Kenneth Levin

A SINGLE-INSTITUTION EXPERIENCE WITH CONCURRENT CAPECITABINE AND RADIATION THERAPY IN GASTROINTESTINAL MALIGNANCIES

PURPOSE We report our clinical experience with 32 patients receiving concurrent irradiation and capecitabine. METHODS AND MATERIALS Medical records of patients with gastrointestinal malignancies treated with radiation and capecitabine therapy were reviewed. RESULTS The population consisted of 20 males and 12 females, with a median age of 67.5 years (45-84 years) and adequate hepatic and bone marrow function. Histology was adenocarcinoma in all patients, except two with esophageal squamous carcinoma. Twenty-one patients received the regimen as adjuvant therapy, three received preoperative therapy, and 8 patients received therapy for palliation. The median dose of capecitabine was 1600 mg/m(2)/day (1200-2500 mg/m(2)/day) orally for 5 days per week for the duration of radiation therapy. Thirty patients received a total dose ranging from 45 Gy to 64 Gy over 4-6 weeks. Two previously radiated patients received total doses of 29.9 Gy and 46 Gy. Grade 3/4 toxicities observed were neutropenia in 3 patients and diarrhea, thrombocytopenia, fatigue, and myocardial infarction in 1 patient each. No treatment-related mortality was observed. Twenty of 21 patients (95.2%) who received adjuvant therapy continue to be in complete remission. Four of 11 (36%) evaluable patients demonstrated a response. CONCLUSION Concurrent capecitabine and radiation were very well tolerated and warrant further investigation in prospective trials.

Effect of MLC leaf width on the planning and delivery of SMLC IMRT using the CORVUS inverse treatment planning system

This study investigates the influence of multileaf collimator (MLC) leaf width on intensity modulated radiation therapy (IMRT) plans delivered via the segmented multileaf collimator (SMLC) technique. IMRT plans were calculated using the Corvus treatment planning system for three brain, three prostate, and three pancreas cases using leaf widths of 0.5 and 1 cm. Resulting differences in plan quality and complexity are presented here. Plans calculated using a 1 cm leaf width were chosen over the 0.5 cm leaf width plans in seven out of nine cases based on clinical judgment. Conversely, optimization results revealed a superior objective function result for the 0.5 cm leaf width plans in seven out of the nine comparisons. The 1 cm leaf width objective function result was superior only for very large target volumes, indicating that expanding the solution space for plan optimization by using narrower leaves may result in a decreased probability of finding the global minimum. In the remaining cases, we can conclude that we are often not utilizing the objective function as proficiently as possible to meet our clinical goals. There was often no apparent clinically significant difference between the two plans, and in such cases the issue becomes one of plan complexity. A comparison of plan complexity revealed that the average 1 cm leaf width plan required roughly 60% fewer segments and over 40% fewer monitor units than required by 0.5 cm leaf width plans. This allows a significant decrease in whole body dose and total treatment time. For very complex IMRT plans, the treatment delivery time may affect the biologically effective dose. A clinically significant improvement in plan quality from using narrower leaves was evident only in cases with very small target volumes or those with concavities that are small with respect to the MLC leaf width. For the remaining cases investigated in this study, there was no clinical advantage to reducing the MLC leaf width from 1 to 0.5 cm. In such cases, there is no justification for the increased treatment time and whole body dose associated with the narrower MLC leaf width.

Chemoradiotherapy in the treatment of regional pancreatic carcinoma: a phase II study.

In locally advanced pancreatic cancer, the utilization of chemotherapy and radiotherapy is increasing, although in view of the reported long-term results of several contemporary trials, further improvements are certainly needed. Encouraging results using the combination of cisplatin, cytarabine, caffeine, and continuous infusion (CI) 5-fluorouracil (5-FU) (PACE) for the treatment of advanced pancreatic carcinoma prompted a phase II study using PACE followed by external beam radiotherapy with CI of 5-FU (PACE-RT) for localized disease. Forty-one patients were treated with PACE-RT as adjuvant therapy after surgical resection (21 patients), or as primary therapy for locally advanced, unresectable disease (20 patients), with reevaluation for resection after completion of treatment. PACE consisted of cisplatin 100 mg/m2 IV on day 1, cytarabine 2 g/m2 IV every 12 hours × 2 doses, and caffeine 400 mg/m2 subcutaneously after each cytarabine dose; and days 3 to 21, 5-FU 250 mg/m2/d given by CI. Cycles were repeated every 28 days. After 2 cycles of PACE, radiation therapy was given concurrently with 5-FU at 200 mg/m2/d. In the adjuvant setting, the tumor bed and the draining lymph node basin received 50.4 Gy and 45 Gy, respectively. In the neoadjuvant setting, the primary and regional lymph nodes were to receive 39.6 Gy followed by a neutron boost of 8 NGy to the gross tumor volume. Photon therapy was delivered at 1.8 Gy per fraction and neutron therapy at 0.8 NGy per fraction, 5 days a week. All patients were evaluable for toxicity and survival. The most common toxicity was myelosuppression, with grade III to IV neutropenia occurring in 59% of the patients. The median survival times in the locally advanced and adjuvant patients were 13.4 and 18.1 months, with 1-year survival rates of 52% and 65%, respectively. Nine of 20 patients receiving PACE-RT for unresectable carcinoma had sufficient tumor regression to meet clinical criteria for exploration; three were resected with curative intent. The survival of these three patients undergoing resection after neo-adjuvant therapy was 22.4, 24.3 and 40 months. The treatment program was active, but only moderately well tolerated. Modification of this regimen with newer, less toxic drugs may provide better results and reduced toxicity.

Permanent Iodine-125 Interstitial Radiation Therapy in the Treatment of Non-Glioblastoma multiforme High-Grade Gliomas

Background: This study evaluates prognostic factors influencing survival outcomes for 60 patients with permanent iodine-125 implants in the primary treatment of non-glioblastoma multiforme (GBM) high-grade gliomas. Methods: Stereotactic treatment planning aimed to encompass the contrast-enhancing rim of the tumor visualized by CT, with an initial dose rate of 0.05 Gy/h with 125I, delivering 100 Gy at 1 year and 103.68 Gy at infinity. Survival was evaluated using the Kaplan-Meier method for univariate analysis and the Cox regressional method for multivariate analysis. In addition to the implant, 34 patients received external radiation therapy (5,000–6,000 cGy) before the implant; 13 patients were implanted without additional external beam radiation, and 13 patients underwent external radiation therapy before implant placement. Results: With a mean follow-up of 77.6 months (range 3.5–164 months), 1-, 3-, 5- and 10-year survival were 86.7% (±0.05%), 60% (±0.07%), 50% (±0.07%) and 45.7% (±0.7%), respectively. The median survival time was 57 months. Second surgery was performed following the implant in 19 patients. Findings were tumor recurrence in 11 patients (22.5%), radiation necrosis in 7 patients (14.3%) and brain abscess in 1 patient (2%). Age, sex, tumor location, side of brain, tumor volume, Karnofsky score and neurological status were correlated with survival outcome. Favorable prognostic factors were age younger than 45 years, superficial tumor location and preoperative Karnofsky score greater than 70. RPA classification was used to define this group of patients. In RPA classes I and II (n = 43), 1-year survival was 93%, while 3-, 5- and 10-year survival was 67.4, 60.5 and 55.5%, respectively, and median survival time was 91 months. In RPA class III (n = 7), 1-year survival was 71.4%, while 3- and 5-year survival was 42.9 and 28.6%, respectively, and median survival time was 47 months. In RPA class IV (n = 10), 1-year survival was 60%, while 3-, 5- and 10-year survival was 50, 22.2 and 11.1%, respectively, and median survival time was 37 months. Conclusion: Brachytherapy with permanent implant of 125I appears promising in the treatment of primary non-GBM malignant gliomas. It improved survival time and reduced the incidence of complications and provided good quality of life. In order to further confirm these results, multicenter randomized prospective studies are needed. RPA analysis is a valid tool to define prognostically distinct survival groups. In this study, 2-year survival and median survival time were improved in all prognostic classes. This would suggest that selection bias alone does not account for the survival benefit seen with 125I implants. Further randomized studies with effective stratification are needed.

Treatment Planning for Boron Neutron Capture Enhanced Fast Neutron Therapy

Clinical data in fast neutron therapy suggests that the normal brain tolerance dose for fractionated whole brain irradiations with fast neutrons is about 14Gy while the tumor control dose is about 21 Gy for glioblastoma multiforme.1 If 6Gy equivalent of fast neutron dose can be delivered to the tumor by the boron neutron capture (BNC) dose, a therapeutic window opens up for the treatment of these highly malignant tumors. In previous studies, we have shown that by passing the d(48.5) + Be fast neutron beam through 25 cms of steel, we create a beam that is capable of meeting the above requirement.2,3 Our current need is to create patient treatment plans with this beam to verify its clinical utility. Existing Monte Carlo based treatment planning algorithms for BNCT are not readily applicable to BNCEFNT because of the lack of reliable cross-section data for the higher energy neutrons encountered in these beams. Consequently, we have investigated the following treatment planning strategy for BNCEFNT.

Progress towards Boron Neutron Capture Enhancement of Fast Neutron Therapy at the Harper Hospital Neutron Therapy Facility

The neutron beam at the Gershenson Radiation Oncology Center is produced in a unique gantry mounted superconducting cyclotron.1 A 48.5 MeV deuteron beam is incident on an internal beryllium target and a beam current of up to 15µA produces a fast neutron dose rate of 48cGy per minute. The beam current is presently limited by the power dissipation characteristics of the target, but a relatively simple target modification will allow this limit to be increased by a factor of 3–3.5. Although the thermal neutron fluence is reasonable compared to that produced in a reactor, the physical dose enhancement due to the boron neutron capture reaction is only 2 to 4% for a 15cm × 15cm field at depths between 2.5 and 15cm with a 10B concentration of 50µgg−1 (Figure 1). Therefore, in order to have a fast neutron beam which is suitable for boron neutron capture enhanced fast neutron therapy (BNCEFNT) it is necessary to increase the thermal neutron component of the beam relative to the fast neutron dose by filtration and/or moderation or some other strategy. Using a high Z target to increase the yield of low energy neutrons through spallation reactions may be one option, although it is desirable to retain the fast neutron characteristics of the beam. In particular a fast neutron component with a reasonable depth dose characteristic is required if the fast neutron component of the dose is going to be effectively exploited. It has been shown that beams with a suitable mix of dose components (i.e. 50–60% of the biological effect due to fast Open image in new window Figure 1 Results of dose enhancement measurements in a d(48.5)-Be (circles) and a d(48.5)-W (square) fast neutron beam for a 15 cm × 15 cm with 50 µgg−1. Measurements were made using the dual microdosimetric counter technique described in the text. neutrons, 10% due to gamma rays and 25–35% due to boron neutron capture products) can be produced by using an iron or tungsten filter.2,3

SU‐E‐T‐487: Spatial Assessment of Dose Distributions for Patients with Lung Cancer Treated with Stereotactic Ablative Radiotherapy (SABR)

PURPOSE We hypothesize that PTV margin dose is an important factor for local tumor control. We evaluated dose distributions for patients originally treated with pencil-beam (PB)-based plans and retrospectively calculated with Monte Carlo (MC) method, with emphasis on the spatial region between the ITV and PTV (PTV-margin), where the largest dose differences were expected. METHODS Forty-six stage I-II lung cancer patients with 51 lesions treated with SABR were retrospectively analyzed (23 central and 28 peripheral tumors). All patients received 4DCT imaging, and an ITV was generated from the maximum intensity projection and subsequent review of four 4DCT phases. An isotropic 3mm ITV-to-PTV margin was used. The iPlan TPS was used to generate the original treatment plans using PB-based heterogeneity correction. MC doses were recalculated using the same MUs as in the PB plan. Dose distributions for the ITV, PTV-margin, and PTV were analyzed using generalized equivalent uniform dose (gEUD) with a = - 20. Students paired t-test elucidated differences between PB and MC-based gEUD and the two different tumor locations. RESULTS Mean ITV and PTV volumes were 24.2 cc (range: 2.2 to 99.3 cc) and 50.4 cc (range: 6.4 to 229.7 cc), respectively. The mean gEUDs of ITV, PTV-margin and PTV, normalized to PB-based 100% isodose were 1.02+/-0.04, 1.01+/-0.04 and 1.01+/-0.04 for PB-based plans, compared to 0.94+/-0.06, 0.88+/-0.08 and 0.90+/-0.08 (all p<0.05) for MC-based plans. The maximum overestimations with the PB algorithm in the PTV-margin average dose were 10.4% and 19.6% (p < 0.05) for peripheral tumor cases and central tumor cases, respectively. CONCLUSIONS PB-based dose distributions showed the highest dose overestimation (relative to MC) in the PTV-margin spatial region. Analysis of spatial dose differences is an important precursor toward assessment of patterns-of-local failure, to be investigated in future work to explore possible association between dose and regions of failure. Acknowledgement: supported in part by grants from NIH R01 CA106770 and from Varian Medical Systems.

γ-Knife Radiosurgery for Brainstem Lesions: The Wayne State University Experience

Stereotactic radiosurgery (SRS) is increasingly being used for tumors of the brainstem because it suits the anatomical constraints of this area. We now report on the 2-year experience at Wayne State University using γ-knife SRS for such lesions, with an emphasis on toxicity and morbidity. From January 1996 to January 1998, sixteen patients (6 males and 10 females) with lesions in the area of the brainstem were treated with SRS. Average age was 53 years (range 19–80). Nine lesions were malignant; 7 were benign. Median Karnofsky performance status (KPS) prior to SRS was 80 (range 50–100). Median follow-up period from initial diagnosis to analysis, and from the date of SRS to analysis, was 24 months (range 11–73) and 15 months (range 4–29), respectively. Results were analyzed for the whole population treated and then stratified by diagnosis: benign versus malignant. At analysis, 10 (62.6%) patients were alive and 6 (37.5%) were dead. No deaths followed SRS. Values for KPS prior to SRS were compared to 3 months post-SRS. No significant change in KPS scores could be observed for those with benign lesions, but 67% of patients with malignant tumors showed a KPS drop ≥30 points. There was no correlation between the treated volume and survival. At the time of review, no patients had developed new neurological symptoms after SRS. Results for benign lesions indicate that SRS is well tolerated, provides good local control, and does not cause unusual rates of morbidity or mortality. Results for malignant lesions demonstrate that pretreatment performance status influences the post-SRS values. The post-SRS Median Survival (MS) of 10 months for the Malignant Lesions (M) is impressive, in light of the drop of KPS observed; the outcome for such patients is likely determined by the activity of the primary disease process. Our results suggest that SRS in the brainstem is safe, feasible, and merits further study.

Adjuvant γ-knife radiosurgery for a resected suprasellar pituitary adenoma with atypical immunohistochemistry: Case report

A resected suprasellar mass was found to be an ectopic pituitary adenoma on light microscopy, but immunohistochemistry revealed unusual staining patterns. Residual disease was demonstrated on postoperative studies and γ-knife radiosurgery was used for treatment. The literature on ectopic pituitary tumors was reviewed. We concluded that postoperative stereotactic radiosurgery (SRS) for ectopic, suprasellar pituitary adenomas (and variants thereof) is an appropriate management option for persistent disease.