomyosarcoma; RMA ⫽ alveolar rhabdomyosarcoma; RMS ⫽ rhabdomyosarcoma; S ⫽ sarcoma; LC ⫽ local control. * Follow-up too short to evaluate late sequelae. † At the time of diagnosis.
B. TIMMERMANN et al.
Postsurgical grouping (IRS)
●
Tumor site
Tumor histology
Spot-scanning proton therapy for soft tissue sarcoma in childhood
Table 3. Characteristics of all 16 children treated with spot-scanning proton therapy †
501
502
I. J. Radiation Oncology
●
Biology
●
Physics
1,0
probability
0,8
0,6
0,4
0,2
0,0 0,00
1,00
2,00
3,00
4,00
year
Fig. 3. Kaplan-Meier plot of the estimated progression-free survival rates.
without risking lifelong impairment of the children. In these cases, local radiotherapy is administered to achieve local control. Outcome in rhabdomyosarcomas as well as other soft tissue sarcomas is well described. The German CWS trial reported on nearly 200 rhabdomyosarcoma and rhabdomyosarcoma-like patients IRS Group II with or without radiotherapy and found 5-year event-free survival rates of 76% and 58%, respectively (13). The American IRS group published results of 559 children irradiated for IRS Group III rhabdomyosarcoma. Estimated 5-year event-free survival was 73% and overall survival 77% (8). However, the majority of the children were above 5 years of age and 65% of the children had embryonal rhabdomyosarcoma. Information concerning the outcome in pediatric localized nonrhabdomyosarcoma soft tissue sarcomas without resection is rare. However, there are some data reporting recurrence rates of over 30% and overall survival rates of less than 60% after 5 years (14). Ferrari et al. reported from the European Pediatric Soft Tissue Sarcoma Study Group an event-free survival rate of 26.2% for high-risk adult-type soft tissue sarcoma, with the minority receiving radiotherapy (15). In another analysis of the same group, patients with initially unresectable disease and large tumors were reported to be at high risk for treatment failure (16). In our series, four nonrhabdomyosarcoma soft tissue sarcomas were included. It is interesting that the patients receiving more than 60 CGE were controlled, whereas both patients receiving less than 60 CGE have died, supporting the administration of higher doses in nonrhabdomyosarcoma soft tissue sarcomas. However, both surviving patients were prescribed the higher doses of PT because neither had any previous or concomitant chemotherapy. The observation time in our study is very short. Still, estimated 2-year progression-free survival was 71.6% in our group and overall survival was 69.3%. However, the median
Volume 67, Number 2, 2007
age in our patient group was extremely young, at 3.3 years. In 11 children (68.7%), the tumor site was unfavorable (parameningeal, trunk, or prostate). In 3 of 4 locally recurrent sarcomas, the histology was unfavorable (synovial sarcoma in 1 and unclassified in 2). In the child with embryonal rhabdomyosarcoma experiencing recurrence, the tumor was metastasized before PT. Therefore, all failing children were high-risk patients. Additionally, the total doses applied at our institute to all children were derived from cooperative protocols dealing mainly with conventional photon therapy, and no dose escalation has been performed so far at our institute. Therefore, it is not surprising that the local control rates we have achieved are similar to that expected from conventional photon therapy. Radiotherapy was found to achieve local control in the majority of children with soft tissue sarcoma when complete surgery was not possible (8, 13, 17–20). However, treatment of the subgroup of children with soft tissue sarcoma requiring radiotherapy is challenging. Predominantly unfavorable tumor sites such as prostate or parameningeal area are affected and at high risk for treatment sequelae following any local therapy. In these localizations, radiotherapy therefore is very likely associated with major complications. In our study all children had soft tissue sarcoma located near the base of skull or in the trunk. The irradiation of the parameningeal site is known to cause severe long-term problems, including cataracts, growth inhibition, and facial asymmetry as well as impaired dentition and hearing (21). However, also in “favorable” sites such as orbit, the risk for treatment-related sequelae is very high. Reports are available describing in detail the damage of orbital bone, lens, chiasm, optical nerve, lacrimal gland, or the pituitary gland (22). Unfortunately, very young children comprise nearly 50% of all soft tissue sarcoma patients and have an increased risk of irradiation damage because of their immature, growing tissues. Therefore, it is important to search for
Fig. 4. Kaplan-Meier plot of the estimated overall survival rates.
Spot-scanning proton therapy for soft tissue sarcoma in childhood
new techniques that can potentially reduce treatment sequelae for pediatric soft tissue sarcoma. Proton beams are attractive because of their excellent dose distribution. The steep dose fall-off beyond the target differs considerably from any X-ray irradiation. Protons have the ability to confine the high-dose region to the target volume while minimizing the dose to the surrounding tissues considerably. This was already shown with dose plan comparisons of photons with protons in brain tumors, retinoblastomas, and orbital tumors (23–26). Also potential reduction of the risk for secondary cancer after proton beam treatment as compared with after photon treatment is assumed (27). Therefore, there is general agreement that protons will play a major role in treating childhood cancer when more widely accessible (28, 29). However, there is a lack of clinical data evaluating the acute and late toxicity of proton treatment in children. There are some promising reports about clinical results in low-grade astrocytomas and chordomas or chondrosarcomas (30, 31). However, any aggressive local treatment will be associated with side effects. Even if the surrounding tissue is being spared, the target volume receives full dose and is at risk for toxicity. Additionally, any conformal modern treatment will not be able to avoid growth asymmetry as we are no longer treating two lateral fields administering symmetrical dose. Therefore, the price of preserving the function of selected organs might worsen cosmetic results in some children. From our cohort, we can report an excellent acute tolerance of spot-scanning PT in the young age group with soft tissue sarcoma. The long-term effects are difficult to assess because of the short observation time in most of our patients. The preliminary data, however, suggest satisfying results. Clearly, prospective standardized evaluation of long-term side effects and quality of life will be needed to analyze the cost/benefit ratio of PT. It is an open question whether PT will be able to increase local control rates in soft tissue sarcoma. Different studies failed to demonstrate a dose–response relationship for local control in combined radiotherapy and chemotherapy in rhabdomyosarcoma (8, 32). However, in adult type soft tissue sarcoma, a dose increment is likely to be beneficial. A further major advantage of protons is to be ex-
●
B. TIMMERMANN et al.
503
pected from the ability to provide adequate coverage of the target volume while reducing the side effects in critical tumor sites. Currently, not only protons but also IMRT is under evaluation for improving conformity of treatment, allowing better sparing of critical organs near the target. Similar to protons, clinical data are still limited. Studies report on advantages for sparing the spinal cord or salivary glands in head-and-neck cancer (33). Also, very promising early results have been reported with rhabdomyosarcoma of the head and neck (34). Early data suggest benefit for the posterior fossa boost in brain tumor patients regarding ototoxicity (35). However, the higher number of fields needed with IMRT compared with spot scanning PT (and even IMPT) distributes low and median dose to a considerable volume around the target, carrying an increased risk of secondary cancer (36). Therefore, IMRT requires careful evaluation, especially with regard to the pediatric population, before widespread implementation. Additionally, spot-scanning PT has a significantly reduced neutron component and a consequently lowered risk of inducing secondary cancer compared with both IMRT and other proton machines (36). Therefore, the experiences of the Paul Scherrer Institute are of special interest considering it is currently the only existing spot-scanning facility worldwide. However, long-term follow-up is necessary to determine the clinical impact of protons as compared with IMRT or three-dimensional conformal radiotherapy regarding radiation effects. At the Paul Scherrer Institute the expansion of the proton facility is ongoing. A dedicated medical facility is being built and will start operation in 2007. It will provide uninterrupted beam throughout the year, and also allow for normal 5 day-per-week fractionation regimens using 1.6 to 1.8 Gy fractions as recommended in most of the pediatric protocols for optimal tissue sparing. Pediatric patients will be preferred, as they are considered the individuals potentially benefiting most from PT. We began performing a prospective evaluation of side effects and quality-of-life investigation in 2004 and are looking forward to long-term results. Additionally, matched-pair analyses for subgroups, i.e., orbital sarcomas, treated with either protons or photons are planned.
REFERENCES 1. Suit HD, Willett CG. Radiation therapy of sarcomas of the soft tissues. Cancer Treat Res 1991;56:61–74. 2. Kepka L, DeLaney TF, Suit HD, et al. Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2005;63:852– 859. 3. Flamant F, Rodary C, Rey A, et al. Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence. Results of the second study of the International Society of Paediatric Oncology: MMT84. Eur J Cancer 1998;34:1050 –1062. 4. Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: Third study of the International Society of Paediatric Oncology–
5.
6. 7.
8.
SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 2005;23:2618 –2628. Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomyosarcoma: Survival and late effects of treatment— results of an international workshop. J Clin Oncol 2001;19: 197–204. Saran F. New technology for radiotherapy in paediatric oncology. Eur J Cancer 2004;40:2091–2105. DeLaney TF, Trofimov AV, Engelsman M, et al. Advancedtechnology radiation therapy in the management of bone and soft tissue sarcomas. Cancer Control 2005;12:27–35. Donaldson SS, Meza J, Breneman JC, et al. Results from the
504
9.
10. 11.
12. 13. 14.
15.
16.
17. 18.
19.
20.
21. 22.
I. J. Radiation Oncology
●
Biology
●
Physics
IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma: A report from the IRSG. Int J Radiat Oncol Biol Phys 2001;51:718 –728. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. Lomax AJ, Bohringer T, Bolsi A, et al. Treatment planning and verification of proton therapy using spot scanning: Initial experiences. Med Phys 2004;31:3150 –3157. Pedroni E, Scheib S, Bohringer T, et al. Experimental characterization and physical modelling of the dose distribution of scanned proton pencil beams. Phys Med Biol 2005;50:541– 561. Lomax A. Intensity modulation methods for proton radiotherapy. Phys Med Biol 1999;44:185–205. Schuck A, Mattke AC, Schmidt B, et al. Group II rhabdomyosarcoma and rhabdomyosarcomalike tumors: Is radiotherapy necessary? J Clin Oncol 2004;22:143–149. Spunt SL, Hill DA, Motosue AM, et al. Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 2002; 20:3225–3235. Ferrari A, Brecht IB, Koscielniak E, et al. The role of adjuvant chemotherapy in children and adolescents with surgically resected, high-risk adult-type soft tissue sarcomas. Pediatr Blood Cancer 2005;45:128 –134. Ferrari A, Casanova M, Collini P, et al. Adult-type soft tissue sarcomas in pediatric-age patients: Experience at the Istituto Nazionale Tumori in Milan. J Clin Oncol 2005;23:4021– 4030. Donaldson SS, Castro JR, Wilbur JR, et al. Rhabdomyosarcoma of head and neck in children: Combination treatment by surgery, irradiation, and chemotherapy. Cancer 1973;31:26 –35. Wolden SL, Anderson JR, Crist WM, et al. Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 1999;17:3468 – 3475. Tefft M, Lindberg RD, Gehan EA. Radiation therapy combined with systemic chemotherapy of rhabdomyosarcoma in children: Local control in patients enrolled in the Intergroup Rhabdomyosarcoma Study. Natl Cancer Inst Monogr 1981; 56:69 –74. Wharam MD, Hanfelt JJ, Tefft MC, et al. Radiation therapy for rhabdomyosarcoma: Local failure risk for Clinical Group III patients on Intergroup Rhabdomyosarcoma Study II. Int J Radiat Oncol Biol Phys 1997;38:797– 804. Wharam MD, Jr. Rhabdomyosarcoma of parameningeal sites. Semin Radiat Oncol 1997;7:212–216. Heyn R, Ragab A, Raney RB Jr., et al. Late effects of therapy
Volume 67, Number 2, 2007
23.
24.
25.
26.
27.
28. 29. 30. 31. 32.
33. 34. 35.
36.
in orbital rhabdomyosarcoma in children: A report from the Intergroup Rhabdomyosarcoma Study. Cancer 1986;57:1738 – 1743. Yock T, Schneider R, Friedmann A, et al. Proton radiotherapy for orbital rhabdomyosarcoma: Clinical outcome and a dosimetric comparison with photons. Int J Radiat Oncol Biol Phys 2005;63:1161–1168. Miralbell R, Cella L, Weber D, et al. Optimizing radiotherapy of orbital and paraorbital tumors: Intensity-modulated X-ray beams vs. intensity-modulated proton beams. Int J Radiat Oncol Biol Phys 2000;47:1111–1119. Yuh GE, Loredo LN, Yonemoto LT, et al. Reducing toxicity from craniospinal irradiation: Using proton beams to treat medulloblastoma in young children. Cancer J 2004;10:386 – 390. St. Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 2004;58:727–734. Miralbell R, Lomax A, Cella L, et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002;54:824 – 829. Wilson VC, McDonough J, Tochner Z. Proton beam irradiation in pediatric oncology: An overview. J Pediatr Hematol Oncol 2005;27:444 – 448. Hug EB, Slater JD. Proton radiation therapy for pediatric malignancies: Status report. Strahlenther Onkol 1999;175 (Suppl. 2):89 –91. Hug EB, Muenter MW, Archambeau JO, et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol 2002;178:10 –17. Hug EB, Sweeney RA, Nurre PM, et al. Proton radiotherapy in management of pediatric base of skull tumors. Int J Radiat Oncol Biol Phys 2002;52:1017–1024. Regine WF, Fontanesi J, Kumar P, et al. Local tumor control in rhabdomyosarcoma following low-dose irradiation: Comparison of Group II and select Group III patients. Int J Radiat Oncol Biol Phys 1995;31:485– 491. Eisbruch A. Clinical aspects of IMRT for head-and-neck cancer. Med Dosim 2002;27:99 –104. Wolden SL, Wexler LH, Kraus DH, et al. Intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 2005;61:1432–1438. Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52:599 – 605. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006;65:1–7.
doi:10.1016/j.ijrobp.2006.08.053
CLINICAL INVESTIGATION
Sarcoma
SPOT-SCANNING PROTON THERAPY FOR MALIGNANT SOFT TISSUE TUMORS IN CHILDHOOD: FIRST EXPERIENCES AT THE PAUL SCHERRER INSTITUTE BEATE TIMMERMANN, M.D.,* ANDREAS SCHUCK, M.D.,† FELIX NIGGLI, M.D.,‡ MARKUS WEISS, M.D.,§ ANTONY JONATHAN LOMAX, PH.D.,* EROS PEDRONI, PH.D.,* ADOLF CORAY, PH.D.,* MARTIN JERMANN, PH.D.,* HANS PETER RUTZ, M.D.,* AND GUDRUN GOITEIN, M.D.* *Division of Radiation Medicine, Proton Therapy, Paul Scherrer Institut, Villigen, Switzerland; †Department of Radiation Oncology, University of Münster, Münster, Germany; ‡Department of Paediatric Oncology, University Children’s Hospital, Zürich, Switzerland; §Department of Anaesthesia, University Children’s Hospital, Zürich, Switzerland Purpose: Radiotherapy plays a major role in the treatment strategy of childhood sarcomas. Consequences of treatment are likely to affect the survivor’s quality of life significantly. We investigated the feasibility of spot-scanning proton therapy (PT) for soft tissue tumors in childhood. Methods and Materials: Sixteen children with soft tissue sarcomas were included. Median age at PT was 3.3 years. In 10 children the tumor histology was embryonal rhabdomyosarcoma. All tumors were located in the head or neck, parameningeal, or paraspinal, or pelvic region. In the majority of children, the tumor was initially unresectable (Intergroup Rhabdomyosarcoma Study [IRS] Group III in 75%). In 50% of children the tumors exceeded 5 cm. Fourteen children had chemotherapy before and during PT. Median total dose of radiotherapy was 50 cobalt Gray equivalent (CGE). All 16 children were treated with spot-scanning proton therapy at the Paul Scherrer Institute, and in 3 children the PT was intensity-modulated (IMPT). Results: After median follow-up of 1.5 years, local control was achieved in 12 children. Four children failed locally, 1 at the border of the radiation field and 3 within the field. All 4 children died of tumor recurrence. All 4 showed unfavorable characteristic either of site or histopathology of the tumor. Acute toxicity was low, with Grade 3 or 4 side effects according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria occurring in the bone marrow only. Conclusions: Proton therapy was feasible and well tolerated. Early local control rates are comparable to those being achieved after conventional radiotherapy. For investigations on late effect, longer follow-up is needed. © 2007 Elsevier Inc. Sarcomas, Proton therapy, Irradiation, Treatment, Childhood.
sarcomas are treated with radiotherapy as compared with approximately 50% in the German and European Cooperative Childhood Soft Tissue Sarcoma trial (CWS) protocols and even less with approximately 30 – 40% in the International Society of Pediatric Oncology–Malignant Mesenchymal Tumor (SIOP-MMT) trials (5). Most commonly, radiotherapy is given by external beam photons, usually with three-dimensional conformal techniques. In the management of childhood tumors, special treatment techniques such as intensity-modulated radiotherapy (IMRT) and, in selected cases, brachytherapy or intraoperative electron treatment have also been introduced (6). Additionally, due to the unique characteristics of proton beam, an increasing proportion of children are treated with proton therapy (PT) (7). The selection of the appropriate mode of radiotherapy for
INTRODUCTION For patients with sarcomas, the treatment regimen includes a multidisciplinary strategy of combined surgery, chemotherapy, and radiotherapy depending specifically on tumor type, site of the primary tumor, and stage of disease (1, 2). In general, the strategy is individually adapted to achieve maximal chance for cure while trying to minimize the risk of late treatment sequelae. Radiotherapy plays a dominant role in those tumors, which cannot be surgically removed without leading to major impairment (2). However, the knowledge of severe late effects of radiotherapy has led to significant differences in treatment philosophies. For many years, European pediatric oncologists have attempted to avoid any irradiation by implementing intensive chemotherapy and second surgery (3, 4). It is estimated that in the American protocols approximately 70% of all children with Reprint requests to: Beate Timmermann, M.D., Division of Radiation Medicine, Paul Scherrer Institute, CH-5232 VilligenPSI, Villigen, Switzerland. Tel: (⫹41) 56-3103695; Fax: (⫹41) 56-3103515; E-mail: [email protected]
Conflict of interest: none. Received July 5, 2006, and in revised form Aug 18, 2006. Accepted for publication Aug 18, 2006. 497
498
I. J. Radiation Oncology
●
Biology
●
Physics
each individual child will be an important objective in the near future. Thus, more information about the spectrum of advantages as well as risks of the available radiotherapy techniques is needed. METHODS AND MATERIALS Since 1995, 262 patients have been treated with spot-scanning protons at the Paul Scherrer Institute. For principal patient selection, priority was given to pediatric patients and to diagnoses that require high cumulative doses for cure, i.e., chordoma and lowgrade chondrosarcoma. In 1997 the first child was treated. Herein we present an analysis on the subgroup of patients treated for soft tissue tumors in childhood. A signed informed consent was mandatory in all patients.
Patient selection Patients under 21 years of age with malignant soft tissue tumors in the region of head and neck, spine, and pelvis were included in this analysis. Since 2004 the decision for PT in children has been made by an interdisciplinary discussion of the reference radiotherapist of the German and European Cooperative Childhood Soft Tissue Sarcoma trial (CWS). Diagnoses were made by the institutional pathologist and in the majority of cases confirmed by a review pathologist. Patients were referred from several hospitals in different European countries.
Evaluation of disease In all children, initial images (magnetic resonance imaging or computed tomography scan) and pre-PT images were available. The staging was performed according to the specific protocol in which the respective child was treated. Retrospectively all patients were assigned to the respective Intergroup Rhabdomyosarcoma Study (IRS) group, according to the criteria of the IRS SurgicalPathologic Grouping Classification (8).
Evaluation of toxicity No prospective standardized evaluation of toxicity and quality of life was performed during the first years. Since 2003, radiationinduced acute and late toxicity was evaluated according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria for general status, bone marrow, skin, mucosa, salivary glands, pharynx/esophagus, larynx, lung, heart, upper gastrointestinal tract, bone, joints, central nervous system, spinal cord/peripheral nerves, ears, and eyes (9). The evaluation of toxicity was performed by the treating radiation oncologists. In patients treated before 2003, toxicity was scored retrospectively, according to RTOG/EORTC criteria. In 2004, a selfrating quality of life questionnaire for childhood cancer survivors (PEDQUOL) was introduced, completed by each patient and their parents and sent to the study center in Düsseldorf, Germany.
Pretreatment Surgery. In all children at least one biopsy was performed to ensure diagnosis. The extent of surgical procedure (complete or incomplete resection) was evaluated from the operation report and the postoperative imaging. Chemotherapy. Chemotherapy was administered according to the specific protocol in which the child was treated (Table 1). The
Volume 67, Number 2, 2007
Table 1. Applied treatment protocols and chemotherapeutic agents in the children receiving proton therapy Trial
Patients (n)
Agents
CWS2002
8
MMT-95 (3)
5
COG-D9803
1
No chemotherapy
2
Ifosfamide, actinomycin D, vincristine adriamycin* Ifosfamide, actinomycin D, vincristine, Epirubicin*, etoposide*, carboplatin* Vincristine, adriamycin, cyclophosphamide, topotecan† —
Abbreviations: CWS2002 ⫽ German and European Cooperative Childhood Soft Tissue Sarcoma trial; MMT-95 ⫽ Malignant Mesenchymal Tumor 1995 trial; COG-D9803 ⫽ Children’s Oncology Group Protocol-D9803. * For high-risk patients. † For experimental arm.
children were treated according to the MMT-95 protocol or CWS2002 protocol or Children’s Oncology Group (COG) protocol D9803. For some diagnoses no chemotherapy was recommended at all.
Proton beam therapy Immobilization aids were created individually for all patients to avoid patient motion and to achieve reproducible positioning of the patient. Patient positioning was checked before every fraction by generating one lateral and one frontal computed tomography scout view. Anatomic reference points were compared with the same points in the planning computed tomography. Planning computed tomography was the base for planning procedures in all patients. In case of setup deviation, the position of the patient was corrected by table movement. All patients were treated at the 360°-rotatable gantry at the Paul Scherrer Institute. The proton source at Paul Scherrer Institute is a sector cyclotron producing an intensive proton beam of 590 MeV. A small part is split from the main proton beam and degraded for medical application. The energy of the beam dedicated to medical application can be chosen between 85 and 270 MeV (mainly used are 138, 160, or 177 MeV, respectively). The energy of the beam can be chosen individually for each patient and for each field. Dose calculation for PT was calculated three-dimensionally using an algorithm developed at the Paul Scherrer Institute (PSI-Plan). It is based on a superposition of pencil beams, which are scanned within the target volume by a magnetic sweeper and table movements. To vary the depth of the Bragg peak, range shifters are shifted into the beam line. An optimization program calculates the necessary weighting of each Bragg peak to achieve a homogenous dose within the complete target volume (10, 11). Definition of target volume and dose as well as dose constraints for the organ at risks were derived from each protocol and individually adapted. A relative biologic effectiveness factor for protons of 1.1 relative to 60Co was employed (cobalt Gy equivalent ⫽ CGE ⫽ Proton Gy ⫻ 1.1). All plans were normalized to the mean dose of the planning target volume. Since 2004, intensity-modulated proton therapy (IMPT) has been administered at the Paul Scherrer Institute for selected patients, distributing several individually inhomogeneous fields in analogous manner to intensity modulation of photons (12). The source of high-energy protons at Paul Scherrer Institute is a research cyclotron predominately used for physics research. Con-
Spot-scanning proton therapy for soft tissue sarcoma in childhood
sequently, the beam is available for PT approximately 8 months a year, and then for only 4 days each week. Since 2004, documentation of radiation dose was performed according to the study on radiotherapy-associated late effects in childhood and adolescence (RISK) for all children and subsequently collected at the study center in Münster.
Sedation In children younger than 4 years of age, all planning and treatment procedures were performed in deep propofol sedation, because these children were too young for full cooperation and deliberate immobility. Sedations were performed by a team of pediatric anesthesiologists. Sedation was introduced with midazolam and propofol and maintained with continuous propofol infusion with spontaneous ventilation. Children were continuously monitored during and after sedation until they were again awake and able to walk.
Statistical considerations The data of children below 21 years of age with soft tissue tumors, as diagnosed by the institutional pathologists and treated at the Paul Scherrer Institute, served as the base for statistical evaluation. Evaluation of the extent of disease at diagnosis was performed by each treating center. Clinical data were collected and monitored by the Division of Radiation Medicine, Paul Scherrer Institute, Villigen, Switzerland. Documentation of radiotherapy was also performed at the Paul Scherrer Institute. The follow-up period was calculated from the date of biopsy to the last patient contact or last event. The length of survival was calculated from the date of first biopsy. Terminal events were defined as the date of death from any cause (overall survival) or date of progression or relapse (progression-free survival). For all patients alive without events, length of survival was censored for the statistical analysis at the last date of documented contact with the patient. Data for patients who died without evidence of progression were censored. Local disease control was defined as no evidence of recurrence or progression of the primary tumor. The Kaplan-Meier method was used to estimate overall survival. All analysis was performed by SPSS (version 13.0; SPSS Inc., Chicago, IL).
●
B. TIMMERMANN et al.
499
initial tumor size exceeded 5 cm in 8 children (50%). One child had metastases in lung and lymph nodes before PT. Pretreatment All children underwent at least one biopsy for histopathologic verification of the diagnosis. Postsurgical stages according to the IRS grouping system were Group I in 1 child (indication for radiotherapy was considered because of second local recurrence after third surgery), Group II in 2 children, Group III in 12, and Group IV in 1 child. Fourteen children received chemotherapy before and during PT; 12 were treated according to standardized treatment protocols (Table 1). In 2 children no chemotherapy was administered (malignant peripheral nerve sheath tumor, desmoid). Twelve children presented with macroscopical tumor residue when starting the PT. The interval between first diagnoses and PT was 2.4 to 18.6 months (median, 5.1 months). In 2 children the interval exceeded 10 months, both treated after local recurrence of disease. Proton beam therapy At the time of PT, the median age of the children was 3.7 years (range, 1.4 –14.1 years). In 9 children between the age of 1.4 and 4.2 years, all planning and treatment procedures were performed under deep sedation because of young age and insufficient cooperation. In 14 children, the PT was the only radiotherapy modality. In 2 children 10.0 and 10.8 CGE, respectively were added with photons for treatment completion after the proton beam period ended. The median total dose of PT was 50.0 CGE (range, 46 – 61.2). The median total duration of proton treatment was 42.5 days (range, 38 –50 days) giving 1.8 or 2.0 CGE per fraction, 4 times per week. The initial tumor volume was included for the clinical target volume in 15 children, and in 1 the tumor residue only was included. For the planning target volume, 15-mm safety margin was added (range, 10 –20 mm). However, to spare critical structures, it was necessary to compromise safety margin during treatment in some cases. In 7 children, the clinical target volume was restricted to the
RESULTS Patient population Between 1997 and 2005, 49 children and adolescents under the age of 21 years were treated at the Paul Scherrer Institute with PT for various diagnoses at various sites. We report on 16 of them treated for soft tissue tumors. These children were referred from 10 different hospitals in Germany, Switzerland, and The Netherlands. Age at time of first diagnosis ranged from 0.9 to 12.1 years (median, 3.3 years). Seven girls and 9 boys were included. Tumor histology was embryonal rhabdomyosarcoma in 10 patients and alveolar rhabdomyosarcoma, unclassified rhabdomyosarcoma, synovial sarcoma, undifferentiated sarcoma, malignant peripheral nerve sheath tumor, and desmoid tumor in 1 patient, respectively. The tumor site was parameningeal in 7, orbital in 4, paraspinal in 3, and head and neck and prostate in 1 patient, respectively. The
Fig. 1. Example of the dose distribution for “conventional” proton therapy of a parameningeal rhabdomyosarcoma in a 13-year-old girl. Thin green line: planning target volume.
500
I. J. Radiation Oncology
●
Biology
●
Physics
Volume 67, Number 2, 2007
collected. The patients’ characteristics and outcome are summarized in Table 3 (Table 3). Response In 12 children tumor residue was radiologically measurable before PT. Therefore, in 12 children response to PT could be evaluated. Results of the first imaging after PT were complete remission in 3, partial remission in 3, and stable disease in 6 patients. No progressive disease was observed during PT. Four children underwent a second surgery procedure to evaluate tumor residue after PT; in none of those was vital tumor tissue detected.
Fig. 2. Example of an intensity-modulated proton therapy plan with sparing of the lacrimal gland for a 12-year-old boy with an orbital rhabdomyosarcoma initially infiltrating the surrounding soft tissue.
residual tumor after 46 CGE (range, 36 –50). The volume of the planning target volume encompassed between 52.3 and 1224.4 cm3 (median, 234.8). Between one and three different treatment plans were calculated and irradiated per each child during PT (mean, 2.1) (Fig. 1). In 3 children PT was delivered with IMPT (in 2 for the entire treatment course, and in 1 in part of the series) (Fig. 2). Acute and late toxicity Acute side effects during treatment were mild (Table 2). Grade 3 or 4 toxicity occurred only for the bone marrow when parallel chemotherapy was applied. In 1 girl with a huge parameningeal tumor, severe lethargy occurred and resolved within 6 weeks after PT. Additionally, recurrent otitis and mastoiditis was observed and led to surgical intervention. In 2 children some reddening and swelling of the lower eyelid persisted for 8 weeks after orbital treatment. Five surviving children were observed for more than 1 year. For them information about late effects could be
Local control and survival After a median follow-up of 18.6 months (range, 4.3– 70.8 months), 12 of the 16 patients have maintained disease control (75%). Four children developed local failures. Local failures were observed in 50% of nonrhabdomyosarcoma-like tumors (2/4), but only in 16.7% of rhabdomyosarcoma-like tumors (2/12). Three recurrences were located within the radiation field and one at the field border. The failures occurred after 11.2, 11.7, 14.5, and 36.2 months (median time to recurrence, 13.4 months). Applied total doses for the children experiencing recurrences were 50.0, 50.4, 54.0, and 57.6 CGE. In the nonrhabdomyosarcoma group, both recurrences occurred in the patients receiving less than 60 CGE (50.4 and 54.0 CGE), whereas the nonrhabdomyosarcoma tumors receiving 60.0 and 61.2 CGE were both locally controlled. All 4 children who developed local recurrences died after a median time of 18.2 months. Estimated progression-free survival rates after 1 and 2 years were 81.8% and 71.6%, respectively. Estimated overall survival rates after 1 and 2 years were 90.9% and 69.3%, respectively (Figs. 3 and 4). DISCUSSION In soft tissue sarcoma, a multimodal approach is generally used, consisting of systemic and local treatment. For local treatment, a complete resection is preferred. However, complete surgery is frequently not possible
Table 2. Acute toxicity related to proton therapy Critical organ
Patients evaluable (n)
Grade 0
Grade I
Grade II
Grade III
Grade IV
Karnofsky Bone marrow Skin Mucosa GI tract GU tract CNS Eye Ear
16 13 16 13 3 2 13 12 12
13 — 1 2 3 2 13 5 11
3 1 11 5 — — — 5 1
— 5 4 6 — — — 2 —
— 4 — — — — — — —
— 3 — — — — — — —
Abbreviations: GI ⫽ gastrointestinal; GU ⫽ genitourinary; CNS ⫽ central nervous system.
Parameter/ Case
Age (years), gender
1 2 3
10.7, F 7.2, M 12.1, M
4
Interval to RT (mo)
RT dose (CGE)
Follow-up time (mo)
Time to LF (mo)
Synovial S RME Desmoid
Paraspinal Parameningeal Paraspinal
II IV I
3.4 3.8 14.6
50.4 57.6 60
70.8 16.6 51.9
36.2 11.7 —
9.2, F
MPNST
Paraspinal
II
5.4
61.2
35.2
—
5
10.8, M
RME
Parameningeal
III
3.4
54
32.4
—
6
1.4, M
RMA
Orbital
III
8.6
54
26.0
—
7 8 9 10 11 12 13 14 15 16
2.8, F 0.9, M 1.9, F 2.6, F 11.9, M 1.2, M 2.5, M 1.4, M 13.9, F 3.8, F
Undiff. S RME RMS.unclass RME RME RME RME RME RME RME
Parameningeal Prostate Parapharyngeal Parameningeal Orbital Orbital Parameningeal Orbital Parameningeal Parameningeal
III III III III III III III III III III
5.2 5.9 5.8 4.6 3.1 18.6 5.1 5.9 2.4 4.1
54 52 50 50 50 50 50 46 52 50
20.0 19.5 11.4 12.3 9.1 23.8 8.3 9.4 4.5 6.9
14.5 — 11.2 — — — — — — —
Outcome Dead Dead Alive, skin: hyperpigmentation! Neurology: normal Alive, skin: hyperpigmentation! Neurology: normal Alive, caries: hearing, vision, and neurology: normal Alive, mild myopia, orbital asymmetry! Dead Alive, no sequelae Dead Alive* Alive* Alive* Alive* Alive* Alive* Alive*
Abbreviations: RT ⫽ radiotherapy; IRS ⫽ Intergroup Rhabdomyosarcoma Study; CGE ⫽ cobalt Gray equivalent; LF ⫽ local failure; F/M ⫽ female/male; MPNST ⫽ malignant peripheral nerve sheath tumor; RME ⫽ embryonal rhabdomyosarcoma; RMA ⫽ alveolar rhabdomyosarcoma; RMS ⫽ rhabdomyosarcoma; S ⫽ sarcoma; LC ⫽ local control. * Follow-up too short to evaluate late sequelae. † At the time of diagnosis.
B. TIMMERMANN et al.
Postsurgical grouping (IRS)
●
Tumor site
Tumor histology
Spot-scanning proton therapy for soft tissue sarcoma in childhood
Table 3. Characteristics of all 16 children treated with spot-scanning proton therapy †
501
502
I. J. Radiation Oncology
●
Biology
●
Physics
1,0
probability
0,8
0,6
0,4
0,2
0,0 0,00
1,00
2,00
3,00
4,00
year
Fig. 3. Kaplan-Meier plot of the estimated progression-free survival rates.
without risking lifelong impairment of the children. In these cases, local radiotherapy is administered to achieve local control. Outcome in rhabdomyosarcomas as well as other soft tissue sarcomas is well described. The German CWS trial reported on nearly 200 rhabdomyosarcoma and rhabdomyosarcoma-like patients IRS Group II with or without radiotherapy and found 5-year event-free survival rates of 76% and 58%, respectively (13). The American IRS group published results of 559 children irradiated for IRS Group III rhabdomyosarcoma. Estimated 5-year event-free survival was 73% and overall survival 77% (8). However, the majority of the children were above 5 years of age and 65% of the children had embryonal rhabdomyosarcoma. Information concerning the outcome in pediatric localized nonrhabdomyosarcoma soft tissue sarcomas without resection is rare. However, there are some data reporting recurrence rates of over 30% and overall survival rates of less than 60% after 5 years (14). Ferrari et al. reported from the European Pediatric Soft Tissue Sarcoma Study Group an event-free survival rate of 26.2% for high-risk adult-type soft tissue sarcoma, with the minority receiving radiotherapy (15). In another analysis of the same group, patients with initially unresectable disease and large tumors were reported to be at high risk for treatment failure (16). In our series, four nonrhabdomyosarcoma soft tissue sarcomas were included. It is interesting that the patients receiving more than 60 CGE were controlled, whereas both patients receiving less than 60 CGE have died, supporting the administration of higher doses in nonrhabdomyosarcoma soft tissue sarcomas. However, both surviving patients were prescribed the higher doses of PT because neither had any previous or concomitant chemotherapy. The observation time in our study is very short. Still, estimated 2-year progression-free survival was 71.6% in our group and overall survival was 69.3%. However, the median
Volume 67, Number 2, 2007
age in our patient group was extremely young, at 3.3 years. In 11 children (68.7%), the tumor site was unfavorable (parameningeal, trunk, or prostate). In 3 of 4 locally recurrent sarcomas, the histology was unfavorable (synovial sarcoma in 1 and unclassified in 2). In the child with embryonal rhabdomyosarcoma experiencing recurrence, the tumor was metastasized before PT. Therefore, all failing children were high-risk patients. Additionally, the total doses applied at our institute to all children were derived from cooperative protocols dealing mainly with conventional photon therapy, and no dose escalation has been performed so far at our institute. Therefore, it is not surprising that the local control rates we have achieved are similar to that expected from conventional photon therapy. Radiotherapy was found to achieve local control in the majority of children with soft tissue sarcoma when complete surgery was not possible (8, 13, 17–20). However, treatment of the subgroup of children with soft tissue sarcoma requiring radiotherapy is challenging. Predominantly unfavorable tumor sites such as prostate or parameningeal area are affected and at high risk for treatment sequelae following any local therapy. In these localizations, radiotherapy therefore is very likely associated with major complications. In our study all children had soft tissue sarcoma located near the base of skull or in the trunk. The irradiation of the parameningeal site is known to cause severe long-term problems, including cataracts, growth inhibition, and facial asymmetry as well as impaired dentition and hearing (21). However, also in “favorable” sites such as orbit, the risk for treatment-related sequelae is very high. Reports are available describing in detail the damage of orbital bone, lens, chiasm, optical nerve, lacrimal gland, or the pituitary gland (22). Unfortunately, very young children comprise nearly 50% of all soft tissue sarcoma patients and have an increased risk of irradiation damage because of their immature, growing tissues. Therefore, it is important to search for
Fig. 4. Kaplan-Meier plot of the estimated overall survival rates.
Spot-scanning proton therapy for soft tissue sarcoma in childhood
new techniques that can potentially reduce treatment sequelae for pediatric soft tissue sarcoma. Proton beams are attractive because of their excellent dose distribution. The steep dose fall-off beyond the target differs considerably from any X-ray irradiation. Protons have the ability to confine the high-dose region to the target volume while minimizing the dose to the surrounding tissues considerably. This was already shown with dose plan comparisons of photons with protons in brain tumors, retinoblastomas, and orbital tumors (23–26). Also potential reduction of the risk for secondary cancer after proton beam treatment as compared with after photon treatment is assumed (27). Therefore, there is general agreement that protons will play a major role in treating childhood cancer when more widely accessible (28, 29). However, there is a lack of clinical data evaluating the acute and late toxicity of proton treatment in children. There are some promising reports about clinical results in low-grade astrocytomas and chordomas or chondrosarcomas (30, 31). However, any aggressive local treatment will be associated with side effects. Even if the surrounding tissue is being spared, the target volume receives full dose and is at risk for toxicity. Additionally, any conformal modern treatment will not be able to avoid growth asymmetry as we are no longer treating two lateral fields administering symmetrical dose. Therefore, the price of preserving the function of selected organs might worsen cosmetic results in some children. From our cohort, we can report an excellent acute tolerance of spot-scanning PT in the young age group with soft tissue sarcoma. The long-term effects are difficult to assess because of the short observation time in most of our patients. The preliminary data, however, suggest satisfying results. Clearly, prospective standardized evaluation of long-term side effects and quality of life will be needed to analyze the cost/benefit ratio of PT. It is an open question whether PT will be able to increase local control rates in soft tissue sarcoma. Different studies failed to demonstrate a dose–response relationship for local control in combined radiotherapy and chemotherapy in rhabdomyosarcoma (8, 32). However, in adult type soft tissue sarcoma, a dose increment is likely to be beneficial. A further major advantage of protons is to be ex-
●
B. TIMMERMANN et al.
503
pected from the ability to provide adequate coverage of the target volume while reducing the side effects in critical tumor sites. Currently, not only protons but also IMRT is under evaluation for improving conformity of treatment, allowing better sparing of critical organs near the target. Similar to protons, clinical data are still limited. Studies report on advantages for sparing the spinal cord or salivary glands in head-and-neck cancer (33). Also, very promising early results have been reported with rhabdomyosarcoma of the head and neck (34). Early data suggest benefit for the posterior fossa boost in brain tumor patients regarding ototoxicity (35). However, the higher number of fields needed with IMRT compared with spot scanning PT (and even IMPT) distributes low and median dose to a considerable volume around the target, carrying an increased risk of secondary cancer (36). Therefore, IMRT requires careful evaluation, especially with regard to the pediatric population, before widespread implementation. Additionally, spot-scanning PT has a significantly reduced neutron component and a consequently lowered risk of inducing secondary cancer compared with both IMRT and other proton machines (36). Therefore, the experiences of the Paul Scherrer Institute are of special interest considering it is currently the only existing spot-scanning facility worldwide. However, long-term follow-up is necessary to determine the clinical impact of protons as compared with IMRT or three-dimensional conformal radiotherapy regarding radiation effects. At the Paul Scherrer Institute the expansion of the proton facility is ongoing. A dedicated medical facility is being built and will start operation in 2007. It will provide uninterrupted beam throughout the year, and also allow for normal 5 day-per-week fractionation regimens using 1.6 to 1.8 Gy fractions as recommended in most of the pediatric protocols for optimal tissue sparing. Pediatric patients will be preferred, as they are considered the individuals potentially benefiting most from PT. We began performing a prospective evaluation of side effects and quality-of-life investigation in 2004 and are looking forward to long-term results. Additionally, matched-pair analyses for subgroups, i.e., orbital sarcomas, treated with either protons or photons are planned.
REFERENCES 1. Suit HD, Willett CG. Radiation therapy of sarcomas of the soft tissues. Cancer Treat Res 1991;56:61–74. 2. Kepka L, DeLaney TF, Suit HD, et al. Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2005;63:852– 859. 3. Flamant F, Rodary C, Rey A, et al. Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence. Results of the second study of the International Society of Paediatric Oncology: MMT84. Eur J Cancer 1998;34:1050 –1062. 4. Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: Third study of the International Society of Paediatric Oncology–
5.
6. 7.
8.
SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 2005;23:2618 –2628. Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomyosarcoma: Survival and late effects of treatment— results of an international workshop. J Clin Oncol 2001;19: 197–204. Saran F. New technology for radiotherapy in paediatric oncology. Eur J Cancer 2004;40:2091–2105. DeLaney TF, Trofimov AV, Engelsman M, et al. Advancedtechnology radiation therapy in the management of bone and soft tissue sarcomas. Cancer Control 2005;12:27–35. Donaldson SS, Meza J, Breneman JC, et al. Results from the
504
9.
10. 11.
12. 13. 14.
15.
16.
17. 18.
19.
20.
21. 22.
I. J. Radiation Oncology
●
Biology
●
Physics
IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma: A report from the IRSG. Int J Radiat Oncol Biol Phys 2001;51:718 –728. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. Lomax AJ, Bohringer T, Bolsi A, et al. Treatment planning and verification of proton therapy using spot scanning: Initial experiences. Med Phys 2004;31:3150 –3157. Pedroni E, Scheib S, Bohringer T, et al. Experimental characterization and physical modelling of the dose distribution of scanned proton pencil beams. Phys Med Biol 2005;50:541– 561. Lomax A. Intensity modulation methods for proton radiotherapy. Phys Med Biol 1999;44:185–205. Schuck A, Mattke AC, Schmidt B, et al. Group II rhabdomyosarcoma and rhabdomyosarcomalike tumors: Is radiotherapy necessary? J Clin Oncol 2004;22:143–149. Spunt SL, Hill DA, Motosue AM, et al. Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 2002; 20:3225–3235. Ferrari A, Brecht IB, Koscielniak E, et al. The role of adjuvant chemotherapy in children and adolescents with surgically resected, high-risk adult-type soft tissue sarcomas. Pediatr Blood Cancer 2005;45:128 –134. Ferrari A, Casanova M, Collini P, et al. Adult-type soft tissue sarcomas in pediatric-age patients: Experience at the Istituto Nazionale Tumori in Milan. J Clin Oncol 2005;23:4021– 4030. Donaldson SS, Castro JR, Wilbur JR, et al. Rhabdomyosarcoma of head and neck in children: Combination treatment by surgery, irradiation, and chemotherapy. Cancer 1973;31:26 –35. Wolden SL, Anderson JR, Crist WM, et al. Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 1999;17:3468 – 3475. Tefft M, Lindberg RD, Gehan EA. Radiation therapy combined with systemic chemotherapy of rhabdomyosarcoma in children: Local control in patients enrolled in the Intergroup Rhabdomyosarcoma Study. Natl Cancer Inst Monogr 1981; 56:69 –74. Wharam MD, Hanfelt JJ, Tefft MC, et al. Radiation therapy for rhabdomyosarcoma: Local failure risk for Clinical Group III patients on Intergroup Rhabdomyosarcoma Study II. Int J Radiat Oncol Biol Phys 1997;38:797– 804. Wharam MD, Jr. Rhabdomyosarcoma of parameningeal sites. Semin Radiat Oncol 1997;7:212–216. Heyn R, Ragab A, Raney RB Jr., et al. Late effects of therapy
Volume 67, Number 2, 2007
23.
24.
25.
26.
27.
28. 29. 30. 31. 32.
33. 34. 35.
36.
in orbital rhabdomyosarcoma in children: A report from the Intergroup Rhabdomyosarcoma Study. Cancer 1986;57:1738 – 1743. Yock T, Schneider R, Friedmann A, et al. Proton radiotherapy for orbital rhabdomyosarcoma: Clinical outcome and a dosimetric comparison with photons. Int J Radiat Oncol Biol Phys 2005;63:1161–1168. Miralbell R, Cella L, Weber D, et al. Optimizing radiotherapy of orbital and paraorbital tumors: Intensity-modulated X-ray beams vs. intensity-modulated proton beams. Int J Radiat Oncol Biol Phys 2000;47:1111–1119. Yuh GE, Loredo LN, Yonemoto LT, et al. Reducing toxicity from craniospinal irradiation: Using proton beams to treat medulloblastoma in young children. Cancer J 2004;10:386 – 390. St. Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 2004;58:727–734. Miralbell R, Lomax A, Cella L, et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002;54:824 – 829. Wilson VC, McDonough J, Tochner Z. Proton beam irradiation in pediatric oncology: An overview. J Pediatr Hematol Oncol 2005;27:444 – 448. Hug EB, Slater JD. Proton radiation therapy for pediatric malignancies: Status report. Strahlenther Onkol 1999;175 (Suppl. 2):89 –91. Hug EB, Muenter MW, Archambeau JO, et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol 2002;178:10 –17. Hug EB, Sweeney RA, Nurre PM, et al. Proton radiotherapy in management of pediatric base of skull tumors. Int J Radiat Oncol Biol Phys 2002;52:1017–1024. Regine WF, Fontanesi J, Kumar P, et al. Local tumor control in rhabdomyosarcoma following low-dose irradiation: Comparison of Group II and select Group III patients. Int J Radiat Oncol Biol Phys 1995;31:485– 491. Eisbruch A. Clinical aspects of IMRT for head-and-neck cancer. Med Dosim 2002;27:99 –104. Wolden SL, Wexler LH, Kraus DH, et al. Intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 2005;61:1432–1438. Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52:599 – 605. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006;65:1–7.