Japanese Journal of Clinical Oncology 33:271-277 (2003)
© 2003 Foundation for Promotion of Cancer Research
Feasibility Study of the Simultaneous Integrated Boost (SIB) Method for Malignant Gliomas Using Intensity-modulated Radiotherapy (IMRT)
1 Department of Radiology, 3 Central Radiological Service and 4 Department of Neurosurgery, School of Medicine, Kinki University, Osaka Sayama, Osaka and 2 Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Intensity-modulated radiotherapy (IMRT) using the simultaneous integrated boost (SIB) method was designed for treating malignant gliomas. The purpose of this study was to investigate feasibility of this treatment.
Methods: Between December 2000 and November 2002, six patients with malignant gliomas were enrolled in this study. IMRT delivered 70 Gy/28 fractions (fr)/daily 2.5 Gy to the gross tumor volume (GTV) and 56 Gy/28 fr/daily 2.0 Gy to the surrounding edema defined as the clinical target volume annulus (CTV-a). The feasibility of the treatment was assessed from both physical and clinical points of view.
Results: No delay due to acute radiation toxicity was observed in any of the patients. The tumor recurred locoregionally in five of the six patients. The glioblastoma (GBM) recurred in two patients during the radiotherapy and in three patients at 5.4, 4.0 and 7.0 months after the start of radiotherapy. The sites of recurrence or progression were local in the GTV in four patients and in one patient subependymal dissemination was observed. Three patients, two with GBMs and one with anaplastic astrocytoma, died of the disease at 4, 16 and 7 months after the start of radiotherapy, respectively.
Conclusions: The treatment of 70 Gy/28 fr/daily 2.5 Gy to the GTV and 56 Gy/28 fr/daily 2.0 Gy to the CTV-a was feasible both physically and clinically.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Malignant gliomas have been treated with surgery and adjuvant external beam radiotherapy with or without chemotherapy. However, most patients experience local recurrence and the prognosis of the patients remains dismal (1–5).
We started a feasibility study of treating malignant gliomas using intensity-modulated radiotherapy (IMRT). IMRT has spread as a new form of radiotherapy for treating cancers in many sites, namely head and neck cancers, brain tumors and prostate cancers (6–8). With IMRT, irradiation dose to organs at risk (OARs: spinal cord, lens, parotid glands, etc.) can be lowered when delivering high doses to the target volume.
The strategy of our study was to treat the gross tumor and surrounding edema with different doses simultaneously. According to the ICRU 50 reports (9), the gross tumor volume (GTV) is defined as the volume including the macroscopic tumor and the clinical target volume (CTV) is defined as the volume including microscopic tumor cells. In the present study, the surrounding edema at risk of microscopic invasion was defined as a CTV-annulus (CTV-a), which was part of the CTV excluding the GTV. IMRT can deliver a conformal dose to the concave or doughnut-shaped CTV-a, which has been impossible with conventional external beam radiotherapy (10,11). Thus, IMRT can deliver a higher fraction size to the GTV and a conventional fraction size to the CTV-a using a simultaneous integrated boost (SIB) method. The purpose of this study was to investigate the feasibility of the treatment.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Between December 2000 and November 2002, six patients with histologically confirmed malignant gliomas were enrolled in this study. Six patients (three males and three females, age range 53–71 years, median 61 years), including four with glioblastoma multiform (GBM), one with anaplastic astrocytoma (AA) and one with anaplastic oligodendroglioma (AO), were treated with IMRT (Table 1). Except for the patient with AA diagnosed by biopsy, all other patients were treated by IMRT after resection of the tumor which had been diagnosed as malignant glioma. Gross total resection was performed in three patients and subtotal resection in two patients (Table 1).
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The eligibility criteria included 20–75 years of age and Eastern Cooperative Oncology Group performance status 0–2. Patients previously treated with radiotherapy were excluded. Patients with major heart or infectious disease were also excluded. Written informed consent was obtained from all of the patients.
Simulation and Immobilization
All patients were immobilized with a thermoplastic mask covering the head, neck and shoulders (Uni-frame form, MED-TEC, Orange City, IA). Treatment-planning computed tomography (CT) was performed at 5 mm slice intervals from the head down through the clavicles using contrast media.
Delineation of Target Volumes
Following the ICRU 50 recommendations (9), the GTV and the CTV were delineated on the axial CT images. The GTV was defined by contrast-enhanced tumors on contrast-enhanced CT. If the gross tumor was resected, the area where the brain tumor had existed on the contrast-enhanced magnetic resonance image (MRI) obtained before surgery was outlined as the GTV. The CTV was defined as the GTV plus a 2 cm margin. The margin was modified to be expanded to include the edema beyond 2 cm from the GTV or to be shrunk to the anatomical defense such as intracerebral fissures or tentorium cerebelli.
Three planning target volumes (PTVs) were defined. The PTV-G was defined as the GTV plus a 0.5 cm margin. The PTV-C was defined as the CTV plus a 0.5 cm margin additional to setup errors. The PTV-annulus (PTV-a) was delineated by subtracting the PTV-G from the PTV-C (PTV-C minus PTV-G). Fig. 1 demonstrates the relations among the three targets.
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In the present study, the PTV-G and the PTV-a were treated as two separate targets with IMRT at different fraction sizes.
Treatment Planning
A commercial treatment-planning system, Cadplan Helios version 6.01 (Varian, Palo Alto, CA) was used. The IMRT beam arrangements consisted of five coplanar beams. Five beams were equally spaced at 72° intervals following gantry angles of 20, 92, 164, 236 and 308°.
The prescribed doses to the PTV-G and the PTV-a were 70 Gy in 28 fractions (fr) and 56 Gy in 28 fr, respectively. Daily fractions of 2.5 Gy and 2.0 Gy were prescribed to the PTV-G and the PTV-a, respectively. The treatment goals were as follows: (1) the doses to 95% volume (D95) of the PTV-G and the PTV-a were greater than the prescribed doses, (2) the dose to 5% volume (D05) of the PTV-G was <77 Gy, i.e. 110% of the prescribed dose to the PTV-G, and (3) the D05 of the PTV-a was less than the prescribed dose to the PTV-G (70 Gy).
The optimization process in inverse planning is the process of automated generation of beam intensity distributions by adjusting the difference between the planner-defined dose constraints for the targets or the OARs and the actual dose according to the weighted penalties (12). The step determined by the treatment planner was to input the maximum and minimum dose constraints for the targets and the maximum dose constraints or the dose–volume constraints for the OARs. Table 2 shows the starting template for the dose constraints and the penalties of the targets and the OARs. The maximum and minimum dose constraints for the PTV-G were 71.4 and 68.6 Gy (±2% of the prescribed dose to the PTV-G), respectively, and those for the PTV-a were 64–70 Gy and 53.2 Gy (95% of the prescribed dose), respectively.
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The final step of the treatment planning was the normalization process of the dose intensity. The treatment plan was normalized to permit the delivery of the prescribed dose to 95% volume (D95) of the PTV-G according to the treatment goal. If the treatment plan did not fulfil the other treatment goals or a dose higher than the tolerant doses was delivered to the OARs, the optimization process was repeated with modification of the dose constraints or penalties of the targets and OARs.
Treatment Delivery and Quality Assurance (QA)
Treatment was delivered using dynamic multileaf collimation (DMLC) on a Clinac-600C accelerator (Varian) equipped with a 40-leaf dynamic multileaf collimator. A beam energy of 4-MV X-rays was used. The daily treatment time was about 15–20 min.
During radiotherapy with IMRT, routine QA was crucial. For verification of the leaf motion of each beam, various QA measurements were performed. The first was assessment for accuracy of the leaf positions by using a test pattern of leaf motion on an exposed film (13). To obtain the test pattern film, a 0.1 x 40 cm2 slit beam intermittently irradiated the film at 1 cm intervals, yielding narrow, dark lines on the film. A leaf position error >0.2 mm could be easily detected by viewing the film on a light-box. This QA procedure for leaf position was performed once per week. The second QA procedure was measurement of the shape of the dose profile through the isocenter with a diode array (Profiler, Sun Nuclear, Melbourne, FL) (14). This QA procedure was performed every day before the start of IMRT. The third QA procedure was a check for the intensity maps on portal films for each beam. The identity of the intensity maps from the patients and the phantom was verified by visual inspection. All the beams were assessed at first treatment day and one beam from the second day. For verification of the isocenter of the treatment field, the lateral and anterior–posterior (A–P) portal films were taken every day for the first week and weekly from the second week.
Dose–Volume Analysis of Treatment Plans
Dose–volume histograms of the PTV-G, the PTV-a and the brain for the six patients were analyzed. For the PTV-G and the PTV-a, the D95 and the D05 were recorded to evaluate conformity and homogeneity of the targets and the mean doses were also evaluated. For the brain, the mean doses were evaluated.
Chemotherapy
Five of six patients received one or two courses of ACNU (100 mg/m2) and vincristine (1.2 mg/body) and interferon-ß (3 x 106 units) three times per week during radiotherapy. Adjuvant chemotherapy, ACNU and vincristine, was repeated every 6 weeks and interferon-ß every 2 weeks at the same dose during radiotherapy.
Follow-up
Every patient was evaluated at least once per week during radiotherapy. The patients were followed up every 1–2 months for the first 6 months and every 3 months thereafter. MRI with contrast enhancement was usually evaluated every 3 months. Acute toxicities were graded using National Cancer Institute Common Toxicity Criteria (version 2.0). Late toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. The time to recurrence and death and the failure patterns (local or distant) were estimated.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment Outcome
Table 1 summarizes the patients’ characteristics and the treatment outcome. The median interval from the time of the operation to the starting of IMRT was 23 days (range 18–39 days). All the patients completed the planned radiotherapy. The median follow-up period was 6.9 months (range 3.6–15.7 months). Five of six patients showed recurrence or progression. Two patients with GBM showed recurrence during the radiotherapy and three other patients at 5.4, 4.0 and 7.0 months. The sites of recurrence or progression of the four patients were local in the PTV-G delivered a 70 Gy dose (Figs. 2 and 3). One patient with GBM had subependymal seeding out of the irradiation field. Only one patient with AO was still alive with no recurrence or progression. Three patients, two GBMs and one AA, died of the diseases at 4, 16 and 7 months after the start of radiotherapy, respectively.
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Toxicity
All six patients completed the scheduled radiotherapy. One patient had treatment interruption for 18 days owing to grade 4 leucopenia due to concurrent chemotherapy. No delay due to acute radiation toxicity was observed in any of the patients. One patient developed grade 3 radiation dermatitis on the scalp with moist desquamation. No apparent acute neurotoxicity was observed.
Dose–Volume Histogram (DVH) Analysis
Table 3 summarizes the treatment volumes, the D95, D05 and mean doses for the PTV-G and the PTV-a and the mean doses for the brain. Fig. 4 shows the DVH of case 4 for the PTV-G, the PTV-C and the brain. In the first case of treatment (case 1), the treatment goal was to deliver the prescribed dose to 90% of the volume of the PTV-G; the D95 for the PTV-G was 68 Gy. In case 2 with AA, the involvement of the tumor was so extensive that the prescribed dose for the PTV-G was reduced to 66 Gy/28 fr. The other four cases fulfilled the current treatment goals.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It was our treatment protocol for malignant gliomas with IMRT using the SIB method to deliver 70 Gy/28 fr/5.6 week (w) with a fraction size of 2.5 Gy to the PTV-G and 56 Gy/28 fr/5.6 w with a fraction size of 2.0 Gy to the PTV-a. Our preliminary clinical outcomes were that five out of the six patients showed recurrence and three died of the diseases at 4, 16 and 7 months after the start of radiotherapy.
Chan et al. (5) reported the outcome for 34 GBM patients treated with three-dimensional (3D) conformal radiotherapy using the IMRT technique. Their analysis of the local failure patterns revealed that 78% of the recurrence occurred within the 95% isodose surface of the volumes delivered a 90 Gy dose as a 2.0 Gy daily fraction. Although the number of cases was very small in our study, four of six patients had local recurrence within the GTV that was delivered a 70 Gy dose as a 2.5 Gy daily fraction. The present findings suggest that dose intensification of the GTV is essential to improve local control or survival.
The SIB method can deliver different doses to each target volume. There were two rationales to employ this method for the treatment of malignant gliomas. One is that the SIB method, using a large fraction size for the GTV, can shorten the overall treatment time (OTT). Shortening the OTT is beneficial especially for patients with malignant glioma, which is hardly a curative disease. The other is that this method is expected to improve local control without increasing toxicity, including brain necrosis, by delivering different fraction sizes to the GTV and the surrounding edema.
We are currently planning a phase I study for dose intensification of the GTV using a large fraction size. We decided to adopt this strategy because hypofractionated radiotherapy with a large fraction size has been reported to be effective for tumors with a low 
/ß ratio (15,16). Although there has been no report regarding the /ß ratio of malignant gliomas in the clinical setting, the survival curves for malignant glioma cell lines in vitro show a large shoulder indicating a low /ß ratio (17). In an in vivo xenograft study using a mouse model of human malignant glioma, Hasegawa et al. (18) reported that hypofractionated (20 Gy/4 fr) treatment brought about a longer delay of tumor growth than conventional (20 Gy/10 fr) or hyperfractionated (24 Gy/20 fr) irradiation. In a clinical study of hypofractionated radiotherapy, Tamura et al. (19) reported that GBM patients treated with hypofractionation (40 Gy/8 fr) showed a slightly longer survival time than those treated with conventional fractionation (60 Gy/30 fr). On the other hand, it was shown in several clinical studies of the treatment of malignant gliomas that accelerated hyperfractionated radiotherapy with small fraction sizes had no clinical benefit over conventional fractionated radiotherapy (20–22). These results suggest that malignant glioma has a low /ß ratio.
In general, a high radiation dose and a large fraction size increase the risk of tumor and peritumoral necrosis. Corn et al. (23) reported that treatment-induced brain necrosis was observed in 19% of patients. Sneed et al. (24) reported an incidence of 56% for symptomatic radiation necrosis which required surgical resection following brachytherapy. Tamura et al. (19) reported that histological evaluation revealed extensive necrotic areas in the surrounding normal brain in autopsied cases treated with hypofractionated radiotherapy (40 Gy/8 fr). Chan et al. (5) applied the segmental multileaf collimator (SMLC) IMRT technique for the treatment of high-grade gliomas with dose weighting among three PTVs, PTV1 (GTV + 0.5 cm), PTV2 (GTV + 1.5 cm) and PTV3 (GTV + 2.5 cm). It was encouraging in their study that no normal tissue complication was observed, including brain necrosis. It should be noted that dose gradients between the GTV and surrounding edema by IMRT may contribute to preventing or reducing central nervous system (CNS) toxicity. Thus, for reducing treatment-related toxicities, IMRT will be an indispensable technique to our phase I study for dose intensification of the GTV, as it provides dose gradients between the GTV and surrounding edema.
As shown in Table 3, high conformity of the dose distribution within the PTV-G was achieved without reducing the homogeneity within the PTV-G. Although the high conformity was the result of the normalization process to cover 95% of the volume of the PTV-G with the prescribed dose, the high homogeneity within the PTV-G was achieved by setting the maximum and minimum dose constraints for the PTV-G within a very narrow range, namely ±2% of the prescribed dose to the GTV with a strict penalty, 100. On the other hand, the minimum and maximum dose constraints for the PTV-a were set at a wider range, 53.2 and 64–70 Gy (Table 2). This setting of the dose constraints led to a more inhomogeneous dose distribution within the PTV-a than that within the PTV-G. However, this dose inhomogeneity within the PTV-a appears to be favorable from the clinical point of view, because greater microscopic invasion will be expected within the region closer to the PTV-G. As shown in the present study, IMRT can deliver a highly conformal dose distribution to large or irregular target volumes with high homogeneity. We suggest that IMRT has the possibility to be applied to other brain tumors.
Through the present pilot study, useful information for a phase I study was obtained. With regard to the physical aspects, we found an appropriate starting template for the dose–volume constraints (Table 2) as a result of trial and error. The appropriate starting template can reduce the time-consuming optimization process (30–60 min), which is practical in the clinical situation. Thus, some modifications of the starting template were thought pertinent to obtaining the optimum treatment plan.
With regard to clinical aspects, although our study included only six patients and the duration of the follow-up was too short to evaluate late toxicity such as brain necrosis, it is encouraging that our treatment protocol, delivering 70 Gy/28 fr to the PTV-G and 56 Gy/28 fr to the PTV-a, was well tolerated by the patients. Therefore, we adopted the following protocol as a starting dose level for our phase I study: 77.5 Gy/31 fr/6.2 w with a fraction size of 2.5 Gy to the PTV-G and 58.9 Gy/31 fr/6.2 w with a fraction size of 1.9 Gy.
Owing to the laborious dosimetric verification, the median interval from the time of operation to the start of IMRT was 23 days (range 18–39 days) in the present study. In head and neck cancers, some researchers have reported that a prolonged duration of this interval impairs local control (25,26). In the case of brain tumors, to our knowledge, there has been no report of the effects of the operation-to-radiotherapy interval on local control. In the present study, two local recurrences during radiotherapy were observed in spite of gross total removal of the tumor. These results suggest that microscopic glioma cells may enter a repopulation cycle in a short period between the operation and the start of radiotherapy. Hence a short interval from operation to radiotherapy may be preferable for the treatment of malignant gliomas. Recently, it has usually taken 1 week to prepare for IMRT. We should be able to start the IMRT treatment within 2 weeks after operation.
In conclusion, the present study revealed the feasibility of the application of IMRT using the SIB method for the treatment of malignant gliomas. The treatment of 70 Gy/28 fr/daily 2.5 Gy to the GTV and 56 Gy/28 fr/daily 2.0 Gy to the CTV-a was feasible both physically and clinically.
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ACKNOWLEDGEMENT |
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This study was partially supported by a Grant-in-Aid for Scientific Research (14570887) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Minoru Suzuki, Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Noda, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan. E-mail: msuzuki{at}rri.kyoto-u.ac.jp
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Received January 29, 2003; accepted April 16, 2003
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