The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent terminal differentiation.

The non-receptor protein tyrosine kinase Syk (spleen tyrosine kinase) is an important mediator of signal transduction in B cells. By acting downstream of the B-cell antigen receptor, Syk promotes signaling pathways involved in proliferation, differentiation and survival of B cells. To study the oncogenic potential of Syk, we generated a mouse model for the inducible expression of the leukemia-derived TEL-Syk fusion protein exhibiting constitutive kinase activity. To achieve B-cell-specific expression of TEL-Syk in adult mice, we used a tamoxifen-inducible Cre mouse line. This study shows that inducible expression of TEL-Syk in B cells leads to transient proliferation and subsequent plasma cell differentiation. However, it does not lead to B-cell transformation. Instead, Syk activation induces the tumor suppressor B-lymphocyte-induced maturation protein-1 (Blimp-1), which interferes with the expression of the antiapoptotic protein Bcl-2. Combined induction of TEL-Syk with transgenic expression of Bcl-2 results in a severe phenotype and plasma cell expansion. Our results suggest that deregulated Syk activity by itself is not sufficient for the transformation of B cells, as downstream effectors, such as Blimp-1, limit the survival and expansion of the activated B cell.

Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms.

PURPOSE: Mesenchymal tumours require high-dose radiation therapy (RT). Small bowel (SB) dose constraints have historically limited dose delivery to paraspinal and retroperitoneal targets. This retrospective study correlated SB dose-volume histograms with side-effects after proton radiation therapy (PT). PATIENTS AND METHODS: Between 1997 and 2008, 31 patients (mean age 52.1 years) underwent spot scanning-based PT for paraspinal/retroperitoneal chordomas (81%), sarcomas (16%) and meningiom (3%). Mean total prescribed dose was 72.3 Gy (relative biologic effectiveness, RBE) delivered in 1.8-2 Gy (RBE) fractions. Mean follow-up was 3.8 years. Based on the pretreatment planning CT, SB dose distributions were reanalysed. RESULTS: Planning target volume (PTV) was defined as gross tumour volume (GTV) plus 5-7 mm margins. Mean PTV was 560.22 cm(3). A mean of 93.2% of the PTV was covered by at least 90% of the prescribed dose. SB volumes (cm(3)) receiving doses of 5, 20, 30, 40, 50, 60, 70, 75 and 80 Gy (RBE) were calculated to give V5, V20, V30, V40, V50, V60, V70, V75 and V80 respectively. In 7/31 patients, PT was accomplished without any significant SB irradiation (V5=0). In 24/31 patients, mean maximum dose (Dmax) to SB was 64.1 Gy (RBE). Despite target doses of >70 Gy (RBE), SB received >50 and >60 Gy (RBE) in only 61 and 54% of patients, respectively. Mean SB volumes (cm(3)) covered by different dose levels (Gy, RBE) were: V20 (n=24): 45.1, V50 (n=19): 17.7, V60 (n=17): 7.6 and V70 (n=12): 2.4. No acute toxicity ≥ grade 2 or late SB sequelae were observed. CONCLUSION: Small noncircumferential volumes of SB tolerated doses in excess of 60 Gy (RBE) without any clinically-significant late adverse effects. This small retrospective study has limited statistical power but encourages further efforts with higher patient numbers to define and establish high-dose threshold models for SB toxicity in modern radiation oncology.

Is it necessary to plan with safety margins for actively scanned proton therapy?

In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume.

Proton range verification using a range probe: definition of concept and initial analysis.

Proton therapy can be particularly sensitive to changes or errors in range. Thus, methods for the in vivo measurement of range could be of great use to improve the quality and accuracy of proton-based radiotherapy. In this paper, we introduce the concept of the 'range probe'. This is a low-dose, high-energy proton pencil beam that would pass through a patient, and whose integral Bragg peak would be measured on the exit side using a multi-layer detector. We propose that by comparing the measured integral Bragg peak with that calculated based on the patient's planning CT, such a range probe could provide useful information about the accuracy of range calculations in vivo. To study the feasibility of this approach, a Monte Carlo-based study has been performed. Using a patient's planning CT, MC simulations (VMCpro) have been made for single pencil beams laterally traversing the head and stopping in a simulated range telescope behind the patient. Range probes have been calculated for different locations, and the residual range from the Bragg peak 'signal' in the range telescope has been assessed for different assumed detector thicknesses. The sensitivity of this approach to changes in CT values, calibration curve and positional shifts of the CT have been investigated. From our analysis, range resolutions of 1 mm may be possible with a detector thickness of 4 mm for homogeneous regions. Additionally, for heterogeneous regions, changes of the Bragg peak shape due to spatial shifts of the CT could be a sensitive measure for detecting patient set-up errors directly in the treatment position. The concept of the proton 'range probe' appears to be feasible for high-resolution range verification. We now want to test this concept experimentally using different possible range telescope detectors.

The influence of the optimization starting conditions on the robustness of intensity-modulated proton therapy plans.

In this paper the influence of varying the starting conditions on intensity-modulated proton therapy (IMPT) plans has been studied. In particular IMPT plans have been optimized based on four different starting conditions of initial beamlet fluences: (a) all beamlets with an initial constant weight, delivering a gradient from the proximal to the distal edge of the target (forward wedge approach); (b) beamlet weights reduced from the distal to the proximal aspect of the target such as to deliver a flat 'spread-out-Bragg-peak' (SOBP approach); (c) beamlet weights calculated to deliver a gradient from the distal (maximal dose) to the proximal edge (inverse wedge); (d) beamlet weights set universally to zero except the most distal one, for each given lateral direction (i.e. distal-edge-tracking, DET). An analysis of robustness to range errors has been performed by recalculating plans, assuming a systematic 3% error in CT values. Results showed that IMPT plans optimized with the forward wedge approach were very sensitive to range errors, since organs-at-risk (OAR) were spared by patching single-field lateral and distal fall-offs, the last ones being strongly sensitive to range errors. In addition a plan robust to range errors can be achieved by starting the optimization process in the case of low-dose constraints to OAR, with the initial flat SOBP approach, and with either the DET or the inverse wedge approaches, in the case of stringent dose-volume constraints to OAR. 'Starting condition-based optimization' as proposed here can therefore provide a tool to transparently 'steer' the optimization outcome to solutions more robust to uncertainties.

The transnasal transclival approach for clivus chordoma.

BACKGROUND: We present our experience using a standardized transnasal transclival approach (TTA) for endoscopic removal of chordomas of the clivus. PATIENTS: 13 patients with clival chordoma (CC) underwent tumor resection. Patients were operated by a surgical team consisting of a rhinosurgeon and a neurosurgeon. All patients underwent postoperative proton radiotherapy. Residual tumor was left in situations where radical removal would have entailed an increased risk of neurological deficits. RESULTS: Radical or near total removal of CC was accomplished in 12/13 patients. Intraoperative MRI (IMRI) was used in 4/13 CC patients. A watertight dural seal presented as the main challenge specifically for tumor extensions resulting in large dural defects. CONCLUSION: The TTA provides an elegant alternative to classical approaches to clival lesions especially for midline tumor locations. For large tumors iMRI is of significant help. Dural reconstruction of large defects emerged as the greatest challenge of this technique even for experienced endoscopic surgeons.

Tumour tracking with scanned proton beams: assessing the accuracy and practicalities.

The potential of tumour tracking for active spot-scanned proton therapy was assessed. Using a 4D-dose calculation and simulated target motion, a tumour tracking algorithm has been implemented and applied to a simple target volume in both homogenous and heterogeneous in silico phantoms. For tracking and retracking (a hybrid solution combining tumour tracking and rescanning), three tracking modes were analysed: 'no tracking' (uncorrected irradiation of a moving target), 'perfect tracking' (no time delays and exact knowledge of target position) and 'imperfect tracking' (simulated time delays or position prediction errors). For all plans, dose homogeneity in the target volume was assessed as the difference between D5 and D95 in the CTV. For the homogeneous phantom, perfect tracking could retrieve nominal dose homogeneity for all motion phases and amplitudes while severe deterioration of treatment outcomes was found for imperfect tracking. The use of retracking reduced the sensitivity to position errors significantly in the homogeneous phantom. In the heterogeneous phantoms (simulated rib proximal to target), the nominal dose homogeneity could not be obtained with perfect tracking. Adjustments in pencil beam positions could cause pencil beams to deform under the influence of the bone, resulting in loss of dose homogeneity. As retracking was not capable of reducing these effects, rescanning provided the best treatment outcomes for moving heterogeneous targets in this study.

[Diffusion-weighted MRI--a new parameter for advanced rectal carcinoma?]. / Diffusionsgewichtete Magnetresonanztomographie--Ein neuer Prognoseparameter beim fortgeschrittenen Rektumkarzinom?

PURPOSE: To evaluate the predictive value of apparent diffusion coefficient (ADC) on therapy outcome of combined chemoradiation in patients with primary carcinoma of the rectum. MATERIALS AND METHOD: Prior to standardized, combined, neoadjuvant chemoradiation, 16 patients with primary carcinoma of the rectum (cT3) were examined with magnetic resonance imaging (MRI). Diffusion-weighted spin echo echo-planar images (SE-EPI) and contrast-enhanced T 1 -weighted spin echo (SE) images at 1.5 Tesla were obtained. The mean ADC of the tumor region was calculated and correlated with the therapy outcome substantiated by postsurgical histopathologic staging. RESULTS: Tumor down-staging (pT0-2) occurred in 9 patients (therapy responders) and no down-staging (pT3) in 7 patients (therapy non-responders). The mean ADC measured 0.476 +/- 0.114 x 10(-3) mm 2/s in the responder group and 0.703 +/- 0.085 x 10(-3) mm 2/s in the non-responder group. Comparison of the mean ADC between the groups reached statistical significance (p = 0.001). CONCLUSION: The mean ADC might be a new quantitative parameter to predict therapy outcome of combined preoperative chemoradiation in patients with primary carcinoma of the rectum.

Conformal proton radiation treatment for retroperitoneal neuroblastoma: introduction of a novel technique.

BACKGROUND: Postoperative irradiation for locoregionally advanced neuroblastoma requires coverage of the paraspinal retroperitoneum. The proximity of both kidneys and the liver, and a more complex target configuration, can pose a dosimetric challenge for conventional X-ray treatment and intraoperative irradiation. We utilized proton radiation therapy (PRT) to reduce dose to uninvolved kidneys, liver, intestine, and spinal cord. PROCEDURE: A 4-year-old male underwent PRT for neuroblastoma of the right adrenal gland, following chemotherapy and delayed surgical resection. Clinical target volume (CTV), boost volume, and normal structures were outlined on the 3D treatment planning CT scan. The patient received 25.2 CGE (cobalt Gray equivalent) to the CTV and 34.2 CGE to the boost region, using 1.8 CGE per fraction, five treatments per week. Dose-volume histograms (DVHs) were obtained for target and nontarget structures. RESULTS: The 95% isodose volume enclosed CTV and boost volumes. The dose to 50% of the ipsilateral kidney, with tumor involvement of the medial renal surface, was < or = 16 CGE (47% of prescribed total dose). Doses to 50% and 20% of the contralateral kidney in close proximity to deep left-side, paraspinal soft tissue involvement were restricted to 1 CGE and 10 CGE, respectively. Eighty percent of the liver received 27 CGE (80% of prescribed dose). Using a patch technique, unique to charged particle therapy, the spinal cord was almost completely spared during boost volume irradiation. CONCLUSIONS: PRT can achieve excellent dose conformity for advanced retroperitoneal, paraspinal lesions, while respecting normal tissue tolerance levels.

Review of skull base chordomas: prognostic factors and long-term results of proton-beam radiotherapy.

Fractionated proton beam radiotherapy has been used for skull base tumors in the United States since the mid-70s, and more than 300 patients in whom diagnosis of chordoma of the skull base has been made have been treated. The ability to achieve high degrees of radiation dose conformity by using protons has resulted in higher radiation doses than can be delivered with conventional radiotherapy in the base of skull. High target volume doses have led to improved tumor control and patient survival. Side effects such as severe toxicity are acceptable considering the alternatives of uncontrolled tumor growth. The authors of various analyses have identified prognostic factors that can be used to predict a patient's chance of treatment success. On the horizon are important technical developments that will further increase dose conformity and increase target doses. In this paper the author reviews long-term outcome data and prognostic predictors for survival of patients with skull base chordomas based on the largest worldwide patient series.

Conformal proton radiation therapy of the posterior fossa: a study comparing protons with three-dimensional planned photons in limiting dose to auditory structures.

PURPOSE: Conventional radiation therapy for pediatric posterior fossa tumors can cause sequelae such as hearing loss and impairments in language and learning. Modern three-dimensional (3D) treatment techniques have improved dose conformity to the posterior fossa. This report compares the normal tissue dose-sparing capabilities of proton radiation therapy (PRT) with 3D conformal photon plans. METHODS AND MATERIALS: Nine children underwent previous PRT for primary CNS malignancies. Using original planning CT scans, the posterior fossa, inner and middle ear, and temporal lobes were delineated. Three-dimensional treatment plans were generated for protons and photons. Normal tissue exposures were calculated by averaging mean doses received and by analysis of dose-volume histogram. RESULTS: The 95% isodose encompassed the posterior fossa in all plans. Normal structures received markedly less radiation from PRT plans than from 3D photon plans. The cochlea received an average mean of 25 +/- 4% of the prescribed dose from PRT, and 75 +/- 6% from photons. Forty percent of temporal lobe volume was completely excluded using protons; with photons 90% of the temporal lobe received 31% of the dose. CONCLUSION: PRT resulted in increased dose sparing of normal structures analyzed. Posterior fossa conformity of 3D photons came at the expense of increasing amounts of normal tissue receiving low to moderate doses.

Proton radiation therapy for chordomas and chondrosarcomas of the skull base.

Most patients with conventional radiotherapy after surgery die with local disease progression. The superior local tumor control and overall survival achieved with fractionated proton RT can be attributed to improved dose localization characteristics of protons, resulting in higher doses delivered. Patients with base of skull neoplasms are increasingly considered for stereotactic radiosurgery. Recently, Muthukumar et al reported for the University of Pittsburgh group on cobalt-60 Gamma Knife (Elekta Instruments, Atlanta, GA) therapy for 15 patients with chordomas or chondrosarcomas of the base of the skull. With tumor volumes ranging between 0.98 and 10.3 mL (mean, 4.6 mL), doses to the tumor margin varying from 12 to 20 Gy (median, 18 Gy) were delivered. Two patients were treated without histologic tumor confirmation. After a median follow-up time of 40 months, 2 patients had died of disease, 2 patients had succumbed to intercurrent disease, and 1 patient surviving at the time of analysis had developed tumor progression. Neither actuarial local control nor actuarial survival data were presented. In the LLUMC series, most tumors exceeded sizes reportedly suitable for radiosurgery or were of a highly irregular configuration. Nevertheless, in 11 patients, tumors less than 15 mL in size remained locally controlled as did tumors sized between 15 and 25 mL in 11 additional patients; these patients were thus potential candidates for stereotactic radiosurgery. At present, too few reports on radiosurgery contain sufficient patient numbers and statistical analyses to permit one to draw conclusions about the feasibility of radiosurgery for chordomas and chondrosarcomas of the base of the skull. A principal difference between proton RT and radiosurgery as currently practiced in most centers concerns target definition. In proton RT, the GTV is treated. In addition, a clinical volume is defined, which is distinctly different from the GTV in size and shape, to include the operative site and other areas of microscopic risk. In many instances, only the GTV is targeted in radiosurgery. Although it is certainly appropriate to explore the role that radiosurgical techniques may have in treating these tumors, results should be evaluated against the excellent outcome that can be achieved with fractionated proton RT, particularly in patients with tumors small enough and of favorable configuration and location to make them candidates for radiosurgery. The present problem of particle therapy is its limited availability. In the United States, only two proton centers can currently provide treatment for base of skull lesions. The HCL is soon to be replaced by a hospital-based facility at the MGH. Several other proton centers in the United States are currently under active consideration. Proton RT is an evolutionary process. Recent developments in proton RT include intensity modulated therapy and improvements in beam delivery systems, namely, the introduction of active beam scanning. These should further increase the degree of dose conformity. In addition, other heavy particles are also being investigated so as to combine the physical advantages of protons with the differential increased biologic effectiveness of particles in tumor as compared to normal tissues. A report from the Heavy Ion Research Facility in Darmstadt, Germany, has not revealed any increased acute toxicities in the first 13 patients with skull base chordomas or chondrosarcomas treated using carbon ions. Several important factors have emerged from recently published results: Patients with low-grade chondrosarcomas and male patients with chordomas have an excellent chance of durable tumor control and long-term survival after proton RT. Severe complications are within the acceptable range considering the high doses delivered and given the major morbidity associated with uncontrollable tumor growth in such patients. Female patients with chordomas experience increased early and late failures

Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy.

OBJECTIVE: Atypical and malignant meningiomas are at high risk for local failure. The role of radiation therapy (RT) and dose levels required to improve tumor control are poorly defined. This study reviews our experience with RT. MATERIAL AND METHODS: Thirty-one patients underwent fractionated RT for atypical (AM, 15 patients) or malignant meningioma (MM, 16 patients) of the cranium. Sixteen patients presented with primary and 15 with recurrent disease. Eight patients received RT following total resection, 21 patients after subtotal resection and 2 patient following biopsy only. RT was given using megavoltage photons in 15 patients and combined photons and 160 MeV protons in 16 patients. Total target doses ranged from 50 to 68 (AM, mean 62) and from 40 to 72 (MM, mean 58) Gy or CGE (= cobalt-gray-equivalent). RESULTS: With mean observation time of 59 months (range: 7-155 months) actuarial local control rates at 5- and 8-years were similar for both histologies (38% and 19% for AM and 52 and 17% for MM). However, significantly improved local control was observed for proton versus photon RT (80% versus 17% at 5 years, p = 0.003) and target doses > or = 60 Gy for both, atypical (p = 0.025) and malignant meningioma (p = 0.0006). At time of analysis, 14/15 patients (93%) with AM and 6/16 (38%) with MM were alive. Three patients (19%) with MM developed distant metastasis. Actuarial 5- and 8-year survival rates for MM were significantly improved by use of proton over photon RT and radiation doses > 60 CGE. Three patients developed symptomatic radiation damage after 59.3, 68.4 and 72 Gy/CGE. CONCLUSION: Conformal, high dose RT resulted in significant improvement of local control for atypical and malignant meningiomas. Increased local control resulted also in improved rates of survival for patients with malignant meningioma.

Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique.

PURPOSE: Most children with orbital rhabdomyosarcoma will survive their disease. However, conventional photon-radiation treatment, as part of multimodality therapy, results in varying degrees of long-term functional and cosmetic side effects. This report introduces external beam proton radiation therapy (PRT) as a conformal, three-dimensional planned radiation technique for this disease, analyzes normal tissue dosimetry, and describes the technique's application in the first 2 patients. MATERIAL AND METHODS: Between January 1995 and February 1996, 2 patients underwent PRT following biopsy and chemotherapy for orbital rhabdomyosarcoma. Fifty and 55 Cobalt Gray Equivalent (CGE) were delivered to the gross tumor volume and 40 CGE to clinical target volumes in both patients. A relative biologic effectiveness (RBE) of 1.1 was utilized to correlate proton dose calculations with CGE. To achieve dose conformity, a "patch technique" was utilized, where target regions were divided into segments, each treated by a separate proton field. Dose-volume histograms were obtained for target and nontarget regions, including lens, bony orbit, pituitary gland, optic chiasm, optic nerves, lacrimal gland, and ipsilateral frontal and temporal lobes. RESULTS: At 3.4 and 2.5 years after PRT, both patients are clinically and radiographically free of disease. Visual acuity remains excellent, without signs of cataract formation; pituitary function is normal; cosmetically, only mild enophthalmos is noticeable. Doses to 90%, 50%, and 5% of lens volume were kept at less than 1%, less than 2%, and less than 8%, respectively. Fifty percent of lacrimal gland volume received less than 36% of the prescribed dose and 50% of the volume of the optic chiasm, pituitary gland, and hypothalamus were restricted to less than 2%. Proton conformity to orbital contents resulted in between 9% and 36% of the prescribed dose reaching the ipsilateral temporal and frontal lobes immediately adjacent to bony orbit (5% volume). CONCLUSION: PRT can offer excellent sparing of lens and selected intraorbital and ocular normal structures, while maintaining conformal target-dose coverage. The steep dose gradient beyond the orbit minimizes irradiation of normal brain parenchyma, with almost complete sparing of the pituitary gland. Reduction of integral irradiation exposure of the periorbital region will, hopefully, reduce the risk of second malignancy later in life. Reduced radiation dose to specific organs in close proximity to, but not part of the target region promises improved functional outcome and better cosmesis for childhood cancer survivors.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

Full Scale IQ (FSIQ) changes in children treated with whole brain and partial brain irradiation. A review and analysis.

PURPOSE: Neuropsychological impairment has been reported following whole brain and partial brain irradiation in children. The purpose of this analysis was to assess current knowledge, with focus on correlation with radiation dose, irradiated volume and age. METHOD: Full Scale IQ (FSIQ) data, representing 1,938 children, were derived from 36 publications and analyzed as to radiation dose, irradiated volume, and age. RESULTS: FSIQ after whole brain irradiation showed a non-linear decline as dosage increased. The dose-effect relationship was age-related, with more pronounced FSIQ decline at younger age. FSIQ test results below the normal level (< 85) were found at doses higher than 24 and 36 Gy in children under age 3, and older than age 6, respectively. Mean FSIQ test result after 18 Gy was 100, thus at the mean standard value; a minor decline was detectable only when compared to test results of a control group. Young children scored at this dose in the low normal range. Partial brain irradiation caused minor FSIQ decline, with measurable effects at dose levels > 50 Gy. CONCLUSION: The collected data suggest that whole brain irradiation doses of 18 and 24 Gy have no major impact on intellectual outcome in children older than age 6, but may cause impairment in younger children. Doses > 24 Gy comprise a substantial risk for FSIQ decline, even in older children. At equal dose levels, partial brain irradiation is less damaging than whole brain irradiation. The authors are well aware of limitations in the interpretation of data collected for the current review. Thus, further research is required to evaluate the effect of low-dose whole brain irradiation as well as partial brain irradiation on FSIQ development.

Normal tissue complication probability (NTCP) calculations as a means to compare proton and photon plans and evaluation of clinical appropriateness of calculated values.

Calculation of normal tissue complication probabilities (NTCP) for proton radiation therapy (PRT) and two photon radiation therapy techniques for cranial irradiation of childhood optic nerve gliomas was made. Evaluation of usefulness of calculated NTCP values for comparison of treatment plans and clinical appropriateness of computed data was used. Three radiation plans were calculated on datasets of children treated previously for optic nerve gliomas with PRT. Dose-volume histograms (DVH) were computed and used to calculate NTCP. Evaluated complication endpoints were necrosis, blindness, and cognitive impairment. Calculated NTCP depended strongly on tumor volume and the normal tissue volume exposed to high radiation doses. Dose conformity and steeper dose-gradient correlated with reduced NTCP. Regarding the chosen complication endpoints, PRT was superior to 3D photons; conventional photons were calculated to have the highest NTCPs. Differences might reach clinical significance for cognitive impairment, a frequently observed toxicity. Calculated NTCP values were highly dependent on implemented clinical data. Calculation of NTCP can be used for ranking of treatment plans and modalities. Highly dependent on implemented clinical data, the calculated percentage of NTCP might be more of a figure of merit than a real predictive value and requires comparison to clinical experience. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 351-358 (2000).

Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique.

PURPOSE: Following adequate therapy, excellent long-term survival rates can be achieved for patients with optic pathway gliomas. Therefore, avoidance of treatment-related functional long-term sequelae is of utmost importance. Optimized sparing of normal tissue is of primary concern in the development of new treatment modalities. The present study compares proton radiation therapy (PRT) with a three-dimensional (3D)-planned multiport photon and a lateral beam photon technique for localized and extensive optic pathway tumors. METHODS AND MATERIALS: Between February 1992 and November 1997, seven children with optic pathway gliomas underwent PRT. For this study, we computed proton, 3D photon, and lateral photon plans based on the same CT data sets, and using the same treatment planning software for all plans. Radiation exposure for normal tissue and discrete organs at risk was quantified based on dose-volume histograms. RESULTS: Gross tumor volume (GTV) ranged from 3.9 cm3 to 127.2 cm3. Conformity index (relation of encompassing isodose to GTV volume) was 2.3 for protons, 2.9 for 3D photons, and 7.3 for lateral photons. The relative increase of normal tissue (NT) encompassed at several isodose levels in relation to NT encompassed by the 95% proton isodose volume was computed. Relative NT volume of proton plan isodoses at the 95%, 90%, 80%, 50%, and 25% isodose level increased from 1 to 1.6, 2.8, 6.4, to a maximum of 13.3. Relative volumes for 3D photons were 1.6, 2.4, 3.8, 11.5, and 34.8. Lateral plan relative values were 6, 8.3, 11.5, 19.2, and 26.8. Analysis for small (<20 cm3) and larger (> 80 cm3) tumors showed that protons encompassed the smallest volumes of NT at all isodose levels. Comparable conformity and high-dose gradient were achieved for proton and 3D photon plans in small tumors. However, with increasing tumor volume and complexity, differences became larger. At the 50% isodose level, 3D photons were superior to lateral photons for small tumors; this advantage was equalized for larger tumors. At the lowest isodose level, 3D photons encompassed the highest amount of NT. Analysis of organs at risk showed that PRT reduced doses to the contralateral optic nerve by 47% and 77% compared to 3D photons and lateral photons, respectively. Reductions were also seen for the chiasm (11% and 16%) and pituitary gland (13% and 16%), with differences at clinically relevant tolerance levels. Furthermore, reduced dose exposure of both temporal lobes (sparing 39% and 54%) and frontal lobes was achieved with PRT. CONCLUSION: PRT offered a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high- and low-dose areas. It is expected that this will result in decreased long-term toxicity in the maturing child. Advantages of proton versus 3D photon plans became increasingly apparent with increasing target size and tumor complexity. Even in small tumors, conformity of 3D photon irradiation came at the expense of a larger amount of NT receiving moderate to low radiation doses. Lateral photons resulted in inferior dose distribution with high radiation exposure of clinically relevant normal tissues.

Megavoltage radiation therapy for axial and inoperable giant-cell tumor of bone.

BACKGROUND: Treatment of giant-cell tumor of bone generally involves wide en bloc resection of the lesion and the surrounding bone or curettage with or without bone-grafting or the use of cement. Radiation therapy has been used for patients who cannot be operated on for medical reasons or who have a tumor that is technically difficult to resect or that cannot be resected because of its location. We performed the present study to evaluate the efficacy of megavoltage radiation in terms of lack of tumor progression and treatment-related morbidity. METHODS: Twenty patients who had giant-cell tumor of bone were managed with a single course of megavoltage radiation (forty to seventy gray administered at 1.8 to 2.0 gray per fraction with an average total duration of treatment of five to seven weeks) between March 1973 and March 1992. We used megavoltage photons, 160-megaelectron-volt proton beams, or a combination of the two. RESULTS: After a median duration of follow-up of 9.3 years, the tumor had not progressed in seventeen of the twenty patients. Thus, the actuarial ten-year rate for lack of progression was 85 percent. Local regrowth was evident in one patient who had received radiation alone and in two of the thirteen patients who had been managed with partial resection and radiation. Operative treatment was successful in the three patients in whom the radiation treatment had failed. No radiation-induced tumors were observed in our series. CONCLUSIONS: We concluded that giant-cell tumor of bone was effectively treated with megavoltage radiation in our series of twenty patients in whom operative resection would have been difficult or was not feasible. The rate of tumors that did not progress with this regimen of radiation is similar to that reported by investigators from several other centers. Furthermore, these results closely rival those obtained with modern curettage procedures. Malignant sarcomatous transformation was not observed in our series. A longer duration of follow-up of a larger group of patients is necessary to provide a better estimate of the risk of malignant transformation.