Final results of a multi-institutional phase II trial of reirradiation with concurrent weekly cisplatin and cetuximab for recurrent or second primary squamous cell carcinoma of the head and neck.

Background: The optimal regimen of chemotherapy and reirradiation (re-XRT) for recurrent head and neck squamous cell carcinoma (HNSCC) is controversial. We report the final outcomes of a multicenter phase II trial evaluating cetuximab and cisplatin-based chemotherapy concurrent with re-XRT for patients with recurrent HNSCC. Materials and methods: Patients with unresectable recurrent disease or positive margins after salvage surgery arising within a previously irradiated field with KPS ≥ 70 were eligible for this trial. Cetuximab 400 mg/m2 was delivered as a loading dose in week 1 followed by weekly cetuximab 250 mg/m2 and cisplatin 30 mg/m2 concurrent with 6 weeks of intensity-modulated radiotherapy to a dose of 60-66 Gy in 30 daily fractions. Patients who previously received both concurrent cetuximab and cisplatin with radiation or who received radiotherapy less than 6 months prior were ineligible. Results: From 2009 to 2013, 48 patients enrolled on this trial, 2 did not receive any protocol treatment. Of the remaining 46 patients, 34 were male and 12 female, with a median age of 62 years (range 36-85). Treatment was feasible and only 1 patient did not complete the treatment course. Common grade 3 or higher acute toxicities were lymphopenia (46%), pain (22%), dysphagia (13%), radiation dermatitis (13%), mucositis (11%) and anorexia (11%). There were no grade 5 acute toxicities. Eight grade 3 late toxicities were observed, four of which were swallowing related. With a median follow-up of 1.38 years, the 1-year overall survival (OS) was 60.4% and 1-year recurrence-free survival was 34.1%. On univariate analysis, OS was significantly improved with young age (P = 0.01). OS was not associated with radiation dose, surgery before re-XRT or interval from prior XRT. Conclusions: Concurrent cisplatin and cetuximab with re-XRT is feasible and offers good treatment outcomes for patients with high-risk features. Younger patients had significantly improved OS. ClinicalTrials.Gov Identifier: NCT00833261.

SU-E-T-551: A Customized Plan Evaluation System for On-Line Adaptive Radiotherapy.

PURPOSE: Treatment plan evaluation based on daily images, to determine whether it is necessary to re-plan the treatment, is an essential element of adaptive radiotherapy. A fully automatic system, incorporating physician preferences and requirements of specific protocols quantified by a series of objective functions, was developed to evaluate treatment plans. METHODS: The evaluation system was developed using IDL 6.1 (ITT Visual Information Solutions, Boulder, CO). Based on customized evaluation guidelines, dosimetric parameters, including maximum dose, minimum dose, uniformity dose, dose coverage, conformity index, heterogeneity index, gEUD, and DVH for the targets and OARs are evaluated as series of cost functions which incorporate specific protocol constraints and physician requirements. The evaluation system was applied to IMRT plans of head/neck cancer patients. The Pinnacle Treatment Planning System (research version 9.0) was used to generate verification treatment plan trials, with image datasets, ROI structures, and dose distributions exported to evaluation system. RESULTS: Results show that the evaluation system can complete evaluation of a dose plan within 2∼8 seconds. The system is capable of displaying and comparing dose distributions among different plans. It also demonstrates great flexibility in customizing cost functions based on physician preferences. This system is supported with various user-friendly options, graphical displays, and feasibly structure in adding new modules. CONCLUSIONS: This evaluation system is capable of quantifying specific protocols and preferences of physicians and completing automatic evaluation almost in real-time. It is an essential a platform for adaptive radiation therapy and also valuable for initial treatment planning. This research is supported by CPRIT Individual Investigator Award RP110329.

Dose-volume histogram computations for small intracranial volumes.

A sampling formalism is presented to accurately compute the absolute volumes and integral dose-volume histograms of small volumes treated in stereotactic radiosurgery. The presence of small volumes and sharp dose gradients places special constraints on the computational formalism and the accuracy required to compute the dose-volume relationships. We use a spatially nonuniform random sampling method to allow an efficient and accurate computation of the dose-volume histograms for an arbitrary number of volumes. The computation of absolute volume vs dose allows intercomparison of dose delivered to target and dose-critical volumes and allows a quantitative trade-off analysis often critical to an optimal treatment of the lesion.

Dynamic field shaping for stereotactic radiosurgery: a modeling study.

PURPOSE: This work assesses the relative field shaping advantages of dynamic field shaping devices for stereotactic radiosurgery using a linear accelerator. METHODS AND MATERIALS: We selected 43 intracranial tumors (2.0-4.2 cm maximum dimension, 1.5-25.5 cc tumor volume) out of the first 64 intracranial tumors treated with radiosurgery at the Joint Center for Radiation Therapy. We modeled five field shaping devices, each including a fixed auxiliary circular collimator: (a) fixed circular collimator alone; (b) two independent parallel jaws; (c) four independent rectangular jaws; (d) four independent rotatable jaws; and (e) "ideal" multileaf collimator. We adjusted the model parameters until the minimum target isodose was 80% of the dose delivered to isocenter. We defined the treatment volume ratio as the target volume divided by the treatment volume (volume receiving at least the minimum target dose). We used the treatment volume ratio to compare the five models and the actual patient treatments. RESULTS: For 34 tumors originally treated with one isocenter, the median Treatment Volume Ratio was higher for all of the device models except the fixed circular collimator compared to the actual patient treatments. For the nine tumors originally treated with multiple isocenters, the median Treatment Volume Ratio for the actual multiple isocenter treatments was similar to that for two parallel jaws, four rectangular jaws and four rotatable jaws. Only the median "ideal" collimator treatment volume ratio was higher for these nine tumors. CONCLUSION: Simple field shaping devices have approximately 50% of the conformal advantage of an "ideal" multileaf collimator. Approximately 50% of typical radiosurgical tumors between 2 and 4 cm have field shaping advantages which exceed the geometrical uncertainties inherent in linear accelerator radiosurgery treatments. The three models, two parallel, four rectangular, or four rotatable independent jaws would improve current linear accelerator technology by providing homogeneous doses with equivalent field shaping for most tumors originally treated with inhomogeneous multiple isocenter plans (6/9 tumors in the current series).

Stereotactic radiosurgery: principles and comparison of treatment methods.

Methods of stereotactic radiosurgery are reviewed and compared with respect to technical factors and published clinical results. Heavy-ion beams, the Leksell cobalt-60 gamma knife, and the conventional linear accelerator (linac) are compared with respect to dosimetry, radiobiology, treatment planning, cost, staffing requirements, and ease of use. Clinical results on the efficacy of treatment of arteriovenous malformations are tabulated, and other applications of radiosurgery are described. It is concluded that although there are dosimetric and radiobiological advantages to charged-particle beams that may ultimately prove critical in the application of radiosurgery to large (> 30 mm) lesions, these advantages have not yet demonstrated clinical effect. On the other hand, equally excellent clinical results are obtained for small lesions with photon beams--the gamma knife and the linac. There are only minor differences between gamma and x-ray beam dose distributions for small, spherical-shaped targets. Mechanical precision is superior for the gamma knife as compared with the linac. The superior mechanical precision is of limited importance for most clinical targets, because inaccuracy of cranial target localization based on radiological imaging is greater than the typical linac imprecision of +/- 1 mm. Treatment planning for the linac is not standardized, but existing systems are based on well-known algorithms. The linac allows flexible, ready access to individualized beam control, without intrinsic field size limitations. Thus, it is more readily possible to achieve homogeneous dose distributions for nonspherical targets with one or more dimensions greater than 25 mm, as compared with that achieved with the gamma unit.(ABSTRACT TRUNCATED AT 250 WORDS)

Variables associated with the development of complications from radiosurgery of intracranial tumors.

Between 5/21/86 and 11/1/89, we treated 64 recurrent or inoperable intracranial tumors in 60 patients (40 primary, 24 metastatic) with stereotactic radiosurgery using a modified 6 MeV linear accelerator at the Joint Center for Radiation Therapy. Patients were followed until death or 1/1/90. The median follow-up was 8 months (2-43 months). Fourteen patients experienced complications from 12 hours to 7 months (median 3 months, but only two patients more than 4 months) following radiosurgery. To determine variables related to complication, we calculated integral dose-volume histograms for 61/64 lesions and the surrounding CT-defined normal tissue. We excluded 16 lesions in 15 patients for follow-up less than 4 months (12 patients) or insufficient treatment information (3 patients). The variables for which higher values were associated with significantly more toxicity in a univariate score test were: a) tumor dose inhomogeneity (p less than 0.00001), b) maximum tumor dose (p = 0.00002), c) number of isocenters (p = 0.00002), d) maximum normal tissue dose (p = 0.00005) and e) tumor volume (p = 0.0001). These variables were all highly correlated with tumor dose inhomogeneity (coefficients of rank correlation 0.75-0.81). Tumor dose inhomogeneity had a much higher loglikelihood in a logistic model than any other single variable and a higher loglikelihood than any other two variables combined. None of the 21 patients with metastatic lesions experienced a complication. When we excluded the metastatic lesions, the above five variables remained significant in univariate tests. The mean tumor dose, number of treatment arcs, total degrees of arc, tumor location, previous radiotherapy, tumor geometry, pretreatment performance status, collimator size, and age were not significantly associated with toxicity. We conclude that radiosurgery of intracranial tumors is associated with a low risk of complications for lesions less than 10cc treated with a single isocenter to maximum tumor doses less than 25 Gy with tumor dose inhomogeneity less than 10 Gy, but that treatment of larger lesions will require new treatment strategies which reduce the tumor dose inhomogeneity associated with multiple isocenter treatments.

Treatment planning for stereotactic radiosurgery of intra-cranial lesions.

Stereotactic radiosurgery of intra-cranial lesions is a treatment modality where a well defined target volume receives a high radiation dose in a single treatment. Our technique delivers this dose using a set of non-coplanar arcs and small circular collimators. We use a standard linear accelerator in our treatments, and the adjustable treatment parameters are: isocenter location, gantry arc rotation interval, couch angle, collimator field size, and dose. The treatment planning phase of the treatment determines these parameters such that the target volume is sufficiently irradiated, and dose to surrounding healthy tissue and critical, dose-limiting structures is minimized. The attachment of a BRW localizing frame to the patient's cranium combined with CT imaging (and optionally MRI or angiography) provides the required accuracy for localizing individual structures in the treatment volume. The treatment is fundamentally 3-dimensional and requires a volumetric assessment of the treatment plan. The selection of treatment arcs relies primarily on geometric constraints and the beam's eye view concept to avoid irradiating critical structures. The assessment of a treatment plan involves isodose distributions throughout the volume and integral dose-volume histograms. We present the essential concepts of our treatment planning approach, and illustrate these in three clinical cases.

Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma.

Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results, we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated, supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery, partial brain external-beam radiotherapy (59.4 Gy in 33 fractions), and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group, we identified 40 patients with glioblastoma treated with surgery and external radiotherapy, with or without chemotherapy, between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%, respectively, for patients receiving brachytherapy versus 40% and 12.5%, respectively, for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately, only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation.

Stereotactic radiosurgery of the brain using a standard linear accelerator: a study of early and late effects.

Between February 1986 and December 1988, 44 patients were treated with stereotactic radiosurgery using a standard linear accelerator. Twenty one patients were treated for cerebrovascular abnormalities and 23 patients were treated for intracranial tumors. Fifteen of the 23 patients treated for intracranial tumors had received previous radiotherapy. The range of doses given by radiosurgery was 1000-2500 cGy. Nausea and vomiting occurred in seven patients within six hours of treatment. The incidence and symptoms were correlated with the dose of radiation to the vomiting center (area postrema) with the median dose to the postrema in symptomatic patients being 618 cGy compared to a range of less than 5 to 184 cGy in the remaining 36 asymptomatic patients. Temporary alopecia occurred in a single patient who received 400 cGy to the scalp. Alopecia did not occur in the remaining 43 patients who received from less than 5 to 175 cGy. Two patients treated for arteriovenous malformations developed an enhancing lesion on CT scanning (one with cerebral edema) on follow-up CT scanning six and twenty-eight months following radiosurgery. The location of these enhancing lesions corresponded to the volumes treated. In one patient, the enhancing pattern and edema disappeared within 18 months of treatment and no neurological deficits developed. Aphasia occurred in one patient treated for a recurrent glioma two hours following treatment to the left temporal lobe and cleared within 12 h of radiosurgery. One patient with an arteriovenous malformation of the pons developed weakness of the contralateral arm and leg six weeks following treatment and this has slowly resolved over the last 12 months. In conclusion, the complications to date have been self-limited and appear to be directly related to the dose and area of brain treated. Prior radiation therapy has not been associated with increased risk of complication in patients treated with radiosurgery for recurrent tumors to date.