The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer.

PURPOSE: The goal of this project was to see if using IMRT to deliver elective pelvic nodal irradiation (EPNI) for prostate cancer reduced acute treatment toxicity. METHODS: Two hundred and thirty patients were enrolled into prospective trials delivering EPNI with a concomitant hypofractionated IMRT boost to the prostate. During accrual, the method of EPNI delivery changed as new literature emerged. Three methods were used (1) 4FB, (2) IMRT with 2cm CTV margins around the pelvic vessels as suggested by Shih et al. (2005) [7] (IMRT-Shih), and (3) IMRT with nodal volumes suggested by the RTOG (IMRT-RTOG). Initially patients were treated with an empty bladder, with the remainder treated with bladder full. RESULTS: Patients in the 4FB group had higher rates of grade 2 acute GI toxicities compared to the IMRT-Shih and IMRT-RTOG groups (31.9% vs 20.8% vs 7.2%, p=0.0009). Patients in the 4FB group had higher rates of grade 3 urinary frequency compared to the two IMRT groups (8.5% vs 0% vs 0%, p=0.027). However, multivariate analysis suggested the factor that most influenced toxicity was bladder filling followed by IMRT. CONCLUSIONS: Bladder filling appeared to be the dominant factor which predicted for acute toxicity, followed by the use of IMRT.

Quality of life after hypofractionated concomitant intensity-modulated radiotherapy boost for high-risk prostate cancer.

PURPOSE: To evaluate the change in health-related quality of life (QOL) of patients with high-risk prostate cancer treated using hypofractionated radiotherapy combined with long-term androgen deprivation therapy. METHODS AND MATERIALS: A prospective Phase I-II study enrolled patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level ≥20 ng/mL, or Gleason score 8-10. Radiotherapy consisted of 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes with a concomitant 22.5 Gy intensity-modulated radiotherapy boost to the prostate, for a total of 67.5 Gy (2.7 Gy per fraction) in 25 fractions over 5 weeks. Daily image guidance was performed using three gold seed fiducials. Quality of life was measured using the Expanded Prostate Cancer Index Composite (EPIC), a validated tool that assesses four primary domains (urinary, bowel, sexual, and hormonal). RESULTS: From 2004 to 2007, 97 patients were treated. Median follow-up was 39 months. Compared with baseline, at 24 months there was no statistically significant change in the mean urinary domain score (p = 0.99), whereas there were decreases in the bowel (p < 0.01), sexual (p < 0.01), and hormonal (p < 0.01) domains. The proportion of patients reporting a clinically significant difference in EPIC urinary, bowel, sexual, and hormonal scores at 24 months was 27%, 31%, 55%, and 60%, respectively. However, moderate and severe distress related to these symptoms was minimal, with increases of only 3% and 5% in the urinary and bowel domains, respectively. CONCLUSIONS: Hypofractionated radiotherapy combined with long-term androgen deprivation therapy was well tolerated. Although there were modest rates of clinically significant patient-reported urinary and bowel toxicity, most of this caused only mild distress, and moderate and severe effects on QOL were limited. Additional follow-up is ongoing to characterize long-term QOL.

Hypofractionated concomitant intensity-modulated radiotherapy boost for high-risk prostate cancer: late toxicity.

PURPOSE: To report the acute and late toxicities of patients with high-risk localized prostate cancer treated using a concomitant hypofractionated, intensity-modulated radiotherapy boost combined with long-term androgen deprivation therapy. METHODS AND MATERIALS: A prospective Phase I-II study of patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level ≥ 20 ng/mL, or Gleason score 8-10. A dose of 45 Gy (1.8 Gy/fraction) was delivered to the pelvic lymph nodes with a concomitant 22.5 Gy prostate intensity-modulated radiotherapy boost, to a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions within 5 weeks. Image guidance was performed using three gold seed fiducials. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, and Radiation Therapy Oncology Group late morbidity scores were used to assess the acute and late toxicities, respectively. Biochemical failure was determined using the Phoenix definition. RESULTS: A total of 97 patients were treated and followed up for a median of 39 months, with 88% having a minimum of 24 months of follow-up. The maximal toxicity scores were recorded. The grade of acute gastrointestinal toxicity was Grade 0 in 4%, 1 in 59%, and 2 in 37%. The grade of acute urinary toxicity was Grade 0 in 8%, 1 in 50%, 2 in 39%, and 3 in 4%. The grade of late gastrointestinal toxicity was Grade 0 in 54%, 1 in 40%, and 2 in 7%. No Grade 3 or greater late gastrointestinal toxicities developed. The grade of late urinary toxicity was Grade 0 in 82%, 1 in 9%, 2 in 5%, 3 in 3%, and 4 in 1% (1 patient). All severe toxicities (Grade 3 or greater) had resolved at the last follow-up visit. The 4-year biochemical disease-free survival rate was 90.5%. CONCLUSIONS: A hypofractionated intensity-modulated radiotherapy boost delivering 67.5 Gy in 25 fractions within 5 weeks combined with pelvic nodal radiotherapy and long-term androgen deprivation therapy was well tolerated, with low rates of severe toxicity. The biochemical control rate at early follow-up has been promising. Additional follow-up is needed to determine the long-term biochemical control and prostate biopsy results.

Hypofractionated accelerated radiotherapy using concomitant intensity-modulated radiotherapy boost technique for localized high-risk prostate cancer: acute toxicity results.

PURPOSE: To evaluate the acute toxicities of hypofractionated accelerated radiotherapy (RT) using a concomitant intensity-modulated RT boost in conjunction with elective pelvic nodal irradiation for high-risk prostate cancer. METHODS AND MATERIALS: This report focused on 66 patients entered into this prospective Phase I study. The eligible patients had clinically localized prostate cancer with at least one of the following high-risk features (Stage T3, Gleason score >or=8, or prostate-specific antigen level >20 ng/mL). Patients were treated with 45 Gy in 25 fractions to the pelvic lymph nodes using a conventional four-field technique. A concomitant intensity-modulated radiotherapy boost of 22.5 Gy in 25 fractions was delivered to the prostate. Thus, the prostate received 67.5 Gy in 25 fractions within 5 weeks. Next, the patients underwent 3 years of adjuvant androgen ablative therapy. Acute toxicities were assessed using the Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment and at 3 months after RT. RESULTS: The median patient age was 71 years. The median pretreatment prostate-specific antigen level and Gleason score was 18.7 ng/L and 8, respectively. Grade 1-2 genitourinary and gastrointestinal toxicities were common during RT but most had settled at 3 months after treatment. Only 5 patients had acute Grade 3 genitourinary toxicity, in the form of urinary incontinence (n = 1), urinary frequency/urgency (n = 3), and urinary retention (n = 1). None of the patients developed Grade 3 or greater gastrointestinal or Grade 4 or greater genitourinary toxicity. CONCLUSION: The results of the present study have indicated that hypofractionated accelerated RT with a concomitant intensity-modulated RT boost and pelvic nodal irradiation is feasible with acceptable acute toxicity.

A study of tumor motion management in the conformal radiotherapy of lung cancer.

PURPOSE: To assess the benefit derived from the reduction of planning target volumes (PTVs) afforded by tumor motion management in treatment planning for lung cancer. METHODS: We use a simple formula that combines measurements of tumor motion and set-up error for 7 patients to determine PTVs based on the following scenarios: standard uniform 15 mm margin, individualized PTVs (no gating), spirometry-based gating, and active breath-control (ABC). We compare the percent volumes of lung receiving at least 20 Gy (V20) for a standard prescription, and the maximum tolerated doses (MTDs) at fixed V20. In anticipation of improvements in set-up accuracy, we repeat the analysis assuming a reduced set-up margin of 3mm. RESULTS: Relative to the standard, the average percent reductions in V20 (+/- 1 standard deviation) for the ungated and gated scenarios are 17+/-5 and 21+/-8; the percent gains in MTD are 25+/-12 and 33+/-11, respectively. For the 3mm set-up margin, the corresponding results for V20 are 28+/-7 and 36+/-7, and for MTD are 57+/-23 and 79+/-31. CONCLUSIONS: Any form of motion management provides a benefit over the use of a standard margin. The benefit derived from gating compared to the use of ungated individualized PTVs increases with tumor mobility but is generally modest. While motion management may benefit patients with highly mobile tumors, we expect efforts to reduce set-up error to be of greater overall significance. The practical limit for lung PTV margins is likely around 4-5mm, provided set-up error can be reduced sufficiently.

Prediction of lung tumour position based on spirometry and on abdominal displacement: accuracy and reproducibility.

BACKGROUND AND PURPOSE: A simulation investigating the accuracy and reproducibility of a tumour motion prediction model over clinical time frames is presented. The model is formed from surrogate and tumour motion measurements, and used to predict the future position of the tumour from surrogate measurements alone. PATIENTS AND METHODS: Data were acquired from five non-small cell lung cancer patients, on 3 days. Measurements of respiratory volume by spirometry and abdominal displacement by a real-time position tracking system were acquired simultaneously with X-ray fluoroscopy measurements of superior-inferior tumour displacement. A model of tumour motion was established and used to predict future tumour position, based on surrogate input data. The calculated position was compared against true tumour motion as seen on fluoroscopy. Three different imaging strategies, pre-treatment, pre-fraction and intrafractional imaging, were employed in establishing the fitting parameters of the prediction model. The impact of each imaging strategy upon accuracy and reproducibility was quantified. RESULTS: When establishing the predictive model using pre-treatment imaging, four of five patients exhibited poor interfractional reproducibility for either surrogate in subsequent sessions. Simulating the formulation of the predictive model prior to each fraction resulted in improved interfractional reproducibility. The accuracy of the prediction model was only improved in one of five patients when intrafractional imaging was used. CONCLUSIONS: Employing a prediction model established from measurements acquired at planning resulted in localization errors. Pre-fractional imaging improved the accuracy and reproducibility of the prediction model. Intrafractional imaging was of less value, suggesting that the accuracy limit of a surrogate-based prediction model is reached with once-daily imaging.

Correlation of lung tumor motion with external surrogate indicators of respiration.

PURPOSE: To assess the correlation of respiratory volume and abdominal displacement with tumor motion as seen with X-ray fluoroscopy. Measurements throughout the patient's treatment course allowed an assessment of the interfractional reproducibility of this correlation. METHODS AND MATERIALS: Data were acquired from 11 patients; 5 were studied over multiple days. Measurements of respiratory volume by spirometry and abdominal displacement by a real-time position tracking system were correlated to simultaneously acquired X-ray fluoroscopy measurements of superior-inferior tumor displacement. The linear correlation coefficient was computed for each data acquisition. The phase relationship between the surrogate and tumor signals was estimated through cross-correlation delay analysis. RESULTS: Correlation coefficients ranged from very high to very low (0.99-0.39, p < 0.0001). The correlation between tumor displacement and respiratory volume was higher and more reproducible from day to day than between tumor displacement and abdominal displacement. A nonzero phase relationship was observed in nearly all patients (-0.65 to +0.50 s). This relationship was observed to vary over inter- and intrafractional time scales. Only 1 of 5 patients studied over multiple days had a consistent relationship between tumor motion and either surrogate. CONCLUSIONS: Respiratory volume has a more reproducible correlation with tumor motion than does abdominal displacement. If forming a tumor-surrogate prediction model from a limited series of observations, the use of surrogates to guide treatment might result in geographic miss.

Reproducibility of lung tumor position and reduction of lung mass within the planning target volume using active breathing control (ABC).

PURPOSE: The active breathing control (ABC) device allows for temporary immobilization of respiratory motion by implementing a breath hold at a predefined relative lung volume and air flow direction. The purpose of this study was to quantitatively evaluate the ability of the ABC device to immobilize peripheral lung tumors at a reproducible position, increase total lung volume, and thereby reduce lung mass within the planning target volume (PTV). MATERIALS AND METHODS: Ten patients with peripheral non-small-cell lung cancer tumors undergoing radiotherapy had CT scans of their thorax with and without ABC inspiration breath hold during the first 5 days of treatment. Total lung volumes were determined from the CT data sets. Each peripheral lung tumor was contoured by one physician on all CT scans to generate gross tumor volumes (GTVs). The lung density and mass contained within a 1.5-cm PTV margin around each peripheral tumor was calculated using CT numbers. Using the center of the GTV from the Day 1 ABC scan as the reference, the displacement of subsequent GTV centers on Days 2 to 5 for each patient with ABC applied was calculated in three dimensions. RESULTS: With the use of ABC inspiration breath hold, total lung volumes increased by an average of 42%. This resulted in an average decrease in lung mass of 18% within a standard 1.5-cm PTV margin around the GTV. The average (+/- standard deviation) displacement of GTV centers with ABC breath hold applied was 0.3 mm (+/- 1.8 mm), 1.2 mm (+/- 2.3 mm), and 1.1 mm (+/- 3.5 mm) in the lateral direction, anterior-posterior direction, and superior-inferior direction, respectively. CONCLUSIONS: Results from this study indicate that there remains some inter-breath hold variability in peripheral lung tumor position with the use of ABC inspiration breath hold, which prevents significant PTV margin reduction. However, lung volumes can significantly increase, thereby decreasing the mass of lung within a standard PTV.

Digital fluoroscopy to quantify lung tumor motion: potential for patient-specific planning target volumes.

PURPOSE: To apply digital fluoroscopy integrated with CT simulation to measure lung tumor motion and aid in the quantification of individualized planning target volumes. METHODS AND MATERIALS: A flat panel digital fluoroscopy unit was modified and integrated with a CT simulator. The stored fluoroscopy images were overlaid with digitally reconstructed radiographs, allowing measurement of the observed lung tumor motion in relation to the corresponding contours on the static digitally reconstructed radiographs. CT simulation and digital fluoroscopy was performed on 10 patients with non-small-cell lung cancer. Actual tumor motion was measured in three dimensions using the overlaid images. RESULTS: Combining the dynamic data with digitally reconstructed radiographs allowed the tumor shadow from the fluoroscopy to be tracked in relation to the CT lung tumor contour. For all patients, the extent of tumor motion in three dimensions was unique. The motion was greatest in the superoinferior direction and minimal in the AP and lateral directions. CONCLUSION: We have developed a tool that allows CT simulation to be combined with digital fluoroscopy. Quantitative evaluation of the tumor motion in relation to the CT plan allows for customization of the planning target volume. The variability observed clearly demonstrates the need to generate patient-specific internal motion margins.

Accelerated hypofractionation for early-stage non-small-cell lung cancer.

PURPOSE: To describe the outcome of treating early-stage non-small-cell lung cancer (NSCLC) with an accelerated hypofractionated course of radiotherapy. METHODS AND MATERIALS: A policy of treating early-stage NSCLC with a dose of 48 Gy in 12 once-daily fractions without elective irradiation of radiologically uninvolved regional nodes was adopted in 1996. We describe the outcome in 33 patients with NSCLC treated with this dose-fractionation schedule. RESULTS: The median patient age was 72.0 years. Most patients (75.8%) were not surgical candidates because of medical comorbidities or old age. For staging, 97.0% underwent CT of the thorax, and mediastinoscopy was performed in 6.1%. All patients had Stage T1-T2N0, except for 4 patients with positive nodes based on pathologically involved or clinically enlarged lymph nodes adjacent to the primary tumor. The overall survival rate was 80.1% at 1 year and 46.0% at 2 years. The median survival was 22.6 months. The cause-specific survival rate was 89.8% at 1 year and 54.1% at 2 years. The recurrence-free survival rate was 66.4% at 1 year and 40.0% at 2 years. Lateral radiotherapy field margins of <2 cm predicted for inferior overall survival, cause-specific survival, and recurrence-free survival on univariate and multivariate analyses (p <0.05). The most commonly reported toxicities were acute dermatitis (30.3%) and late cutaneous/subcutaneous fibrosis (24.2%). CONCLUSION: Accelerated hypofractionation for early-stage NSCLC appears to be safe and produces promising early results. Very small radiotherapy field margins may lead to an inferior outcome. Prospective studies are needed to determine the optimal dose-fractionation schedule.