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Fractionated stereotactic radiotherapy (SRT) requires accurate and reproducible immobilization of the patient's head. This randomized study compared the efficacy of two commonly used forms of immobilization used for SRT. Two routinely used methods of immobilization, which differ in their approach to reproduce the head position from day to day, are the Gill-Thomas-Cosman (GTC) frame and the BrainLab thermoplastic mask. The GTC frame fixates on the patient's upper dentition and thus is in direct mechanical contact with the cranium. The BrainLab mask is a two-part masking system custom fitted to the front and back of the patient's head. After patients signed an IRB-approved informed consent form, eligible patients were randomized to either GTC frame or mask for their course of SRT. Patients were treated as per standard procedure; however, prior to each treatment a set of digital kilovolt images (ExacTrac, BrainLabAB, Germany) was taken. These images were fused with reference digitally reconstructed radiographs obtained from treatment planning CT to yield lateral, longitudinal, and vertical deviations of isocenter and head rotations about respective axes. The primary end point of the study was to compare the two systems with respect to mean and standard deviations using the distance to isocenter measure. A total of 84 patients were enrolled (69 patients evaluable with detailed positioning data). A mixed-effect linear regression and two-tiled t test were used to compare the distance measure for both the systems. There was a statistically significant (p < 0.001) difference between mean distances for these systems, suggesting that the GTC frame was more accurate. The mean 3D displacement and standard deviations were 3.17+1.95 mm for mask and 2.00+1.04 mm for frame. Both immobilization techniques were highly effective, but the GTC frame was more accurate. To optimize the accuracy of SRT, daily kilovolt image guidance is recommended with either immobilization system.

Purpose: The purpose of this study is to analyze changes in quality of life (QOL) and symptoms from pretreatment to 6 weeks posttreatment in a Phase III randomized study (Radiation Therapy Oncology Group 9801) of amifostine (AM) vs. no AM in patients with Stages II-III non-small-cell lung cancer receiving paclitaxel and carboplatin as induction and then concurrently with hyperfractionated radiation therapy (RT)., Methods and Materials: One hundred thirty-eight patients with baseline and 6-week posttreatment QOL data were analyzed. There were no significant differences in baseline demographics between those who did and did not have QOL data. The QOL and symptoms were assessed by using the European Organization for Research and Treatment of Cancer (EORTC) Global QOL and Pain subscales and the EORTC-Lung Cancer-13 symptom tool. Clinically relevant changes in QOL were characterized by 10-point differences in individual scores pre/post treatment. A daily diary of patient-rated difficulty swallowing and a weekly physician-rated dysphagia log (using National Cancer Institute Common Toxicity Criteria) were completed during treatment. Weight loss was monitored. Differences in outcomes were examined according to smoking status, alcohol use, and sex., Results: Patients receiving AM reported significantly greater pain reduction after chemoradiation (34% vs. no AM, 21%), less difficulty swallowing during chemoradiation, and less weight loss than patients not receiving AM. However, physician-rated assessments of dysphagia were not significantly different by treatment arm. There were no other significant changes in QOL or symptoms according to treatment arm, smoking status, alcohol use, or sex., Conclusions: Patient evaluations of difficulty swallowing and pain suggest benefits from AM use that are distinct from clinician-rated assessments.

'Conformal radiation therapy' is the standard of care in radiation oncology, referring to the process of shaping the radiation beam to precisely match a tumor's physical dimensions. We describe 'biologically conformal radiotherapy', in which the radiation oncologist matches the prescribed treatment to a tumor's biological characteristics and the host's predicted tolerance of radiation. This paradigm emphasizes that not all tumors are equally sensitive to radiation; conversely, some patients are especially susceptible to radiation's side effects. Patients bearing radioresistant tumors or those prone to toxicity may be best treated with the incorporation of targeted radiation modulators or, in extreme cases, by a different modality. The biological characteristics of tumors can be assessed by a wide range of techniques: functional imaging (positron emission tomography and advanced magnetic resonance imaging), single gene/protein molecular techniques and 'omic' technologies. This paper reviews the latest advances in the use of biomarkers and functional imaging in guiding patients to receive the most appropriate treatment.

Objective: To review outcomes after fractionated stereotactic radiotherapy (FSR) and stereotactic radiosurgery (SRS) for nonacoustic cranial nerve schwannomas., Methods: We reviewed medical records of 39 patients who received FSR or SRS for nonacoustic cranial nerve schwannomas at our institution during the period from 1996 to 2007., Results: Tumors involved Cranial Nerves V (n = 19), III (n = 2), VI (n = 3), VII (n = 5), IX (n = 2), X (n = 5), and XII (n = 2) and the cavernous sinus (n = 1). Irradiation was performed after partial resection, biopsy, or no previous surgery in 16, 2, and 21 patients, respectively. Twenty-four patients received FSR, delivered in 1.8- to 2.0-Gy fractions to a median dose of 50.4 Gy (range, 45.0-54.0 Gy). Fifteen patients received SRS to a median dose of 12.0 Gy (range, 12-15 Gy). Mild acute toxicity occurred in 23% of the patients. The 2-year actuarial tumor control rate after FSR and SRS was 95%. The median follow-up period was 24 months. Changes in cranial nerve deficits after stereotactic irradiation were analyzed for patients with follow-up periods greater than 12 months (n = 26); cranial nerve deficits improved in 50%, were stable in 46%, and worsened in 4% of the patients. No significant difference was observed for FSR compared with SRS with regard to local control or to improvement of cranial nerve-related symptoms (P = 0.17)., Conclusion: SRS and FSR are both well-tolerated treatments for nonacoustic cranial nerve schwannomas, providing excellent tumor control and a high likelihood of symptomatic improvement.

Cicatricial or scarring alopecia represents permanent destruction of the hair follicle, histopathologically showing a decreased number of follicular units leaving streamers of fibrosis or hyalinization of surrounding collagen. High-dose radiation therapy (RT) used for treating intracranial malignancy can permanently destroy hair follicles, resulting in permanent alopecia. Typically, there also is clinical scarring of the skin with dermal fibrosis. We report a case of radiation-induced cicatricial alopecia confirmed by histopathology, without obvious clinical scarring or dermal fibrosis. This lack of fibrosis made our patient a good candidate for hair transplantation. The clinicopathologic presentation in this case could be related to the method of RT employed in treating our patient's brain tumor. A literature review of radiation-induced cicatricial alopecia, as well as a brief discussion of the current radiation methods used in the treatment of intracranial malignancy, is presented. We believe that because most anagen follicles are approximately 4 mm deep in the skin, if the dose of radiation superficial to a depth of 5 mm is kept under 16 Gy, which is the approximate lethal dose for hair follicles, the incidence of radiation-induced cicatricial alopecia could be avoided or markedly decreased.

Purpose: Patients with non-small-cell lung cancer (NSCLC) in the Radiation Therapy Oncology Group (RTOG) 93-11 trial received radiation doses of 70.9, 77.4, 83.8, or 90.3 Gy. The locoregional control and survival rates were similar among the various dose levels. We investigated the effect of the gross tumor volume (GTV) on the outcome., Methods and Materials: The GTV was defined as the sum of the volumes of the primary tumor and involved lymph nodes. The tumor response, median survival time (MST), and progression-free survival (PFS) were analyzed separately for smaller (< or =45 cm(3)) vs. larger (>45 cm(3)) tumors., Results: The distribution of the GTV was as follows: < or =45 cm(3) in 79 (49%) and >45 cm(3) in 82 (51%) of 161 patients. The median GTV was 47.3 cm(3). N0 status and female gender were associated with better tumor responses. Patients with smaller (< or =45 cm(3)) tumors achieved a longer MST and better PFS than did patients with larger (>45 cm(3)) tumors (29.7 vs. 13.3 months, p < 0.0001; and 15.8 vs. 8.3 months, p < 0.0001, respectively). Increasing the radiation dose had no effect on the MST or PFS. On multivariate analysis, only a smaller GTV was a significant prognostic factor for improved MST and PFS (hazard ratio [HR], 2.12, p = 0.0002; and HR, 2.0, p = 0.0002, respectively). The GTV as a continuous variable was also significantly associated with the MST and PFS (HR, 1.59, p < 0.0001; and HR, 1.39, p < 0.0001, respectively)., Conclusions: Radiation dose escalation up to 90.3 Gy did not result in improved MST or PFS. The tumor responses were greater in node-negative patients and women. An increasing GTV was strongly associated with decreased MST and PFS. Future radiotherapy trials patients might need to use stratification by tumor volume.

Objective: Despite the success of stereotactic radiosurgery, large inoperable arteriovenous malformations (AVMs) of 14 cm3 or more have remained largely refractory to stereotactic radiosurgery, with much lower obliteration rates. We review treatment of large AVMs either previously untreated or partially obliterated by embolization with fractionated stereotactic radiotherapy (FSR) regimens using a dedicated linear accelerator (LINAC)., Methods: Before treatment, all patients were discussed at a multidisciplinary radiosurgery board and found to be suitable for FSR. All patients were evaluated for pre-embolization. Those who had feeding pedicles amenable to glue embolization were treated. LINAC technique involved acquisition of a stereotactic angiogram in a relocatable frame that was also used for head localization during treatment. The FSR technique involved the use of six 7-Gy fractions delivered on alternate days over a 2-week period, and this was subsequently dropped to 5-Gy fractions after late complications in one of seven patients treated with 7-Gy fractions. Treatments were based exclusively on digitized biplanar stereotactic angiographic data. We used a Varian 600SR LINAC (Varian Medical Systems, Inc., Palo Alto, CA) and XKnife treatment planning software (Radionics, Inc., Burlington, MA). In most cases, one isocenter was used, and conformality was established by non-coplanar arc beam shaping and differential beam weighting., Results: Thirty patients with large AVMs were treated between January 1995 and August 1998. Seven patients were treated with 42-Gy/7-Gy fractions, with one patient lost to follow-up and the remaining six with previous partial embolization. Twenty-three patients were treated with 30-Gy/5-Gy fractions, with two patients lost to follow-up and three who died as a result of unrelated causes. Of 18 evaluable patients, 8 had previous partial embolization. MeanAVM volumes at FSR treatment were 23.8 and 14.5 cm3, respectively, for the 42-Gy/7-Gy fraction and 30-Gy/5-Gy fraction groups. After embolization, 18 patients still had AVM niduses of 14 cm3 or more: 6 in the 7-Gy cohort and 12 in the 5-Gy cohort. For patients with at least 5-year follow-up, angiographically documented AVM obliteration rates were 83%for the 42-Gy/7-Gy fraction group, with a mean latency of 108 weeks (5 of 6 evaluable patients), and 22% for the 30-Gy/5-Gy fraction group, with an average latency of 191 weeks (4 of 18 evaluable patients) (P = 0.018). For AVMs that remained at 14 cm3 or more after embolization (5 of 6 patients), the obliteration rate remained 80% (4 of 5 patients) for the 7-Gy cohort and dropped to 9% for the 5-Gy cohort. A cumulative hazard plot revealed a 7.2-fold greater likelihood of obliteration with the 42-Gy/7-Gy fraction protocol (P = 0.0001), which increased to a 17-fold greater likelihood for postembolization AVMs of 14 cm3 or more (P = 0.003)., Conclusion: FSR achieves obliteration for AVMs at a threshold dose, including large residual niduses after embolization. With significant treatment-related morbidities, further investigation warrants a need for better three-dimensional target definition with higher dose conformality.

Purpose: To assess the progression patterns in patients with multifocal glioblastoma multiforme who had undergone whole brain radiotherapy (WBRT), the historical standard, versus three-dimensional conformal radiotherapy, and to identify predictive treatment and pretreatment factors., Methods and Materials: The records of 50 patients with multifocal glioblastoma multiforme treated with RT were reviewed. Univariate analyses were performed using survival methods and the Cox proportional hazards regression method. Multivariate analyses were performed using the Cox proportional hazards regression method., Results: The mean age was 61 years, and 71% had a Karnofsky performance status (KPS) score of > or =70. Of the 50 patients, 32% underwent WBRT and 68%, three-dimensional conformal RT. Progression was local in all evaluable patients, as determined by imaging in 38 patients and early neurologic progression in 12. The median time to progression (TTP) was 3.1 months, and the median survival time (MST) was 8.1 months. The significant independent predictors of TTP on multivariate analysis were a KPS score <70 (p = 0.001), the extent of surgery (p = 0.040), a radiation dose <60 Gy (p = 0.027), and the lack of chemotherapy (p = 0.001). The significant independent predictors of a reduced MST were a KPS score <70 (p = 0.022) and the absence of salvage surgery (p = 0.011) and salvage chemotherapy (p = 0.003)., Conclusion: Local progression was observed in all patients. On multivariate analysis, no significant difference was found in the TTP or MST between three-dimensional conformal radiotherapy and WBRT. The KPS was a consistent independent predictor of both TTP and MST. On the basis of the progression pattern, we do not recommend WBRT as a mandatory component of the treatment of multifocal glioblastoma multiforme.

Lung cancer is the leading cause of cancer mortality in the United States. A significant number of patients present with disease involving mediastinal lymph nodes. As survival after surgery alone for stage III disease is poor, radiation therapy and chemotherapy have been evaluated in the neoadjuvant and adjuvant settings to improve outcomes. The benefit of adjuvant chemotherapy in the subgroup of patients with N2 disease is uncertain. Small randomized trials enrolling patients with stage III disease have shown a benefit of neoadjuvant chemotherapy over surgery alone. Whether neoadjuvant chemotherapy is superior to adjuvant chemotherapy is under investigation. Furthermore, whether neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy is controversial, and few randomized studies comparing these approaches have been reported. Nevertheless, neoadjuvant chemoradiotherapy appears to be associated with higher rates of resection, higher rates of clearance of mediastinal nodal disease, and better local/regional control. The use of postoperative radiation therapy (PORT) has declined since the publication of the 1998 meta-analysis suggested a detriment in survival with this strategy. However, radiation techniques are improving and emerging data support the use of carefully delivered PORT Finally, it remains unclear whether surgical resection offers an advantage over definitive chemoradiotherapy alone for stage III disease. In summary, locally advanced NSCLC remains a formidable challenge with few cures, and optimal treatment requires the careful use of surgery, chemotherapy, and radiation therapy.

Purpose: Long-term brain metastases survivors are at risk for neurologic morbidity after whole-brain radiotherapy (WBRT). Retrospective radiosurgery (RS) reports found no survival difference when compared with WBRT. Before RS alone was evaluated with delayed WBRT in a phase III trial, the feasibility of RS alone was tested prospectively., Patients and Methods: Patients with renal cell carcinoma, melanoma, or sarcoma; one to three brain metastases; and performance status of 0 to 2 were enrolled. Exclusion criteria were leptomeningeal disease; metastases in medulla, pons, or midbrain; or liver metastases. On the basis of tumor size, patients received 24, 18, or 15 Gy RS. At recurrence, management was discretionary. The primary end point was 3- and 6-month intracranial progression., Results: Between July 1998 and August 2003, 36 patients were accrued; 31 were eligible. Median follow-up was 32.7 months and the median survival was 8.3 months (95% CI, 7.4 to 12.2). Three- and 6-month intracranial failure with RS alone was 25.8% and 48.3%. Failure within and outside the RS volume, when in-field and distant intracranial failures were scored independently, was 19.3% and 16.2% (3 months) and 32.2% and 32.2% (6 months), respectively. Approximately 38% of patients experienced death attributable to neurologic cause. There were three grade 3 toxicities related to RS., Conclusion: Intracranial failure rates without WBRT were 25.8% and 48.3% at 3 and 6 months, respectively. Delaying WBRT may be appropriate for some subgroups of patients with radioresistant tumors, but routine avoidance of WBRT should be approached judiciously.

Purpose: Discernment of radiotherapy (XRT) effects vs. tumor activity is difficult in brain tumor patients during the months after XRT when white matter hyperintensities sometimes emerge. We examined brain scans in XRT-treated vs. untreated patients for early-delayed post-XRT effects., Methods and Materials: Brain regions susceptible to XRT injury were examined on magnetic resonance imaging (MRI) for T2-weighted hyperintensities and atrophy in 37 adults with low-grade primary brain tumors (13 nonirradiated and 24 irradiated). Cases evidencing recurrence/growth over the study period were censored. Interactions with age, mood, fatigue, medications, tumor type and grade, extent of resection, and laterality of MRI changes were examined., Results: Hyperintensity and atrophy ratings over time for the treated and untreated groups were not significantly different. White matter atrophy increased unrelated to XRT. In all patients combined, white matter atrophy and hyperintensities were greater at all time points and more lateralized in surgically treated patients., Conclusions: Radiotherapy status was not related to changes in MRI ratings during the weeks/months after XRT. Findings contradict assumptions about radiographically evidenced early-delayed XRT effects. Increases in T2-weighted hyperintensities during the 1-6-month period post-conformal radiotherapy for low-grade tumors are likely not related to early-delayed XRT effects.

Background: Medically refractory trigeminal neuralgia (TN) has been treated with a variety of minimally invasive techniques, all of which have been compared with microvascular decompression. For patients not considered good surgical candidates, percutaneous retrogasserian glycerol rhizotomy (GR) and gamma knife (GK) radiosurgery are two minimally invasive techniques in common practice worldwide and used routinely at Jefferson Hospital for Neuroscience. Using a common pain scale outcomes questionnaire, we sought to analyze efficacies and morbidities of both treatments., Methods and Materials: Between June 1994 and December 2002, 79 patients were treated with GR and 109 patients underwent GK for the treatment of TN. GR was performed with fluoroscopic guidance as an overnight inpatient procedure. GK was performed using a single 4-mm shot positioned at the root exit zone of the trigeminal nerve. Radiation doses of 70-90 Gy prescribed to the 100% isodose line were used. Treatment outcomes including pain response, pain recurrence, treatment failure, treatment-related side effects, and overall patient satisfaction with GK and GR were compared using a common outcomes scale. Using the Barrow Neurologic Institute pain scale, patients were asked to define their level of pain both before and after treatment: I, no pain and no pain medication required; I, occasional pain not requiring medication; IIIa, no pain and pain medication used; IIIb, some pain adequately controlled with medication; IV, some pain not adequately controlled with medication; and V, severe pain with no relief with medication. We used posttreatment scores of I, II, IIIa, and IIIb to identify treatment success, whereas scores of IV and V were considered treatment failure. Results were compiled from respondents and analyzed using SAS software. Statistical comparisons used log-rank test, univariate and multivariate logistic regression, Fisher's exact test, and Wilcoxon test with significance established at p < 0.05., Results: There were 63 evaluable GK patients and 36 evaluable GR patients. The median follow-up time was 34 and 29 months for the GR and GK groups, respectively. The median age was 69 and 70 years and the median number of years with TN pain was 6 and 7 years in the GR and GK groups, respectively. Thirty-one GR (86%) and 58 GK (92%) patients achieved a successful treatment outcome (p = 0.49). The median time to pain relief was < or = 24 h in the GR group and 3 weeks in the GK group (p < 0.001, ordinal logistic regression). Nineteen GR and 26 GK patients experienced pain recurrence or pain never relieved (p = 0.30). The median time to pain recurrence was 5 and 8 months in the GR and GK groups, respectively (p = 0.22). At last follow-up, however, a statistically significant greater number of GR vs. GK patients had failed treatment. Twelve or 33% of GR patients, whereas 8 or 13% of GK patients, had BNI scores of 4 or 5 (p = 0.019, Fisher's exact test). When both initial and late treatment failures were combined, the overall rate of treatment failures was 39% in the GR group and 24% in the GK group (p = 0.023, log-rank). More GR patients developed facial numbness and facial numbness morbidity than GK patients: 19 GR (54%) and 17 GK patients (30%) developed new facial numbness and 12 GR and 7 GK patients reported either somewhat or very bothersome facial numbness (p = 0.018). On multivariate analysis, only treatment with GK and severity of pain before treatment significantly predicted treatment response. GK patients were more likely to have a lower pain score at last follow-up than were GR patients (p = 0.005, OR = 4.3), and patients with pretreatment pain scores of 5 were more likely to have lower posttreatment pain scores than patients with pretreatment pain scores of 4 and lower (p = 0.003, OR = 4.0)., Conclusion: Despite greater facial numbness morbidity and a higher failure rate, GR provided more immediate pain relief than GK. GR therefore should be considered in patients with disabling trigeminal pain requiring urgent pain relief. For all other patients, GK provides better long-term pain relief with less treatment-related morbidity, and should therefore be considered the preferred treatment for patients with medically refractory trigeminal neuralgia who are not suitable candidates for microvascular nerve decompression.

Purpose: To evaluate dosimetric predictors of acute esophagitis (AE) and clinical outcome of patients with non-small-cell lung cancer (NSCLC) receiving reirradiation., Methods and Materials: Seventeen patients with NSCLC received reirradiation to the lung tumors/mediastinum, while immobilized in stereotactic body frame (SBF). CT simulation and hypofractionated three-dimensional radiotherapy were used. Two axial segments of esophagus contours merged together were defined as esophagus disc (ED). For each ED, the percentage (%) of the volume of esophageal circumference treated to % of prescribed dose (PD) was assessed. Number of EDs with 50% or any % of volume (V) of esophageal circumference receiving more than or equal to (>/=) 50%, 80%, and 100% of PD (50% V >/=50% PD; 50% V >/=80% PD; any % V >/=100% PD) were calculated. These dosimetric variables and the length of the esophagus within the radiation therapy (RT) port were correlated with AE using exact Wilcoxon test., Results: A median RT dose was 32 Gy with a median fraction size of 4 Gy. Eleven of 13 patients presenting with pain and/or shortness of breath had complete or partial resolution of symptoms. Median survival time from the start of reirradiation in SBF until death was 5.5 months. AE was observed in 7 patients and resolved within 3 months of RT completion. No Grade 3 or higher events were noticed. The length of the esophagus within RT port did not predict for AE (p = 0.71). However, an increased number of EDs predicted for AE for the following dosimetric variables: 50% V >/=50% PD (p = 0.023), 50% V >/=80% PD (p = 0.047), and any % V >/=100% PD (p = 0.004). Patients with at least 2 EDs receiving >/=100% PD to any % V of circumference had AE compared to those with zero EDs., Conclusions: Reirradiation using hypofractionated three-dimensional radiotherapy and SBF immobilization is an effective strategy for palliation of symptoms in selected patients with recurrent NSCLC. The length of the esophagus in the RT field does not predict for AE. However, an increasing number of EDs displaying the combination of longitudinal and circumferential three-dimensional dose distribution along the esophagus is a valuable predictor for AE.

Current therapeutic approaches for lung cancer favor treatment intensification, with the presumption that dose-intense chemotherapy regimens and/or higher radiation therapy (RT) doses or novel fractionation schemes will result in increased patient survival. Also, the trend for non-operative therapy has favored concurrent over sequential regimens. The incidence of severe acute esophagitis in patients treated for lung cancer with standard (once daily) RT alone is 1.3%, and induction chemotherapy increases the risk of severe acute esophagitis slightly over that of standard RT alone. In contrast, a strong radiosensitizing effect of chemotherapy given concurrently with standard thoracic RT (chemoRT) is associated with an incidence of severe esophagitis of 14% to 49%. Acute esophagitis may be severe and disabling, and result in hospitalization, placement of a feeding tube in the stomach or intravenous feedings, and steady supportive care. Also, RT may need to be halted temporarily to allow for healing of the esophageal lining; treatment breaks in turn decrease survival of patients with unresectable lung cancer. Therefore, esophagitis as a dose-limiting toxicity of chemoRT may have a direct impact on tumor control and survival. Aggressive types of RT fractionation have also been associated with worsening esophagitis grades and duration. Moreover, it is commonly assumed in the radiation oncology clinic that the longer the length of the esophagus segment included in the RT field the higher the probability of esophageal toxicity, although differing opinions are commonly expressed. Recent advances in 3-dimensional conformal RT allow a unique chance to gain volumetric data pertaining to organ damage rather than rely on older estimates based on organ length (eg, esophagus) or portion (ie, lung, spinal cord). The Radiation Therapy Oncology Group (RTOG) conducted a large phase III, randomized study RTOG 98-01 examining chemoRT with or without the amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD), a cyto- and radioprotectant in locally advanced non-small cell lung cancer (n = 243). While amifostine did not significantly reduce severe esophagitis based on National Cancer Institute Common Toxicity Criteria and weekly physician dysphagia logs, swallowing dysfunction over time (based on patient diaries, the equivalent of Esophagitis Index) was significantly lower in the amifostine arm ( P = .03). Therefore, significant progress has been accomplished in our understanding of the basis of esophageal injury resulting from thoracic RT, and future effort may find other effective strategies to either minimize or eliminate esophagitis.

Esophagitis is a major complication of chemoradiation therapy in patients with non-small cell lung cancer, producing significant morbidity and resulting in treatment interruptions. Amifostine at different doses and schedules has been found to reduce frequency or severity of esophagitis in this setting. In the Radiation Therapy Oncology Group 98-01 trial in non-small cell lung cancer patients receiving chemoradiation therapy, amifostine given intravenously four times weekly did not significantly reduce the frequency of grade 3 or 4 esophagitis; however, a significant reduction in severity over time was observed in patient swallowing diaries. The potential benefits of amifostine may have been obscured by inability to provide full amifostine doses due to toxicity associated with infusion, scheduling of doses, and inadequate follow-up to monitor severity of esophagitis over time. These issues are to be addressed in a randomized phase II trial of amifostine given subcutaneously or via intravenous bolus in non-small cell lung cancer patients undergoing chemoradiation treatment.

Purpose: To test the ability of the cytoprotectant, amifostine, to reduce chemoradiotherapy-induced esophagitis and evaluate its influence on quality of life (QOL) and swallowing symptoms., Patients and Methods: A total of 243 patients with stage II to IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m(2) intravenously (IV) days 1 and 22 and carboplatin area under the curve (AUC) days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m(2) IV) and carboplatin (AUC 2), and hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy bid). Patients were randomly assigned at registration to amifostine (AM) 500 mg IV four times per week or no AM during chemoradiotherapy. Beyond standard toxicity end points, physician dysphagia logs (PDLs), daily patient swallowing diaries, and QOL (EORTC QLQ-C30/LC-13) were also collected. Swallowing AUC analyses were calculated from patient diaries and PDLs., Results: A total of 120 patients were randomly assigned to receive AM, and 122, to receive no AM (one patient was ineligible); 72% received AM per protocol or with a minor deviation. AM was associated with higher rates of acute nausea (P = .03), vomiting (P = .007), cardiovascular toxicity (P = .0001), and infection or febrile neutropenia (P = .03). The rate of >/= grade 3 esophagitis was 30% with AM versus 34% without AM (P = .9). Patient diaries demonstrated lower swallowing dysfunction AUC with amifostine (z test P = .025). QOL was not significantly different between the two arms, except for pain, which showed more clinically meaningful improvement and less deterioration at 6 weeks follow-up (v pretreatment) in the AM arm (P = .003). The median survival rates for both arms were comparable (AM, 17.3 v no AM, 17.9 months; P = .87)., Conclusion: AM did not significantly reduce esophagitis >/= grade 3 in patients receiving hyperfractionated radiation and chemotherapy. However, patient self-assessments suggested a possible advantage to AM that is being explored with modified dosing route strategies.

Objective: To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) after surgery in the management of residual or recurrent nonfunctioning pituitary adenomas with respect to tumor control and the development of complications., Methods and Materials: The clinical records of patients with nonfunctioning pituitary adenomas who underwent FSRT were retrospectively analyzed. For newly diagnosed tumors, transsphenoidal surgery was performed, and, if residual tumor was identified at 3 months, FSRT was performed. If significant tumor volume persisted, transcranial surgery was performed before FSRT. We originally initiated FSRT with 2-Gy fractions to 46 Gy. We escalated the dose to 50.4 Gy thereafter. As a final modification, we dropped the daily dose to 1.8-Gy fractions delivered within 6 weeks. High-dose conformality and homogeneity was achieved with arc beam shaping and differential beam weighting. The radiographic, endocrinologic, and visual outcomes after FSRT were evaluated., Results: The 68 patients included 36 males and 32 females with an age range of 15-81 years. The median follow-up was 30 months (range, 2-82 months), and the median tumor volume was 6.2 cm(3). Of the 68 patients, 20 were treated to 46 Gy and 48 to 50-52.2 Gy. Most were treated to 50.4 Gy. Eleven patients had recurrent tumors, 54 had residual tumors, and no surgery was performed in 3 patients before FSRT. We noted no radiation-induced acute or late toxicities, except for radiation-induced optic neuropathy in 2 patients. At latest follow-up, the tumor had decreased in size in 26 patients and remained stable in 41 of the 42 remaining patients. Of the 68 patients, 4 (6%) developed hypopituitarism at 6, 11, 12, and 17 months after FSRT. Reviewing available serial Humphrey visual fields, visual fields were objectively improved in 28 patients, and remained stable in 24 patients, and worsened in 2 patients., Conclusion: The findings of this analysis support the use of surgery followed by FSRT as a safe, effective, and integrated treatment for nonfunctioning pituitary adenomas. Additional follow-up is needed to document the long-term tumor control rates, preservation rates for vision and pituitary function, and neurocognitive outcomes.

While concurrent chemoradiotherapy is a standard treatment for good-performance patients with non-small cell lung cancer, acute esophagitis is a frequent toxicity. The incidence of severe acute esophagitis > or = grade 3 in patients treated with standard (once-daily) radiation therapy alone is 1.3%, increasing to 14% to 25% with the addition of concurrent chemotherapy, and 24% to 34% for the combination of hyperfractionated (twice-daily) radiation therapy plus concomitant chemotherapy. Although esophagitis is almost never a cause of mortality, it results in significant morbidity and may force treatment breaks, which are associated with inferior outcome in non-small cell lung cancer. Substantial investigative efforts to prevent or ameliorate esophagitis have been conducted. We describe herein the rationale/study design for a multi-institutional, phase II randomized study to evaluate either daily subcutaneous or intravenous bolus infusions of amifostine in patients with non-small cell lung cancer who receive standard fractionated thoracic radiation therapy concurrently with weekly paclitaxel and carboplatin chemotherapy.

Purpose: Conventional treatment of glioblastoma multiforme (GBM) cures less than 5% of patients. We investigated the effect of stereotactic radiosurgery (SRS) added to conventional external beam radiation therapy (EBRT) with carmustine (BCNU) on the survival of patients with GBM., Methods and Materials: A total of 203 patients with supratentorial GBM (tumor < or =40 mm) were randomly assigned either to postoperative SRS followed by EBRT (60 Gy) plus BCNU (80 mg/m(2) Days 1-3 every 8 weeks for six cycles) or to EBRT with BCNU alone. The dose of radiosurgery was tumor size-dependent and ranged from 15 Gy for largest to 24 Gy for smallest tumors. RT and BCNU were identical in both arms., Results: At a median follow-up time of 61 months, the median survival in the radiosurgery group was 13.5 months (95% confidence interval, 11.0-14.8) as compared with 13.6 months (95% confidence interval, 11.2-15.2, p = 0.5711) for the standard treatment group. There were also no significant differences in 2- and 3-year survival rates and in patterns of failure between the two arms. Quality of life deterioration and cognitive decline at the end of therapy, compared with baseline, were comparable and there was no difference in quality-adjusted survival between the arms., Conclusions: Stereotactic radiosurgery followed by EBRT and BCNU does not improve the outcome in patients with GBM nor does it change the general quality of life or cognitive functioning.

The purpose of this study is to compare 3 intensity-modulated radiation therapy (IMRT) inverse treatment planning techniques as applied to locally-advanced lung cancer. This study evaluates whether sufficient radiotherapy (RT) dose is given for durable control of tumors while sparing a portion of the esophagus, and whether large number of segments and monitor units are required. We selected 5 cases of locally-advanced lung cancer with large central tumor, abutting the esophagus. To ensure that no more than half of the esophagus circumference at any level received the specified dose limit, it was divided into disk-like sections and dose limits were imposed on each. Two sets of dose objectives were specified for tumor and other critical structures for standard dose RT and for dose escalation RT. Plans were generated using an aperture-based inverse planning (ABIP) technique with the Cimmino algorithm for optimization. Beamlet-based inverse treatment planning was carried out with a commercial simulated annealing package (CORVUS) and with an in-house system that used the Cimmino projection algorithm (CIMM). For 3 of the 5 cases, results met all of the constraints from the 3 techniques for the 2 sets of dose objectives. The CORVUS system without delivery efficiency consideration required the most segments and monitor units. The CIMM system reduced the number while the ABIP techniques showed a further reduction, although for one of the cases, a solution was not readily obtained using the ABIP technique for dose escalation objectives.

Objective: Despite the success of stereotactic radiosurgery, large inoperable arteriovenous malformations (AVMs) of 14 cm(3) or more have remained largely refractory to stereotactic radiosurgery, with much lower obliteration rates. We review treatment of large AVMs either previously untreated or partially obliterated by embolization with fractionated stereotactic radiotherapy (FSR) regimens using a dedicated linear accelerator (LINAC)., Methods: Before treatment, all patients were discussed at a multidisciplinary radiosurgery board and found to be suitable for FSR. All patients were evaluated for pre-embolization. Those who had feeding pedicles amenable to glue embolization were treated. LINAC technique involved acquisition of a stereotactic angiogram in a relocatable frame that was also used for head localization during treatment. The FSR technique involved the use of six 7-Gy fractions delivered on alternate days over a 2-week period, and this was subsequently dropped to 5-Gy fractions after late complications in one of seven patients treated with 7-Gy fractions. Treatments were based exclusively on digitized biplanar stereotactic angiographic data. We used a Varian 600SR LINAC (Varian Medical Systems, Inc., Palo Alto, CA) and XKnife treatment planning software (Radionics, Inc., Burlington, MA). In most cases, one isocenter was used, and conformality was established by non-coplanar arc beam shaping and differential beam weighting., Results: Thirty patients with large AVMs were treated between January 1995 and August 1998. Seven patients were treated with 42-Gy/7-Gy fractions, with one patient lost to follow-up and the remaining six with previous partial embolization. Twenty-three patients were treated with 30-Gy/5-Gy fractions, with two patients lost to follow-up and three who died as a result of unrelated causes. Of 18 evaluable patients, 8 had previous partial embolization. Mean AVM volumes at FSR treatment were 23.8 and 14.5 cm(3), respectively, for the 42-Gy/7-Gy fraction and 30-Gy/5-Gy fraction groups. After embolization, 18 patients still had AVM niduses of 14 cm(3) or more: 6 in the 7-Gy cohort and 12 in the 5-Gy cohort. For patients with at least 5-year follow-up, angiographically documented AVM obliteration rates were 83% for the 42-Gy/7-Gy fraction group, with a mean latency of 108 weeks (5 of 6 evaluable patients), and 22% for the 30-Gy/5-Gy fraction group, with an average latency of 191 weeks (4 of 18 evaluable patients) (P = 0.018). For AVMs that remained at 14 cm(3) or more after embolization (5 of 6 patients), the obliteration rate remained 80% (4 of 5 patients) for the 7-Gy cohort and dropped to 9% for the 5-Gy cohort. A cumulative hazard plot revealed a 7.2-fold greater likelihood of obliteration with the 42-Gy/7-Gy fraction protocol (P = 0.0001), which increased to a 17-fold greater likelihood for postembolization AVMs of 14 cm(3) or more (P = 0.003)., Conclusion: FSR achieves obliteration for AVMs at a threshold dose, including large residual niduses after embolization. With significant treatment-related morbidities, further investigation warrants a need for better three-dimensional target definition with higher dose conformality.

Background: Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG)., Methods: Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements., Findings: From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121)., Interpretation: WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.

The evolution of therapeutic approaches for lung cancer illustrates the trend for treatment intensification, with hopes that dose-intense chemotherapy regimens, higher radiation therapy (RT) doses, or novel fractionation schemes will result in prolongation of survival. Current chemotherapy- and RT-intense regimens may not be intensified further without addressing dose-limiting toxicities such as esophagitis. It is important to understand factors pre-disposing to esophagitis so that strategies to minimize its severity can be investigated. Pulmonary complications such as pneumonitis and fibrosis from RT (with or without chemotherapy) are dose and volume dependent. Methods to better identify the target tissues and improved RT-delivery systems may facilitate increasing target doses or reducing doses to adjacent normal tissues. Biologic predictors may allow clinicians in the future to individualize RT treatment based on a patient's toxicity risk profile. Radiation myelopathy is still the most feared radiation complication of lung cancer treatment. The authors address the known parameters that influence the incidence of thoracic radiation myelopathy and the putative factors that could be considered when a clinician may be required to push the spinal cord dose in favor of tumor control.

Identification of prognostic factors is critical in optimizing treatment for patients with cancer. The purpose of this work is to review the modern literature with regard to prognostic factors for patients with non-small-cell lung cancer (NSCLC) taking into account ongoing advances in clinical evaluation, staging, surgery, radiation therapy, chemotherapy, and molecular biology in this widely heterogeneous patient population., (Copyright 2003 Wiley-Liss, Inc.)

Objective: We investigated the safety and efficacy of stereotactic radiotherapy as an alternative therapy to surgical resection for optic nerve sheath meningiomas (ONSMs)., Methods: Thirty patients and 33 optic nerves with ONSMs were treated with conventional fractionated stereotactic radiotherapy treatment (CF-SRT) between July 1996 and May 2001 with the use of a 6-MeV LINAC designed for and dedicated to radiosurgery. The LINAC technique involved daily CF-SRT involving a relocatable frame, an average of three isocenters, and high-radiation dose conformality established by noncoplanar arc beam shaping and differential beam weighting. The patients who were treated with CF-SRT were followed clinically with serial visual fields and radiographically with both magnetic resonance imaging and functional (111)In-octreotide single-photon emission computed tomography. The results of treatment were compared with a historical control group of ONSM patients who were either observed or treated surgically and then observed., Results: Our study population comprised 18 women and 12 men with a median age of 44 years (age range, 20-76 yr). The median isosurface radiation dose was 51 Gy (dose range, 50-54.0 Gy), and the median clinical follow-up time was 89 weeks (range, 9-284 wk). Of 22 optic nerves with vision before CF-SRT, 20 nerves (92%) demonstrated preserved vision, and 42% manifested improvement in visual acuity and/or visual field at follow-up. Comparison of our patients with a historical control group revealed preserved vision in only 16% of patients in a comparable period of observation, along with a 150% greater probability of visual improvement. Four patients (13%) had posttreatment morbidities, including visual loss (two patients), optic neuritis (one patient), and transient orbital pain (one patient). On magnetic resonance imaging studies, there was no evidence of tumor progression or recurrence in all patients, including tumor volume reductions noted in four patients. All six patients monitored with (111)In-octreotide scintigraphy demonstrated significant decreases in tumor activity after CF-SRT., Conclusion: To date, this article describes the largest reported series of ONSMs. Although longer follow-up is necessary, we think that CF-SRT represents a safe alternative to surgery and offers a higher likelihood of preserved or improved vision in patients with ONSM. Our analysis suggests that CF-SRT is also preferable to observation. Functional (111)In-octreotide single-photon emission computed tomographic scintigraphy provides a useful technique for the assessment of tumor control that complements serial posttreatment magnetic resonance imaging in patients with ONSMs.

Twenty-four patients with non-small cell lung cancer received induction chemotherapy (paclitaxel, carboplatin) followed by concurrent thoracic irradiation (RT) and weekly paclitaxel. Acute esophagitis was scored weekly. Amifostine (AMI), 500 mg intravenously twice weekly, was added to the regimen in the second cohort of 12 patients. AMI was well tolerated. The incidence of grade 3 esophagitis was 18% in the initial 11 patients versus 9% in the AMI-treated patients. Mean esophagitis index (EI) was numerically lower in the AMI-treated patients than in the initial group (5.1 v 11.6, P =.14). The length of esophagus in the RT field was similar in both groups. Median survival time for all patients was 12.4 months. The EI, a novel measure of the severity and duration of acute esophagitis, may be reduced in lung cancer patients receiving AMI twice weekly with thoracic RT and paclitaxel. The effect of AMI was not caused by the shorter irradiated esophageal length. A phase III randomized trial is now open to assess the effect of AMI on esophagitis., (Copyright 2002, Elsevier Science (USA). All rights reserved.)