Phase I clinical trial assessing temozolomide and tamoxifen with concomitant radiotherapy for treatment of high-grade glioma.

PURPOSE: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. METHODS AND MATERIALS: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status ≥ 60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m(2) divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m(2) increments until the MTD was reached. When ≥ 2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m(2). A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. RESULTS: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m(2). One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m(2). CONCLUSIONS: The MTD of tamoxifen was 100 mg/m(2) when given concurrently with temozolomide 75 mg/m(2) and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.

Four-dimensional intensity-modulated radiation therapy planning for dynamic tracking using a direct aperture deformation (DAD) method.

PURPOSE: Planning for the delivery of intensity-modulated radiation therapy (IMRT) to a moving target, referred to as four-dimensional (4D) IMRT planning, is a crucial step for achieving the treatment objectives for sites that move during treatment delivery. The authors proposed a simplistic method that accounts for both rigid and nonrigid respiration-induced target motion based on 4D computed tomography (4DCT) data sets. METHODS: A set of MLC apertures and weights was first optimized on a reference phase of a 4DCT data set. At each beam angle, the apertures were morphed from the reference phase to each of the remaining phases according to the relative shape changes in the beam's eye view of the target. Three different planning schemes were evaluated for two lung cases and one pancreas patient: (1) Individually optimizing each breathing phase; (2) optimizing the reference phase and shifting the optimized apertures to other breathing phases based on a rigid-body image registration; and (3) optimizing the reference phase and deforming the optimized apertures to the other phases based on the deformation and translation of target contours. Planning results using scheme 1 serves as the "gold standard" for plan quality assessment; scheme 2 is the method previously proposed in the literature; and scheme 3 is the method the authors proposed in this article. The optimization results were compared between the three schemes for all three cases. RESULTS: The proposed scheme 3 is comparable to scheme 1 in plan quality, and provides improved target coverage and conformity with similar normal tissue dose compared with scheme 2. CONCLUSIONS: Direct aperture deformation method for 4D IMRT planning improves upon methods that only consider rigid-body motion and achieves a plan quality close to that optimized for each of the phases.

Comparative analysis of the post-lumpectomy target volume versus the use of pre-lumpectomy tumor volume for early-stage breast cancer: implications for the future.

PURPOSE: Three-dimensional conformal accelerated partial breast irradiation (APBI-3D-CRT) is commonly associated with the treatment of large amounts of normal breast tissue. We hypothesized that a planning tumor volume (PTV) generation based on an expansion of the pre-lumpectomy (pre-LPC) intact tumor volume would result in smaller volumes of irradiated normal breast tissue compared with using a PTV based on the post-lumpectomy cavity (post-LPC). Use of PTVs based on the pre-LPC might also result in greater patient eligibility for APBI-3D-CRT. METHODS AND MATERIALS: Forty-one early-stage breast cancers were analyzed. Preoperative imaging was used to determine a pre-LPC tumor volume. PTVs were developed in the pre- and post-LPC settings as per National Surgical Breast and Bowel Project (NSABP)-B39 guidelines. The pre- and post-LPC PTV volumes were compared and eligibility for APBI-3D-CRT determined using NSABP-B39 criteria. RESULTS: The post-LPC PTV exceeded the pre-LPC PTV in all cases. The median volume for the pre- and post-LPC PTVs were 93 cm(3) (range, 24-570 cm(3)) and 250 cm(3) (range, 45-879 cm(3)), respectively, p <0.001. The difference between pre- and post-LPC PTVs represented a median of 165 cc (range, 21-482 cc) or 16% (range, 3%-42%) of the whole breast volume. Three of 41 vs. 13 of 41 cases were ineligible for APBI-3D-CRT when using the pre- and post-LPC PTVs, respectively. CONCLUSION: PTVs based on pre-LPC tumor expansion are likely associated with reduced amounts of irradiated normal breast tissue compared with post-LPC PTVs, possibly leading to greater patient eligibility for APBI-3D-CRT. These findings support future investigation as to the feasibility of neoadjuvant APBI-3D-CRT.

Optimal beam arrangement for stereotactic body radiation therapy delivery in lung tumors.

PURPOSE: To compare the different beam arrangement and delivery techniques for stereotactic body radiation therapy (SBRT) of lung lesions using the criteria of Radiation Therapy Oncology Group (RTOG) 0236 protocol. MATERIAL AND METHODS: Thirty-seven medically inoperable lung cancers were evaluated with various planning techniques including multiple coplanar multiple static beams, multiple non-coplanar static beams and arc delivery. Twelve plans were evaluated for each case, including five plans using coplanar fixed beams, six plans using non-coplanar fixed beams and one plan using arc therapy. These plans were compared using the target prescription isodose coverage, high and low dose volumes, and critical organ dose-volume limits. RESULTS: The prescription isodose coverage, high dose evaluation criteria and dose to critical organs were similar among treatment delivery techniques. However, there were differences in low dose criteria, especially in the ratio of the volume of 50% isodose of the prescription dose to the volume of planning treatment volume (R(50%)). The R(50%) in plans using non-coplanar static beams was lower than other plans in 30 of 37 cases (81%). CONCLUSION: Based on the dosimetric criteria outlined in RTOG 0236, the treatment technique using non-coplanar static beams showed the most preferable results for SBRT of lung lesions.

Long-term outcomes of Gamma Knife radiosurgery for classic trigeminal neuralgia: implications of treatment and critical review of the literature. Clinical article.

OBJECT: Few long-term studies of Gamma Knife surgery (GKS) for trigeminal neuralgia (TN) exist. The authors report their long-term experience with the use of GKS in a previously reported cohort of patients with TN that has now been followed since 1996. METHODS: One hundred twelve patients with TN were treated with GKS at the University of Maryland between June 1996 and July 2001. Of these, 67% had no invasive operations for TN prior to GKS, 13% had 1, 4% had 2, and 16% had >or= 3. The right side was affected in 56% of cases, predominantly involving V2 (26%), V3 (24%), or a combination of both (18%) branches. The median age at diagnosis was 56 years, and median age at GKS was 64 years. The median prescription dose of 75 Gy (range 70-80 Gy) was delivered to the involved trigeminal nerve root entry zone. The authors assessed the degree of pain before and after GKS by using the Barrow Neurological Institute (BNI) pain scale. RESULTS: In total, 102 patients took the survey at least once, for a response rate of 91%. Although not found to alter the conclusions of this study, 7 cases of atypical TN were found and these patients were removed, for a total of 95 cases herein analyzed. The median follow-up was 5.6 years (range 13-115 months). Before GKS, 88% of patients categorized their pain as BNI IV or V (inadequate control or severe pain on medication), whereas the remainder described their pain as BNI III (some pain, but controlled on medication). After GKS, 64% reported a BNI score of I (no pain, no medications), 5% had BNI II (no pain, still on medication), 12% had BNI III, and 19% reported a BNI score of IV or V. The median time to response was 2 weeks (range 0-12 weeks) and the median response duration was 32 months (range 0-112 months). Eighty-one percent reported initial pain relief, and actuarial rates of freedom from treatment failure at 1, 3, 5, and 7 years were 60, 41, 34, and 22%, respectively. Response duration was significantly better for those who had no prior invasive treatment versus those in whom a previous surgical intervention had failed (32 vs 21 months, p < 0.02). New bothersome facial numbness was reported in 6% of cases. CONCLUSIONS: This study represents one of the longest reported median follow-up periods and actuarial results for a cohort of patients with classic TN treated with GKS. Although GKS achieves excellent rates of initial pain relief, these results suggest a steady rate of late failure, particularly among patients who had undergone prior invasive surgical treatment. Despite a higher than expected recurrence rate, GKS remains a viable treatment option, particularly for patients who have had no prior invasive procedures. Patients with recurrences can still be offered salvage therapy with either repeat GKS, microvascular decompression, or rhizotomy.

Efficacy and quality of life outcomes in patients with atypical trigeminal neuralgia treated with gamma-knife radiosurgery.

PURPOSE: To assess efficacy and quality of life (QOL) outcomes associated with gamma-knife radiosurgery (GK-RS) in treating atypical trigeminal neuralgia (ATN) compared with classic trigeminal neuralgia (CTN). METHODS AND MATERIALS: Between September 1996 and September 2004, 35 cases of ATN were treated with GK-RS. Patients were categorized into two groups: Group I comprised patients presenting with ATN (57%); Group II consisted of patients presenting with CTN then progressing to ATN (43%). Median prescription dose 75 Gy (range, 70-80 Gy) was delivered to trigeminal nerve root entry zone. Treatment efficacy and QOL improvements were assessed with a standardized questionnaire. RESULTS: With median follow-up of 29 months (range, 3-74 months), 72% reported excellent/good outcomes, with mean time to relief of 5.8 weeks (range, 0-24 weeks) and mean duration of relief of 62 weeks (range, 1-163 weeks). This rate of pain relief is similar to rate achieved in our previously reported experience treating CTN with GK-RS (p = 0.36). There was a trend toward longer time to relief (p = 0.059), and shorter duration of relief (p = 0.067) in patients with ATN. There was no difference in rate of, time to, or duration of pain relief between Groups I and II. Of the patients with ATN, 88% discontinued or decreased the use of pain medications. Among the patients with sustained pain relief, QOL improved an average of 85%. CONCLUSION: This is the largest reported GK-RS experience for the treatment of ATN. Patients with ATN can achieve rates of pain relief similar to those in patients with CTN. Further follow-up is necessary to assess adequately the durability of response.

Radiation oncology emergencies.

Radiation therapy is an important and effective treatment modality when used in the management of oncologic emergencies. For any patient who has MSCC, ISCM, SVC syndrome, or life-threatening hemoptysis/obstruction, optimal management hinges on efficient multidisciplinary evaluation and communication to arrive at a treatment plan tailored to the individual patient. Optimal management may include steroids, surgery, chemotherapy, or bronchoscopic intervention. When radiation therapy is used, the total dose and fractionation schedule should be tailored to the disease setting and life expectancy of the patient.