Matthew A Manning

The effect of setup uncertainty on normal tissue sparing with IMRT for head-and-neck cancer

PURPOSE Intensity-modulated radiotherapy (IMRT) is being evaluated in the management of head-and-neck cancers at several institutions, and a Radiation Therapy Oncology Group study of its utility in parotid sparing is under development. There is an inherent risk that the sharper dose gradients generated by IMRT amplify the potentially detrimental impact of setup uncertainty. The International Commission on Radiation Units and Measurements Report 62 (ICRU-62) defined planning organ-at-risk volume (PRV) to account for positional uncertainties for normal tissues. The purpose of this study is to quantify the dosimetric effect of employing PRV for the parotid gland and to evaluate the use of PRV on normal-tissue sparing in the setting of small clinical setup errors. METHODS AND MATERIALS The optimized nine-beam IMRT plans for three head-and-neck cancer patients participating in an institutional review board approved parotid-sparing protocol were used as reference plans. A second optimized plan was generated for each patient by adding a PRV of 5 mm for the contralateral parotid gland. The effect of these additions on the quality of the plans was quantified, in terms of both target coverage and normal-tissue sparing. To test the value of PRV in a worst-case scenario, systematic translational setup uncertainties were simulated by shifting the treatment isocenter 5 mm superiorly, inferiorly, left, right, anteriorly, and posteriorly, without altering optimized beam profiles. At each shifted isocenter, dose distributions were recalculated, producing a total of six shifted plans without PRV and six shifted plans with PRV for each patient. The effect of setup uncertainty on parotid sparing and the value of PRV in compensating for the uncertainty were evaluated. RESULTS The addition of the PRV and reoptimization did not significantly affect the dose to gross tumor volume, spinal cord, or brainstem. In contrast, without any shift, the PRV did increase parotid sparing and reduce coverage of the nodal region adjacent to the parotid gland. As expected, when the plans were shifted, the greatest increase in contralateral parotid irradiation was noted with shifts toward the contralateral parotid gland. With these shifts, the average volume of contralateral parotid receiving greater than 30 Gy was reduced from 22% to 4% when a PRV was used. This correlated with a reduction in the average normal-tissue complication probability (NTCP) from 22% to 7%. CONCLUSIONS The use of PRV may limit the volume of normal tissue structures, such as the parotid gland, exceeding tolerance dose as a result of setup errors. Consequently, it will be important to incorporate the nomenclature of ICRU-62 into the design of future IMRT studies, if the clinical gains of increased normal-tissue sparing are to be realized.

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases

PURPOSE Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was

Interstitial high-dose-rate brachytherapy boost: The feasibility and cosmetic outcome of a fractionated outpatient delivery scheme

4119 less costly than SRS. CONCLUSION HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.

Gemcitabine following radiotherapy with concurrent 5-fluorouracil for nonmetastatic adenocarcinoma of the pancreas

PURPOSE To evaluate the feasibility, potential toxicity, and cosmetic outcome of fractionated interstitial high dose rate (HDR) brachytherapy boost for the management of patients with breast cancer at increased risk for local recurrence. METHODS AND MATERIALS From 1994 to 1996, 18 women with early stage breast cancer underwent conventionally fractionated whole breast radiotherapy (50-50.4 Gy) followed by interstitial HDR brachytherapy boost. All were considered to be at high risk for local failure. Seventeen had pathologically confirmed final surgical margins of less than 2 mm or focally positive. Brachytherapy catheter placement and treatment delivery were conducted on an outpatient basis. Preplanning was used to determine optimal catheter positions to enhance dose homogeneity of dose delivery. The total HDR boost dose was 15 Gy delivered in 6 fractions of 2.5 Gy over 3 days. Local control, survival, late toxicities (LENT-SOMA), and cosmetic outcome were recorded in follow-up. In addition, factors potentially influencing cosmesis were analyzed by logistic regression analysis. RESULTS The minimum follow-up is 40 months with a median 50 months. Sixteen patients were alive without disease at last follow-up. There have been no in-breast failures observed. One patient died with brain metastases, and another died of unrelated causes without evidence of disease. Grade 1-2 late toxicities included 39% with hyperpigmentation, 56% with detectable fibrosis, 28% with occasional discomfort, and 11% with visible telangiectasias. Grade 3 toxicity was reported in one patient as persistent discomfort. Sixty-seven percent of patients were considered to have experienced good/excellent cosmetic outcomes. Factors with a direct relationship to adverse cosmetic outcome were extent of surgical defect (p = 0.00001), primary excision volume (p = 0.017), and total excision volume (p = 0.015). CONCLUSIONS For high risk patients who may benefit from increased doses, interstitial HDR brachytherapy provides a convenient outpatient method for boosting the lumpectomy cavity following conventional whole breast irradiation without overdosing normal tissues. The fractionation scheme of 15 Gy in 6 fractions over 3 days is well tolerated. The volume of tissue removed from the breast at lumpectomy appears to dominate cosmetic outcome in this group of patients.

BIOLOGIC TREATMENT PLANNING FOR HIGH-DOSE-RATE BRACHYTHERAPY

Gemcitabine has been shown to be an active agent in the treatment of pancreatic cancer. This study was conducted to prospectively examine the tolerance and early efficacy of adjuvant gemcitabine following radiotherapy with concurrent 5‐fluorouracil (5‐FU) for nonmetastatic pancreatic adenocarcinoma. Twenty‐three patients, median age 64 years, were treated with combined modality therapy. Nine patients underwent tumor resection before chemoradiation; 14 patients with locally unresectable tumors received definitive chemoradiation. Radiotherapy utilized four fields to the tumor and lymphatics to 45 Gy, plus a lateral boost to 50.4 Gy. Concurrent 5‐FU 500 mg/m2/day was administered on days 1–3 and 29–31, followed by 4 months of gemcitabine 1,000 mg/m2/week for 3 weeks (fourth week break). Adjuvant gemcitabine was well tolerated. Eighty‐three percent of the patients completed three to four cycles. The primary dose‐limiting toxicity was leukopenia, which was observed in 10 patients (43%). Nonhematologic toxicities were reported in five patients (22%). There were no cases of gemcitabine‐induced radiation recall and there have been no deaths attributed to treatment toxicity. Median follow‐up for the 23 patients was 12 months (range, 5–50); the actuarial median survival was 13 months. This report confirms that adjuvant gemcitabine following radiotherapy with concurrent 5‐FU for nonmetastatic pancreatic adenocarcinoma can be safely administered.

Bladder preservation for localized muscle-invasive bladder cancer: the survival impact of local utilization rates of definitive radiotherapy.

PURPOSE Interstitial brachytherapy treatment plans are conventionally optimized with respect to total target dose and dose homogeneity, which does not account for the biologic effects of dose rate. In an HDR implant, with a stepping source, the dose rate dramatically changes during the course of treatment, depending on location, as the source moves from dwell position to dwell position. These widely varying dose rates, together with the related sequencing of the dwell positions, may impart different biologic effects at points receiving the same total dose. This study applies radiobiologic principles to account for the potential biologic impact of dose delivery at varying dose rates within an HDR implant. METHODS AND MATERIALS The model under study uses a generalized version of the linear-quadratic (LQ) cell kill formula to calculate the surviving fraction of cells subjected to HDR irradiation. Using a planar interstitial HDR implant with the dwell times optimized to produce a homogeneous dose distribution along a reference plane parallel to the implant plane, surviving fractions were compared at selected reference points subjected to the same total dose. Biologic effect homogeneity was compared to dose homogeneity by plotting the effects at the reference points. The effects were examined with LQ parameters alpha, beta, and sublethal repair time T(1) varied over a range typical of human cells. RESULTS In a region in which dose is relatively uniform, surviving fraction for some values of the model parameters are found to vary by as much as an order of magnitude due to differences in the HDR irradiation profiles at different dose points. This effect is more pronounced for shorter repair times and smaller alpha/beta ratios, and increases with increasing total irradiation time. CONCLUSION Conventional HDR treatment planning currently considers dose distribution as the primary indicator of clinical effect. Our results demonstrate that plans optimized to maximize homogeneity within a target volume may not reflect the effect of the sequential nature of HDR dose delivery on cell kill. Biologic effect modeling may improve our understanding and ability to predict the adverse effects of our treatment, such as fat necrosis and fibrosis. Accounting for irradiation history and repair kinetics in the evaluation of HDR brachytherapy plans may add an important new dimension to our planning capabilities.

Accelerated superfractionated radiotherapy with concomitant boost for locally advanced head-and-neck squamous cell carcinomas

PURPOSE This study examines the management and outcomes of muscle-invasive bladder cancer in the United States. METHODS AND MATERIALS Patients with muscle-invasive bladder cancer diagnosed between 1988 and 2006 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified according to three mutually exclusive treatment categories based on the primary initial treatment: no local management, radiotherapy, or surgery. Overall survival was assessed with Kaplan-Meier analysis and Cox models based on multiple factors including treatment utilization patterns. RESULTS The study population consisted of 26,851 patients. Age, sex, race, tumor grade, histology, and geographic location were associated with differences in treatment (all p < 0.01). Patients receiving definitive radiotherapy tended to be older and have less differentiated tumors than patients undergoing surgery (RT, median age 78 years old and 90.6% grade 3/4 tumors; surgery, median age 71 years old and 77.1% grade 3/4 tumors). No large shifts in treatment were seen over time, with most patients managed with surgical resection (86.3% for overall study population). Significant survival differences were observed according to initial treatment: median survival, 14 months with no definitive local treatment; 17 months with radiotherapy; and 43 months for surgery. On multivariate analysis, differences in local utilization rates of definitive radiotherapy did not demonstrate a significant effect on overall survival (hazard ratio, 1.002; 95% confidence interval, 0.999-1.005). CONCLUSIONS Multiple factors influence the initial treatment strategy for muscle-invasive bladder cancer, but definitive radiotherapy continues to be used infrequently. Although patients who undergo surgery fare better, a multivariable model that accounted for patient and tumor characteristics found no survival detriment to the utilization of definitive radiotherapy. These results support continued research into bladder preservation strategies and suggest that definitive radiotherapy represents a viable initial treatment strategy for those who wish to attempt to preserve their native bladder.

THE EFFECT OF HIGH-DOSE-RATE BRACHYTHERAPY DWELL SEQUENCE ON CELL SURVIVAL

PURPOSE A growing body of evidence supports the efficacy of accelerated superfractionated radiotherapy with concomitant boost for advanced head-and-neck carcinomas. This study represents a single-institution experience, performed to identify the factors influencing tumor control, survival, and toxicity. MATERIALS AND METHODS Between 1988 and 1999, 133 patients with primary squamous cell head-and-neck carcinoma underwent accelerated superfractionated radiotherapy using a concomitant boost. The concomitant boost in this regimen was delivered using reduced fields delivered 3 times weekly in a twice-daily schedule during the final phase. The total radiation dose ranged from 64.8 Gy to 76.5 Gy (mean 71.1). Patients were evaluated in follow-up for local control and late toxicity. Multivariate analysis of treatment and patient parameters was performed to evaluate their influence on toxicity, local control, and overall survival. RESULTS With a mean follow-up of 37 months, the actuarial overall survival rate for the entire group at 5 years was 24% and the local control rate was 57%. The tumor volume was the most significant predictor of local control, such that each 1-cm(3) increase in volume was associated with a 1% decrease in local control. For patients with tumor volumes </=30 cm(3) vs. >30 cm(3), the 5-year disease-specific survival rate was 52% and 27% (p = 0.004) and locoregional control rate was 76% and 26% (p <0.001), respectively. Seventy-six patients with a minimum of 12 months and median of 39 months toxicity follow-up were studied for late effects. None of these patients experienced Grade 4 or 5 toxicity. The actuarial rate of significant toxicity (Grade III or greater) was 32% at 5 years. Of the toxicities observed, xerostomia (19%) was the most common. Multivariate analysis revealed N stage and dose as independent predictors of Grade 3 effects. CONCLUSION The locoregional control and survival for patients in this institutional experience compare favorably to other published reports. Tumors of the larynx had the best prognosis. Larger volume tumors were associated with significantly lower local control and survival. Significant late effects were related to dose and nodal status.

Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers

PURPOSE During a high-dose-rate (HDR) brachytherapy treatment, as the source steps through different dwell positions, the dose rate at any fixed point within the implant varies, because the distance between the point and the source continually changes. The instantaneous dose rate may vary by a factor of 100 or more, in a complex dwell position sequence. Two different points which receive the same total dose may have received that dose with a very different sequence of dose rates. Any effects due to the complex changes in dose rate, including the sequence of dose delivery, are ignored. We investigated the possible effects of the sequence in which dose is delivered at two different dose rates, representative of dose rates that occur during an HDR treatment. METHODS AND MATERIALS The target consisted of a tube containing a 1.0 cm(3) suspension of V-79 Chinese hamster cells. Two fixed source dwell positions near and far from the target, representing high and intermediate dose rates, were considered. The experiments compared the survival of V-79 cells exposed to an irradiation sequence consisting of either an HDR component followed by an intermediate-dose-rate component (H-I arm), or the reverse (I-H arm). In either case, the total dose and the dose ratio were the same, only the order in which the high- or intermediate-dose-rate components of the dose were delivered was changed. RESULTS When the intermediate-dose-rate component was given before the HDR component, there was increased survival. All data pairs from three experiments showed greater survival for the I-H arm than the H-I arm by amounts ranging from 4% to 24%. Simple linear-quadratic models such as the Lea-Catchside model, which is invariant to time reversal of irradiation sequence, do not predict these results. CONCLUSIONS These results suggest that targets receiving the same total dose of radiation during an HDR implant may not experience the same biological effect. This may be related to induced radioresistance or sublethal damage repair.