Controversies in the treatment of high-risk prostate cancer--what is the optimal combination of hormonal therapy and radiotherapy: a review of literature.

BACKGROUND: In high-risk prostate carcinoma, there is controversy whether these patients should be treated with escalated-dose (> or =74 Gy) or conventional-dose radiotherapy (<74 Gy) combined with hormonal therapy. Furthermore, the issue of the optimal duration and timing of hormonal therapy are not well crystallized. PATIENTS AND METHODS: A search for evidence from randomized- and large non-randomized studies in order to address these issues, was therefore initiated. For this purpose, MedLine, EMbase, and PubMed and the data base of the Dutch randomized dose-escalation trial, were consulted. RESULTS AND CONCLUSIONS: From this search it was concluded that the benefit of hormonal therapy in combination with conventional-dose radiotherapy (<74 Gy) in high-risk prostate cancer is evident (Level 2 evidence); Levels 2 and 3 evidence were provided by several studies supporting the use of escalated-dose radiotherapy in high-risk prostate cancer. For the combination of hormonal therapy with escalated-dose radiotherapy in these patients, there is Level 2 evidence for moderately escalated dose (74 Gy) and high escalated dose (> or =78 Gy). The optimal duration and timing of hormonal therapy are not well defined. More randomized-controlled trials and meta-analyses are therefore needed to clearly determine the independent role of dose-escalation in high-risk patients treated with hormonal therapy and the optimal duration and timing of hormonal therapy.

Modeling radiation pneumonitis of pulmonary stereotactic body radiotherapy: The impact of a local dose-effect relationship for lung perfusion loss.

PURPOSE: To investigate if a local dose-effect (LDE) relationship for perfusion loss improves the NTCP model fit for SBRT induced radiation pneumonitis (RP) compared to conventional LDEs. METHODS AND MATERIALS: Multi-institutional data of 1015 patients treated with SBRT were analyzed. Dose distributions were converted to NTD with α/ß = 3 Gy. The Lyman-Kutcher-Burman NTCP model was fitted to the incidence grade ≥2 RP by maximum likelihood estimation with mean lung dose (MLD), equivalent uniform doses (EUD) using three LDE functions (power-law (EUDpower), logistic with 2 free parameters (EUDlog-free) and logistic with fixed parameters describing local perfusion loss (EUDPerfusion)) and volume above a threshold dose (Vx). Models were compared with the Akaike weights (Aw) derived from the Akaike information criteria (AIC). RESULTS: The median time to grade ≥2 RP was 4.2 months and plateaued after 17 months at 5.4%. A strong dose-effect relationship for RP incidence was observed. The EUDPerfusion based NTCP model had the lowest AIC. The Aw were 0.53, 0.19, 0.11, 0.11, 0.05 for the EUDPerfusion, Vx, MLD, EUDlog-free and EUDpower LDEs respectively. CONCLUSION: A LDE for perfusion loss provided modest improvement in NTCP model fit for SBRT induced radiation pneumonitis.

Variability of four-dimensional computed tomography patient models.

PURPOSE: To quantify the interfractional variability in lung tumor trajectory and mean position during the course of radiation therapy. METHODS AND MATERIALS: Repeat four-dimensional (4D) cone-beam computed tomography (CBCT) scans (median, nine scans/patient) routinely acquired during the course of treatment were analyzed for 56 patients with lung cancer. Tumor motion was assessed by using local rigid registration of a region of interest in the 3D planning CT to each phase in the 4D CBCT. Displacements of the mean tumor position relative to the planned position (baseline variations) were obtained by using time-weighted averaging of the motion curve. RESULTS: The tumor trajectory shape was found to be stable interfractionally, with mean variability not exceeding 1 mm (1 SD) in each direction for the inhale and exhale phases. Interfractional baseline variations, however, were large, with 1.6- (left-right), 3.9- (cranial-caudal), and 2.8-mm (anterior-posterior) systematic variations (1 SD) and 1.2- (left-right), 2.4- (cranial-caudal) and 2.2-mm (anterior-posterior) random variations. Eliminating baseline variations by using soft-tissue guidance decreases planning target volume margins by approximately 50% compared with bony anatomy-driven protocols for conventional fractionation schemes. CONCLUSIONS: Systematic and random baseline variations constitute a substantial portion of the geometric variability present in the treatment of patients with lung cancer and require generous safety margins when relying on accurate setup/immobilization or bony anatomy-driven correction strategies. The 4D-CBCT has the ability to accurately monitor tumor trajectory shape and baseline variations and drive image-guided correction strategies that allows safe margin reduction.

Adaptive radiotherapy for prostate cancer using kilovoltage cone-beam computed tomography: first clinical results.

PURPOSE: To evaluate the first clinical results of an off-line adaptive radiotherapy (ART) protocol for prostate cancer using kilovoltage cone-beam computed tomography (CBCT) in combination with a diet and mild laxatives. METHODS AND MATERIALS: Twenty-three patients began treatment with a planning target volume (PTV) margin of 10 mm. The CBCT scans acquired during the first six fractions were used to generate an average prostate clinical target volume (AV-CTV), and average rectum (AV-Rect). Using these structures, a new treatment plan was generated with a 7-mm PTV margin. Weekly CBCT scans were used to monitor the CTV coverage. A diet and mild laxatives were introduced to improve image quality and reduce prostate motion. RESULTS: Twenty patients were treated with conform ART protocol. For these patients, 91% of the CBCT scans could be used to calculate the AV-CTV and AV-Rect. In 96% of the follow-up CBCT scans, the CTV was located within the average PTV. In the remaining 4%, the prostate extended the PTV by a maximum of 1 mm. Systematic and random errors for organ motion were reduced by a factor of two compared with historical data without diet and laxatives. An average PTV reduction of 29% was achieved. The volume of the AV-Rect that received >65 Gy was reduced by 19%. The mean dose to the anal wall was reduced on average by 4.8 Gy. CONCLUSIONS: We safely reduced the high-dose region by 29%. The reduction in irradiated volume led to a significant reduction in the dose to the rectum. The diet and laxatives improved the image quality and tended to reduce prostate motion.

Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer patients.

PURPOSE: To discuss planning target volumes (PTVs) based on internal target volume (PTVITV), exhale-gated radiotherapy (PTVGating), and a new proposed midposition (PTVMidP; time-weighted mean tumor position) and compare them with the conventional free-breathing CT scan PTV (PTVConv). METHODS AND MATERIALS: Respiratory motion induces systematic and random geometric uncertainties. Their contribution to the clinical target volume (CTV)-to-PTV margins differs for each PTV approach. The uncertainty margins were calculated using a dose-probability-based margin recipe (based on patient statistics). Tumor motion in four-dimensional CT scans was determined using a local rigid registration of the tumor. Geometric uncertainties for interfractional setup errors and tumor baseline variation were included. For PTVGating, the residual motion within a 30% gating (time) window was determined. The concepts were evaluated in terms of required CTV-to-PTV margin and PTV volume for 45 patients. RESULTS: Over the patient group, the PTVITV was on average larger (+6%) and the PTVGating and PTVMidP smaller (-10%) than the PTVConv using an off-line (bony anatomy) setup correction protocol. With an on-line (soft tissue) protocol the differences in PTV compared with PTVConv were +33%, -4%, and 0, respectively. CONCLUSIONS: The internal target volume method resulted in a significantly larger PTV than conventional CT scanning. The exhale-gated and mid-position approaches were comparable in terms of PTV. However, mid-position (or mid-ventilation) is easier to use in the clinic because it only affects the planning part of treatment and not the delivery.

The influence of a dietary protocol on cone beam CT-guided radiotherapy for prostate cancer patients.

PURPOSE: To evaluate the influence of a dietary protocol on cone beam computed tomography (CBCT) image quality, which is an indirect indicator for short-term (intrafraction) prostate motion, and on interfraction motion. Image quality is affected by motion (e.g., moving gas) during imaging and influences the performance of automatic prostate localization on CBCT scans. METHODS AND MATERIALS: Twenty-six patients (336 CBCT scans) followed the dietary protocol and 23 patients (240 CBCT scans) did not. Prostates were automatically localized by using three dimensional (3D) gray-value registration (GR). Feces and (moving) gas occurrence in the CBCT scans, the success rate of 3D-GR, and the statistics of prostate motion data were assessed. RESULTS: Feces, gas, and moving gas significantly decreased from 55%, 61%, and 43% of scans in the nondiet group to 31%, 47%, and 28% in the diet group (all p < 0.001). Since there is a known relation between gas and short-term prostate motion, intrafraction prostate motion probably also decreased. The success rate of 3D-GR improved from 83% to 94% (p < 0.001). A decrease in random interfraction prostate motion also was found, which was not significant after Bonferroni's correction. Significant deviations from planning CT position for rotations around the left-right axis were found in both groups. CONCLUSIONS: The dietary protocol significantly decreased the incidence of feces and (moving) gas. As a result, CBCT image quality and the success rate of 3D-GR significantly increased. A trend exists that random interfraction prostate motion decreases. Using a dietary protocol therefore is advisable, also without CBCT-based image guidance.

Strategy for online correction of rotational organ motion for intensity-modulated radiotherapy of prostate cancer.

PURPOSE: To develop and evaluate a correction strategy for prostate rotation using gantry and collimator angle adjustments. METHODS AND MATERIALS: Gantry and collimator angle adjustments were used to correct for prostate rotation without rotating the table. A formula to partially correct for left-right (LR) rotations was derived through geometric analysis of rotation-induced clinical target volume (CTV) beam's-eye-view shape changes. For 10 prostate patients, intensity-modulated radiotherapy (IMRT) plans with different margins were created. Simulating CTV LR rotation and correcting each beam by a collimator rotation, the corrected CTV dose was compared with the original and uncorrected dose. Effects of residual geometric uncertainties were assessed using a Monte Carlo technique. A large number of treatments representative for prostate patients were simulated. Dose probability histograms of the minimum CTV dose (D min) were derived, with and without online correction, resulting in a more realistic margin estimate. RESULTS: Dosimetric analysis of all IMRT plans showed that, with rotational correction and a 2-mm margin, D min was constant to within 3% for LR rotations up to +/-15 degrees . The Monte Carlo dose probability histograms showed that, with correction, a margin of 4 mm ensured that 90% of patients received a D min >or=95% of the prescribed dose. Without correction a margin of 6 mm was required. CONCLUSIONS: We developed and tested a practical method for (online) correction of prostate rotation, allowing safe and straightforward implementation of margin reduction and dose escalation.

An adaptive off-line procedure for radiotherapy of prostate cancer.

PURPOSE: To determine the planning target volume (PTV) margin for an adaptive radiotherapy procedure that uses five computed tomography (CT) scans to calculate an average prostate position and rectum shape. To evaluate alternative methods to determine an average rectum based on a single delineation. METHODS AND MATERIALS: Repeat CT scans (8-13) of 19 patients were used. The contoured prostates of the first four scans were matched on the planning CT (pCT) prostate contours. With the resulting translations and rotations the average prostate position was determined. An average rectum was obtained by either averaging the coordinates of corresponding points on the rectal walls or by selecting the "best" rectum or transforming the pCT rectum. Dose distributions were calculated for various expanded average prostates. The remaining CT scans were used to determine the dose received by prostate and rectum during treatment. RESULTS: For the prostate of the pCT scan and a 10-mm margin, all patients received more than 95% of the prescribed dose to 95% of the prostate. For the average prostate, a margin of 7 mm was needed to obtain a similar result (average PTV reduction 30%). The average rectum overestimated the mean dose to the rectum by 0.4 +/- 1.6 Gy, which was better than the pCT rectum (2.1 +/- 3.0 Gy) and the alternative average rectums (1.0 +/- 2.6 Gy and 1.4 +/- 3.2 Gy). CONCLUSIONS: Our adaptive procedure allows for reduction of the PTV margin to 7 mm without decreasing prostate coverage during treatment. For accurate estimation of the rectum dose, rectums need to be delineated and averaged over multiple scans.

Increased risk of biochemical and clinical failure for prostate patients with a large rectum at radiotherapy planning: results from the Dutch trial of 68 GY versus 78 Gy.

PURPOSE: To investigate whether a large rectum filling visible on the planning CT scan was associated with a decrease in freedom from any failure (FFF) and freedom from clinical failure (FFCF) for prostate cancer patients. METHODS AND MATERIALS: Patients from the Dutch trial (78 Gy vs. 68 Gy) with available acute toxicity data were analyzed (n = 549). A 10-mm margin was applied for the first 68 Gy and 0-5 mm for the 10-Gy boost. The dose in the seminal vesicles (SVs) was prescribed within four treatment groups according to the estimated risk of SV involvement. Two potential risk factors (RFs) for a geometric miss were defined: (1) an anorectal volume > or = 90 cm(3) and > or = 25% of treatment-time diarrhea (RF1); and (2) the mean cross-sectional area of the anorectum (RF2). We tested whether these were significant predictors for FFF and FFCF within each treatment group. RESULTS: Significant results were observed only for patients with a risk of SV involvement > 25% (dose of 68-78 Gy to the SVs, n = 349). We found a decrease in FFF (p = 0.001) and FFCF (p = 0.01) for the 87 patients with RF1 (for RF2, p = 0.02 and p = 0.01, respectively). The estimated decrease in the FFCF rate at 5 years was 15%. CONCLUSION: Tumor control was significantly decreased in patients with a risk of SV involvement > 25% and at risk of geometric miss. Current image guidance techniques offer several solutions to geometrically optimize the treatment. Additional research is needed to evaluate whether geometric misses can be prevented using these techniques.

Kilo-voltage cone-beam computed tomography setup measurements for lung cancer patients; first clinical results and comparison with electronic portal-imaging device.

PURPOSE: Kilovoltage cone-beam computed tomography (CBCT) has been developed to provide accurate soft-tissue and bony setup information. We evaluated clinical CBCT setup data and compared CBCT measurements with electronic portal imaging device (EPID) images for lung cancer patients. METHODS AND MATERIALS: The setup error for CBCT scans at the treatment unit relative to the planning CT was measured for 62 patients (524 scans). For 19 of these patients (172 scans) portal images were also made. The mean, systematic setup error (Sigma), and random setup error (sigma) were calculated for the CBCT and the EPID. The differences between CBCT and EPID and the rotational setup error derived from the CBCT were also evaluated. An offline shrinking action level correction protocol, based on the CBCT measurements, was used to reduce systematic setup errors and the impact of this protocol was evaluated. RESULTS: The CBCT setup errors were significantly larger than the EPID setup errors for the cranial-caudal and anterior-posterior directions (p < 0.05). The mean overall setup errors after correction measured with the CBCT were 0.2 mm (Sigma = 1.6 mm, sigma = 2.9 mm) in the left-right, -0.8 mm (Sigma = 1.7 mm, sigma = 4.0 mm) in cranial-caudal and 0.0 mm (Sigma = 1.5 mm, sigma = 2.0 mm) in the anterior-posterior direction. Using our correction protocol only 2 patients had mean setup errors larger than 5 mm, without this correction protocol 51% of the patients would have had a setup error larger than 5 mm. CONCLUSION: Use of CBCT scans provided more accurate information concerning the setup of lung cancer patients than did portal imaging.

Feasibility of pathology-correlated lung imaging for accurate target definition of lung tumors.

PURPOSE: To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. METHODS AND MATERIALS: High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non-small-cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sections were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. RESULTS: In 4 of 5 patients, the GTV(CT) was, on average, 4 cm(3) ( approximately 53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV(CT) was 16 cm(3) ( approximately 40%) too small. The GTV(PET) was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. CONCLUSIONS: Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread.

Prospective assessment of dosimetric/physiologic-based models for predicting radiation pneumonitis.

PURPOSE: Clinical and 3D dosimetric parameters are associated with symptomatic radiation pneumonitis rates in retrospective studies. Such parameters include: mean lung dose (MLD), radiation (RT) dose to perfused lung (via SPECT), and pre-RT lung function. Based on prior publications, we defined pre-RT criteria hypothesized to be predictive for later development of pneumonitis. We herein prospectively test the predictive abilities of these dosimetric/functional parameters on 2 cohorts of patients from Duke and The Netherlands Cancer Institute (NKI). METHODS AND MATERIALS: For the Duke cohort, 55 eligible patients treated between 1999 and 2005 on a prospective IRB-approved study to monitor RT-induced lung injury were analyzed. A similar group of patients treated at the NKI between 1996 and 2002 were identified. Patients believed to be at high and low risk for pneumonitis were defined based on: (1) MLD; (2) OpRP (sum of predicted perfusion reduction based on regional dose-response curve); and (3) pre-RT DLCO. All doses reflected tissue density heterogeneity. The rates of grade > or =2 pneumonitis in the "presumed" high and low risk groups were compared using Fisher's exact test. RESULTS: In the Duke group, pneumonitis rates in patients prospectively deemed to be at "high" vs. "low" risk are 7 of 20 and 9 of 35, respectively; p = 0.33 one-tailed Fisher's. Similarly, comparable rates for the NKI group are 4 of 21 and 6 of 44, respectively, p = 0.41 one-tailed Fisher's. CONCLUSION: The prospective model appears unable to accurately segregate patients into high vs. low risk groups. However, considered retrospectively, these data are consistent with prior studies suggesting that dosimetric (e.g., MLD) and functional (e.g., PFTs or SPECT) parameters are predictive for RT-induced pneumonitis. Additional work is needed to better identify, and prospectively assess, predictors of RT-induced lung injury.

IMRT optimization including random and systematic geometric errors based on the expectation of TCP and NTCP.

The purpose of this work was the development of a probabilistic planning method with biological cost functions that does not require the definition of margins. Geometrical uncertainties were integrated in tumor control probability (TCP) and normal tissue complication probability (NTCP) objective functions for inverse planning. For efficiency reasons random errors were included by blurring the dose distribution and systematic errors by shifting structures with respect to the dose. Treatment plans were made for 19 prostate patients following four inverse strategies: Conformal with homogeneous dose to the planning target volume (PTV), a simultaneous integrated boost using a second PTV, optimization using TCP and NTCP functions together with a PTV, and probabilistic TCP and NTCP optimization for the clinical target volume without PTV. The resulting plans were evaluated by independent Monte Carlo simulation of many possible treatment histories including geometrical uncertainties. The results showed that the probabilistic optimization technique reduced the rectal wall volume receiving high dose, while at the same time increasing the dose to the clinical target volume. Without sacrificing the expected local control rate, the expected rectum toxicity could be reduced by 50% relative to the boost technique. The improvement over the conformal technique was larger yet. The margin based biological technique led to toxicity in between the boost and probabilistic techniques, but its control rates were very variable and relatively low. During evaluations, the sensitivity of the local control probability to variations in biological parameters appeared similar for all four strategies. The sensitivity to variations of the geometrical error distributions was strongest for the probabilistic technique. It is concluded that probabilistic optimization based on tumor control probability and normal tissue complication probability is feasible. It results in robust prostate treatment plans with an improved balance between local control and rectum toxicity, compared to conventional techniques.

Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: consequential late damage.

PURPOSE: Late gastrointestinal (GI) toxicity after radiotherapy can be partly explained by late effects of acute toxicity (consequential late damage). We studied whether there is a direct relationship between acute and late GI toxicity. PATIENTS AND METHODS: A total of 553 evaluable patients from the Dutch dose escalation trial (68 Gy vs. 78 Gy) were included. We defined three outcomes for acute reactions: 1) maximum Radiation Therapy Oncology Group acute toxicity, 2) maximum acute mucous discharge (AMD), and 3) maximum acute proctitis. Within a multivariable model, late endpoints (overall toxicity and five toxicity indicators) were studied as a function of acute toxicity, pretreatment symptoms, and relevant dose parameters. RESULTS: At multivariable analysis, AMD and acute proctitis were strong predictors for overall toxicity, "intermittent bleeding," and "incontinence pads" (p < or = 0.01). For "stools > or =6/day" all three were strong predictors. No significant associations were found for "severe bleeding" and "use of steroids." The predictive power of the dose parameters remained at the same level or became weaker for most late endpoints. CONCLUSIONS: Acute GI toxicity is an independent significant predictor of late GI toxicity. This suggests a significant consequential component in the development of late GI toxicity.

Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy.

PURPOSE: The aim of this study was to determine the maximum tolerated dose (MTD) delivered within 6 weeks in patients with non-small-cell lung cancer (NSCLC). The impact of tumor volume and delivered dose on failure-free interval (FFI) and overall survival (OS) were also studied. METHODS AND MATERIALS: A Phase I/II trial was performed including inoperable NSCLC patients. According to the relative mean lung dose (rMLD), five risk groups with different starting doses were defined: Group 1, rMLD 0.0 to 0.12; Group 2, rMLD 0.12 to 0.18; Group 3, rMLD 0.18 to 0.24; Group 4, rMLD 0.24 to 0.31; and Group 5, rMLD 0.31 to 0.40. Patients underwent irradiation with 2.25 Gy per fraction and a fixed overall treatment time of 6 weeks. The dose was escalated with 6.75 Gy after 6 months follow-up without dose-limiting toxicity. If more than 30 fractions were prescribed, twice-daily irradiation was performed with at least a 6-h interval. RESULTS: A total of 88 patients were included. Tumor Stage I or II was found in 53%, IIIA in 31%, and IIIB in 17%. The MTD was not achieved in risk Group 1 (reached dose, 94.5 Gy). For risk Groups 2 and 3 the MTD was 81 Gy. The 74.3-Gy dose was determined to be safe for Group 4 and the 60.8-Gy dose for Group 5. In 2 patients (5%) an isolated nodal relapse occurred. Based on multivariable analysis, higher doses significantly increased the FFI (p = 0.02) for the total group. The OS was increased in the lower risk groups (p = 0.05) but not in the higher risk groups (p = 0.4). CONCLUSION: Dose escalation is safe up to 94.5 Gy in 42 fractions in 6 weeks in patients with an MLD 13.6 Gy or less. Higher doses are associated with a better FFI and OS for smaller tumor volumes. Involved-field irradiation results in a low percentage of isolated nodal relapses.

Adaptive radiotherapy for invasive bladder cancer: a feasibility study.

PURPOSE: To evaluate the feasibility of adaptive radiotherapy (ART) in combination with a partial bladder irradiation. METHODS AND MATERIALS: Twenty-one patients with solitary T1-T4 N0M0 bladder cancer were treated to the bladder tumor + 2 cm margin planning target volume (PTV(CONV)). During the first treatment week, five daily computed tomography (CT) scans were made immediately before or after treatment. In the second week, a volume was constructed encompassing the gross tumor volumes (GTVs) on the planning scan and the five CT scans (GTV(ART)). The GTV(ART) was expanded with a 1 cm margin for the construction of a PTV(ART). Starting in the third week, patients were treated to PTV(ART). Repeat CT scans were used to evaluate treatment accuracy. RESULTS: On 5 of 91 repeat CT scans (5%), the GTV was not adequately covered by the PTV(ART). On treatment planning, there was only one scan in which the GTV was not adequately covered by the 95% isodose. On average, the treatment volumes were reduced by 40% when comparing PTV(ART) with PTV(CONV) (p < 0.0001). CONCLUSION: The adaptive strategy for bladder cancer is an effective way to deal with treatment errors caused by variations in bladder tumor position and leads to a substantial reduction in treatment volumes.

Tumor motion and deformation during external radiotherapy of bladder cancer.

PURPOSE: First, to quantify bladder-tumor motion in 3 dimensions during a 4-week to 5-week course of external radiotherapy. Second, to relate the motion to the tumor location on the bladder wall. Third, to extensively evaluate gross tumor volume (GTV) shape and volume changes during the course of the treatment. METHODS AND MATERIALS: Multiple repeat computed tomography (CT) images were obtained for 21 bladder cancer patients. These scans were matched to the rigid bony anatomy. For each patient, the main direction and magnitude of the tumor movement was determined by use of principle-component analysis. To study GTV shape changes, all GTVs were registered to the GTV in the planning CT scan, and the residual shape errors were determined by measurement of edge variations perpendicular to the median surface. RESULTS: Gross tumor volume translations were largest in cranial-caudal and anterior-posterior direction (SD, 0.1 to approximately 0.9 cm). The translations were strongly correlated with the tumor location on the bladder wall. The average value of the local standard deviations of the GTV shape ranged from 0.1 to approximately 0.35 cm. CONCLUSIONS: Despite large differences in bladder filling, variations in GTV shape were small compared with variations in GTV position. Geometric uncertainties in the GTV position depended strongly on the tumor location on the bladder wall.

Mid-ventilation CT scan construction from four-dimensional respiration-correlated CT scans for radiotherapy planning of lung cancer patients.

PURPOSE: Four-dimensional (4D) respiration-correlated imaging techniques can be used to obtain (respiration) artifact-free computed tomography (CT) images of the thorax. Current radiotherapy planning systems, however, do not accommodate 4D-CT data. The purpose of this study was to develop a simple, new concept to incorporate patient-specific motion information, using 4D-CT scans, in the radiotherapy planning process of lung cancer patients to enable smaller error margins. METHODS AND MATERIALS: A single CT scan was selected from the 4D-CT data set. This scan represented the tumor in its time-averaged position over the respiratory cycle (the mid-ventilation CT scan). To select the appropriate CT scan, two methods were used. First, the three-dimensional tumor motion was analyzed semiautomatically to calculate the mean tumor position and the corresponding respiration phase. An alternative automated method was developed to select the correct CT scan using the diaphragm motion. RESULTS: Owing to hysteresis, mid-ventilation selection using the three-dimensional tumor motion had a tumor position accuracy (with respect to the mean tumor position) better than 1.1 +/- 1.1 mm for all three directions (inhalation and exhalation). The accuracy in the diaphragm motion method was better than 1.1 +/- 1.1 mm. Conventional free-breathing CT scanning had an accuracy better than 0 +/- 3.9 mm. The mid-ventilation concept can result in an average irradiated volume reduction of 20% for tumors with a diameter of 40 mm. CONCLUSION: Tumor motion and the diaphragm motion method can be used to select the (artifact-free) mid-ventilation CT scan, enabling a significant reduction of the irradiated volume.

Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling.

PURPOSE: To analyze whether inclusion of predisposing clinical features in the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model improves the estimation of late gastrointestinal toxicity. METHODS AND MATERIALS: This study includes 468 prostate cancer patients participating in a randomized trial comparing 68 with 78 Gy. We fitted the probability of developing late toxicity within 3 years (rectal bleeding, high stool frequency, and fecal incontinence) with the original, and a modified LKB model, in which a clinical feature (e.g., history of abdominal surgery) was taken into account by fitting subset specific TD50s. The ratio of these TD50s is the dose-modifying factor for that clinical feature. Dose distributions of anorectal (bleeding and frequency) and anal wall (fecal incontinence) were used. RESULTS: The modified LKB model gave significantly better fits than the original LKB model. Patients with a history of abdominal surgery had a lower tolerance to radiation than did patients without previous surgery, with a dose-modifying factor of 1.1 for bleeding and of 2.5 for fecal incontinence. The dose-response curve for bleeding was approximately two times steeper than that for frequency and three times steeper than that for fecal incontinence. CONCLUSIONS: Inclusion of predisposing clinical features significantly improved the estimation of the NTCP. For patients with a history of abdominal surgery, more severe dose constraints should therefore be used during treatment plan optimization.

Impact of geometrical uncertainties on 3D CRT and IMRT dose distributions for lung cancer treatment.

PURPOSE: To quantify the effect of set-up errors and respiratory motion on dose distributions for non-small cell lung cancer (NSCLC) treatment. METHODS AND MATERIALS: Irradiations of 5 NSCLC patients were planned with 3 techniques, two (conformal radiation therapy (CRT) and intensity modulated radiation therapy (IMRT1)) with a homogeneous dose in the planning target volume (PTV) and a third (IMRT2) with dose heterogeneity. Set-up errors were simulated for gross target volume (GTV) and organs at risk (OARs). For the GTV, the respiration was also simulated with a periodical motion around a varying average. Two configurations were studied for the breathing motion, to describe the situations of free-breathing (FB) and respiration-correlated (RC) CT scans, each with 2 amplitudes (5 and 10 mm), thus resulting in 4 scenarios (FB_5, FB_10, RC_5 and RC_10). Five thousand treatment courses were simulated, producing probability distributions for the dosimetric parameters. RESULTS: For CRT and IMRT1, RC_5, RC_10 and FB_5 were associated with a small degradation of the GTV coverage. IMRT2 with FB_10 showed the largest deterioration of the GTV dosimetric indices, reaching 7% for Dmin at the 95% probability level. Removing the systematic error due to the periodic breathing motion was advantageous for a 10 mm respiration amplitude. The estimated probability of radiation pneumonitis and acute complication for the esophagus showed limited sensitivity to geometrical uncertainties. Dmax in the spinal cord and the parameters predicting the risk of late esophageal toxicity were associated to a probability up to 50% of violating the dose tolerances. CONCLUSIONS: Simulating the effect of geometrical uncertainties on the individual patient plan should become part of the standard pre-treatment verification procedure.