Acute toxicity of craniospinal irradiation with volumetric-modulated arc therapy in children with solid tumors

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. After resection, patients were classified as having average-risk medulloblastoma ( 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

In this work a novel plan optimization platform is presented where treatment is delivered efficiently and accurately in a single dynamically modulated arc. Improvements in patient care achieved through image-guided positioning and plan adaptation have resulted in an increase in overall treatment times. Intensity-modulated radiation therapy (IMRT) has also increased treatment time by requiring a larger number of beam directions, increased monitor units (MU), and, in the case of tomotherapy, a slice-by-slice delivery. In order to maintain a similar level of patient throughput it will be necessary to increase the efficiency of treatment delivery. The solution proposed here is a novel aperture-based algorithm for treatment plan optimization where dose is delivered during a single gantry arc of up to 360 deg. The technique is similar to tomotherapy in that a full 360 deg of beam directions are available for optimization but is fundamentally different in that the entire dose volume is delivered in a single source rotation. The new technique is referred to as volumetric modulated arc therapy (VMAT). Multileaf collimator (MLC) leaf motion and number of MU per degree of gantry rotation is restricted during the optimization so that gantry rotation speed, leaf translation speed, and dose rate maxima do not excessively limit the delivery efficiency. During planning, investigators model continuous gantry motion by a coarse sampling of static gantry positions and fluence maps or MLC aperture shapes. The technique presented here is unique in that gantry and MLC position sampling is progressively increased throughout the optimization. Using the full gantry range will theoretically provide increased flexibility in generating highly conformal treatment plans. In practice, the additional flexibility is somewhat negated by the additional constraints placed on the amount of MLC leaf motion between gantry samples. A series of studies are performed that characterize the relationship between gantry and MLC sampling, dose modeling accuracy, and optimization time. Results show that gantry angle and MLC sample spacing as low as 1 deg and 0.5 cm, respectively, is desirable for accurate dose modeling. It is also shown that reducing the sample spacing dramatically reduces the ability of the optimization to arrive at a solution. The competing benefits of having small and large sample spacing are mutually realized using the progressive sampling technique described here. Preliminary results show that plans generated with VMAT optimization exhibit dose distributions equivalent or superior to static gantry IMRT. Timing studies have shown that the VMAT technique is well suited for on-line verification and adaptation with delivery times that are reduced to approximately 1.5-3 min for a 200 cGy fraction.