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.

Late Side Effects After Image Guided Intensity Modulated Radiation Therapy Compared to 3D-Conformal Radiation Therapy for Prostate Cancer: Results From 2 Prospective Cohorts.

PURPOSE: Technical developments in the field of external beam radiation therapy (RT) enabled the clinical introduction of image guided intensity modulated radiation therapy (IG-IMRT), which improved target conformity and allowed reduction of safety margins. Whether this had an impact on late toxicity levels compared to previously applied three-dimensional conformal radiation therapy (3D-CRT) is currently unknown. We analyzed late side effects after treatment with IG-IMRT or 3D-CRT, evaluating 2 prospective cohorts of men treated for localized prostate cancer to investigate the hypothesized reductions in toxicity. METHODS AND MATERIALS: Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fractions were recruited from 2 Dutch randomized trials with identical toxicity scoring protocols. Late toxicity (>90 days after treatment) was derived from self-assessment questionnaires and case report forms, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG-EORTC) scoring criteria. Grade ≥2 endpoints included gastrointestinal (GI) rectal bleeding, increased stool frequency, discomfort, rectal incontinence, proctitis, and genitourinary (GU) obstruction, increased urinary frequency, nocturia, urinary incontinence, and dysuria. The Cox proportional hazards regression model was used to compare grade ≥2 toxicities between both techniques, adjusting for other modifying factors. RESULTS: The 5-year cumulative incidence of grade ≥2 GI toxicity was 24.9% for IG-IMRT and 37.6% following 3D-CRT (adjusted hazard ratio [HR]: 0.59, P=.005), with significant reductions in proctitis (HR: 0.37, P=.047) and increased stool frequency (HR: 0.23, P<.001). GU grade ≥2 toxicity levels at 5 years were comparable with 46.2% and 36.4% following IG-IMRT and 3D-CRT, respectively (adjusted HR: 1.19, P=.33). Other strong predictors (P<.01) of grade ≥2 late toxicity were baseline complaints, acute toxicity, and age. CONCLUSIONS: Treatment with IG-IMRT reduced the risk of late grade ≥2 complications, whereas GU toxicities remained comparable. This clinically relevant observation demonstrates that IMRT and image-guidance should therefore be the preferred treatment option, provided that margin reduction is implemented with caution.

Dose-surface maps identifying local dose-effects for acute gastrointestinal toxicity after radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: We evaluated dose distributions in the anorectum and its relation to acute gastrointestinal toxicities using dose surface maps in an image-guided (IG) IMRT and 3D-conformal radiotherapy (3D-CRT) population. MATERIAL AND METHODS: For patients treated to 78 Gy with IG-IMRT (n=260) or 3D-CRT (n=215), for whom acute toxicity data were available, three types of surface maps were calculated: (1) total anorectum using regular intervals along a central axis with perpendicular slices, (2) the rectum next to the prostate, and (3) the anal canal (horizontal slicing). For each toxicity, an average dose map was calculated for patients with and without the toxicity and subsequently dose difference maps were constructed, 3D-CRT and IG-IMRT separately. P-values were based on permutation tests. RESULTS: Dose distributions in patients with grade ⩾2 acute proctitis were significantly different from dose distributions in patients without toxicity, for IG-IMRT and 3D-CRT. At the cranial and posterior rectal site, in areas receiving moderate dose levels (≈25-50 Gy), dose differences up to 10 Gy were identified for IG-IMRT. For pain, cramps, incontinence, diarrhea and mucus loss significant differences were found as well. CONCLUSIONS: We demonstrated significant relationships between acute rectal toxicity and local dose distributions. This may serve as a basis for subsequent dose-effect modeling in IG-IMRT, and improved dose constraints in current clinical practice.

Acute toxicity after image-guided intensity modulated radiation therapy compared to 3D conformal radiation therapy in prostate cancer patients.

PURPOSE: Image-guided intensity modulated radiation therapy (IG-IMRT) allows significant dose reductions to organs at risk in prostate cancer patients. However, clinical data identifying the benefits of IG-IMRT in daily practice are scarce. The purpose of this study was to compare dose distributions to organs at risk and acute gastrointestinal (GI) and genitourinary (GU) toxicity levels of patients treated to 78 Gy with either IG-IMRT or 3D-CRT. METHODS AND MATERIALS: Patients treated with 3D-CRT (n=215) and IG-IMRT (n=260) receiving 78 Gy in 39 fractions within 2 randomized trials were selected. Dose surface histograms of anorectum, anal canal, and bladder were calculated. Identical toxicity questionnaires were distributed at baseline, prior to fraction 20 and 30 and at 90 days after treatment. Radiation Therapy Oncology Group (RTOG) grade ≥1, ≥2, and ≥3 endpoints were derived directly from questionnaires. Univariate and multivariate binary logistic regression analyses were applied. RESULTS: The median volumes receiving 5 to 75 Gy were significantly lower (all P<.001) with IG-IMRT for anorectum, anal canal, and bladder. The mean dose to the anorectum was 34.4 Gy versus 47.3 Gy (P<.001), 23.6 Gy versus 44.6 Gy for the anal canal (P<.001), and 33.1 Gy versus 43.2 Gy for the bladder (P<.001). Significantly lower grade ≥2 toxicity was observed for proctitis, stool frequency ≥6/day, and urinary frequency ≥12/day. IG-IMRT resulted in significantly lower overall RTOG grade ≥2 GI toxicity (29% vs 49%, respectively, P=.002) and overall GU grade ≥2 toxicity (38% vs 48%, respectively, P=.009). CONCLUSIONS: A clinically meaningful reduction in dose to organs at risk and acute toxicity levels was observed in IG-IMRT patients, as a result of improved technique and tighter margins. Therefore reduced late toxicity levels can be expected as well; additional research is needed to quantify such reductions.

Long-term results of the Dutch randomized prostate cancer trial: impact of dose-escalation on local, biochemical, clinical failure, and survival.

PURPOSE: Nowadays, advanced irradiation techniques make it possible to escalate safely the dose in prostate cancer. We studied the effect of a higher dose on tumor control in a randomized trial with a median follow-up of 110 months. PATIENTS AND METHODS: Patients with T1b-T4N0 prostate cancer (n=664) were randomized between 78 Gy and 68 Gy. Primary endpoint was biochemical and/or clinical failure (BCF) according to the American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines (3 consecutive rises), and to Phoenix (nadir plus 2 µg/L). Secondary endpoints were clinical failure (CF), local failure (LF), prostate cancer death (PCD), and overall survival (OS). Explorative subgroup analyses were performed. RESULTS: BCF rate (HR=0.8; 20% less events) and LF rate (HR=0.5; 50% less events) were significantly lower in the 78 Gy arm (p<0.05). CF, PCD and OS were similar in both arms. A significant heterogeneity of treatment effect was found for PSA cutoffs between 7 and 10 µg/L. CONCLUSION: We observed significantly less BCF and LF in the high-dose arm. This suggests improvement of the therapeutic ratio. However, we observed similar rates of CF and PCD at the current update. More follow-up is needed to investigate which patients benefit in terms of prolonged OS.

Alpha/beta ratio for normal lung tissue as estimated from lung cancer patients treated with stereotactic body and conventionally fractionated radiation therapy.

PURPOSE: To estimate the α/ß ratio for which the dose-dependent lung perfusion reductions for stereotactic body radiation therapy (SBRT) and conventionally fractionated radiation therapy (CFRT) are biologically equivalent. METHODS AND MATERIALS: The relations between local dose and perfusion reduction 4 months after treatment in lung cancer patients treated with SBRT and CFRT were scaled according to the linear-quadratic model using α/ß ratios from 0 Gy to ∞ Gy. To test for which α/ß ratio both treatments have equal biological effect, a 5-parameter logistic model was optimized for both dose-effect relationships simultaneously. Beside the α/ß ratio, the other 4 parameters were d50, the steepness parameter k, and 2 parameters (MSBRT and MCFRT) representing the maximal perfusion reduction at high doses for SBRT and CFRT, respectively. RESULTS: The optimal fitted model resulted in an α/ß ratio of 1.3 Gy (0.5-2.1 Gy), MSBRT=42.6% (40.4%-44.9%), MCFRT=66.9% (61.6%-72.1%), d50=35.4 Gy (31.5-9.2 Gy), and k=2.0 (1.7-2.3). CONCLUSIONS: An equal reduction of lung perfusion in lung cancer was observed in SBRT and CFRT if local doses were converted by the linear-quadratic model with an α/ß ratio equal to 1.3 Gy (0.5-2.1 Gy).

Radiotherapy with rectangular fields is associated with fewer clinical failures than conformal fields in the high-risk prostate cancer subgroup: results from a randomized trial.

OBJECTIVE: High-risk prostate cancer patients are at risk for subclinical disease and micro-metastasis at the time of treatment. Nowadays, tight margins reduce dose to periprostatic areas compared to earlier techniques. We investigated whether rectangular fields were associated with fewer failures compared to conformal fields (with lower extraprostatic dose). METHODS: We selected 164 high-risk patients from the trial population of 266 T1-T4N0M0 patients, randomized between rectangular (n=79) and conformal fields (n=85). Prescribed dose was 66 Gy to the prostate and seminal vesicles plus 15 mm margin. We compared clinical failure rates (in- and excluding local failures), between both arms. Dose differences around the prostate were calculated based on an inter-patient mapping method. RESULTS: Median follow-up was 34 months. There were 9 clinical failures in the rectangular arm versus 24 in the conformal arm (p=0.012). Number of failures outside the prostate was 7 and 19, respectively (p=0.025). We observed average dose differences of 5-35 Gy between the arms in the regions around the prostate. CONCLUSIONS: We found a significantly lower risk of early tumor progression for patients treated with rectangular fields. Treatment failure can probably in part be prevented by irradiation of areas suspected of subclinical disease in high-risk prostate cancer.

Local dose-effect relations for lung perfusion post stereotactic body radiotherapy.

PURPOSE: To model the local dose-effect relation for lung perfusion reduction in lung cancer patients treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Forty-two patients having upper-lobe peripheral tumours <5 cm treated with SBRT (3×18 Gy) underwent single-photon emission computed-tomography (SPECT) scans to measure the lung perfusion 2 weeks pre-SBRT, 4-months post-SBRT, and for 8 patients 15-months post-SBRT. The relation between the calculated relative local perfusion reduction and the normalised total dose (α/ß=3 Gy) at 4-months post-SBRT was modeled by 3-parameter logistic model and 2-parameter linear-maximum model. RESULTS: The relation between local dose and perfusion reduction at 4-months post-SBRT showed a maximum effect of 42.6% at doses >100 Gy and was best described by the logistic model with parameters (95% CI): M=42.6% (40.7-44.6), D50=28.7 Gy (26.3-31.1) and k=2.2 (1.8-2.5). A significant increase of this maximum effect to 65.2% was found at 15-months post-SBRT. CONCLUSIONS: The relation between local dose and perfusion reduction in patients treated with SBRT can be modeled by a 3-parameter logistic model. This demonstrated relationship 4-months post-SBRT approaches a plateau for doses >100 Gy, where 90% of the maximum lung-perfusion reduction is observed at NTD=78 Gy. A further perfusion reduction compared to 4-months post-SBRT was observed fifteen months post-SBRT.

Using generalized equivalent uniform dose atlases to combine and analyze prospective dosimetric and radiation pneumonitis data from 2 non-small cell lung cancer dose escalation protocols.

PURPOSE: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination. METHODS AND MATERIALS: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate≥20% were plotted. RESULTS: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD. CONCLUSIONS: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power.

Relating acute esophagitis to radiotherapy dose using FDG-PET in concurrent chemo-radiotherapy for locally advanced non-small cell lung cancer.

PURPOSE: To correlate radiotherapy (RT) dose to acute esophagitis (AE) by means of FDG-PET scans acquired after concurrent chemo-radiotherapy (cCRT) for locally advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients treated with 24 × 2.75 Gy were selected on presence of a post-RT PET (PET(post)) scan acquired within 3 months after cCRT. The value of PET(post) in relation to AE was evaluated by comparing the mean esophageal SUV of the highest 50% (mathematical left angle bracket SUV(50%) mathematical right angle bracket) between gr < 2 and gr ≥ 2AE. The local dose on the esophagus wall was correlated to the SUV and modeled using a power-law fit. The Lyman-Kutcher-Burman (LKB) model was used to predict gr ≥ 2AE. The local dose-response relation was used in the LKB model to calculate the EUD. Resulting prediction accuracy was compared to D(mean), V(35), V(55) and V(60). RESULTS: Eighty-two patients were included (gr < 2 = 25, gr ≥ 2=57). The mathematical left angle bracket SUV(50%) mathematical right angle bracket ≥ was significantly higher for gr ≥ 2AE (2.2 vs. 2.6, p < 0.01). The LKB parameters (95% CI) were n = 0.130 (0.120-0.141), m = 0.25 (0.13-0.85) and TD(50) = 50.4 Gy (37.5-55.4), which resulted in improved predictability of AE compared to other predictors. CONCLUSION: Esophageal uptake of FDG post-cCRT reflects AE severity. Predictability of grade ≥ 2AE was improved by using the local dose-SUV response model, with narrow confidence intervals for the optimized LKB parameters.

The benefits of including clinical factors in rectal normal tissue complication probability modeling after radiotherapy for prostate cancer.

PURPOSE: To study the impact of clinical predisposing factors on rectal normal tissue complication probability modeling using the updated results of the Dutch prostate dose-escalation trial. METHODS AND MATERIALS: Toxicity data of 512 patients (conformally treated to 68 Gy [n = 284] and 78 Gy [n = 228]) with complete follow-up at 3 years after radiotherapy were studied. Scored end points were rectal bleeding, high stool frequency, and fecal incontinence. Two traditional dose-based models (Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) and a logistic model were fitted using a maximum likelihood approach. Furthermore, these model fits were improved by including the most significant clinical factors. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminating ability of all fits. RESULTS: Including clinical factors significantly increased the predictive power of the models for all end points. In the optimal LKB, RS, and logistic models for rectal bleeding and fecal incontinence, the first significant (p = 0.011-0.013) clinical factor was "previous abdominal surgery." As second significant (p = 0.012-0.016) factor, "cardiac history" was included in all three rectal bleeding fits, whereas including "diabetes" was significant (p = 0.039-0.048) in fecal incontinence modeling but only in the LKB and logistic models. High stool frequency fits only benefitted significantly (p = 0.003-0.006) from the inclusion of the baseline toxicity score. For all models rectal bleeding fits had the highest AUC (0.77) where it was 0.63 and 0.68 for high stool frequency and fecal incontinence, respectively. LKB and logistic model fits resulted in similar values for the volume parameter. The steepness parameter was somewhat higher in the logistic model, also resulting in a slightly lower D(50). Anal wall DVHs were used for fecal incontinence, whereas anorectal wall dose best described the other two endpoints. CONCLUSIONS: Comparable prediction models were obtained with LKB, RS, and logistic NTCP models. Including clinical factors improved the predictive power of all models significantly.

Residual seminal vesicle displacement in marker-based image-guided radiotherapy for prostate cancer and the impact on margin design.

PURPOSE: The objectives of this study were to quantify residual interfraction displacement of seminal vesicles (SV) and investigate the efficacy of rotation correction on SV displacement in marker-based prostate image-guided radiotherapy (IGRT). We also determined the effect of marker registration on the measured SV displacement and its impact on margin design. METHODS AND MATERIALS: SV displacement was determined relative to marker registration by using 296 cone beam computed tomography scans of 13 prostate cancer patients with implanted markers. SV were individually registered in the transverse plane, based on gray-value information. The target registration error (TRE) for the SV due to marker registration inaccuracies was estimated. Correlations between prostate gland rotations and SV displacement and between individual SV displacements were determined. RESULTS: The SV registration success rate was 99%. Displacement amounts of both SVs were comparable. Systematic and random residual SV displacements were 1.6 mm and 2.0 mm in the left-right direction, respectively, and 2.8 mm and 3.1 mm in the anteroposterior (AP) direction, respectively. Rotation correction did not reduce residual SV displacement. Prostate gland rotation around the left-right axis correlated with SV AP displacement (R(2) = 42%); a correlation existed between both SVs for AP displacement (R(2) = 62%); considerable correlation existed between random errors of SV displacement and TRE (R(2) = 34%). CONCLUSIONS: Considerable residual SV displacement exists in marker-based IGRT. Rotation correction barely reduced SV displacement, rather, a larger SV displacement was shown relative to the prostate gland that was not captured by the marker position. Marker registration error partly explains SV displacement when correcting for rotations. Correcting for rotations, therefore, is not advisable when SV are part of the target volume. Margin design for SVs should take these uncertainties into account.

Subgroup analysis of patients with localized prostate cancer treated within the Dutch-randomized dose escalation trial.

PURPOSE: To investigate the effect of dose escalation within prognostic risk groups in prostate cancer. PATIENTS AND METHODS: Between 1997 and 2003, 664 patients with localized prostate cancer were randomly assigned to receive 68- or 78-Gy of radiotherapy. Two prognostic models were examined: a risk group model (low-, intermediate-, and high-risk) and PSA-level groupings. High-risk patients with hormonal therapy (HT) were analyzed separately. Outcome variable was freedom from failure (FFF) (clinical failure or PSA nadir+2 microg/L). RESULTS: In relation to the advantage of high-dose radiotherapy, intermediate-risk patients benefited most from dose escalation. However no significant heterogeneity could be demonstrated between the risk groups. For two types of PSA-level groupings: PSA<10 and > or = 10 microg/L, and <8, 8-18 and >8 microg/L, the test for heterogeneity was significant (p=0.03 and 0.05, respectively). Patients with PSA 8-18 microg/L (n=297, HR=0.59) derived the greatest benefit from dose escalation. No heterogeneity could be demonstrated for high-risk patients with and without HT. CONCLUSION: Intermediate-risk group derived the greatest benefit for dose escalation. However, from this trial no indication was found to exclude low-risk or high-risk patients from high-dose radiotherapy. Patients could be selected for high-dose radiotherapy based on PSA-level groupings: for patients with a PSA<8 microg/L high-dose radiotherapy is probably not indicated, but should be confirmed in other randomized studies.

Radiation pneumonitis after hypofractionated radiotherapy: evaluation of the LQ(L) model and different dose parameters.

PURPOSE: To evaluate the linear quadratic (LQ) model for hypofractionated radiotherapy within the context of predicting radiation pneumonitis (RP) and to investigate the effect if a linear (L) model in the high region (LQL model) is used. METHODS AND MATERIALS: The radiation doses used for 128 patients treated with hypofractionated radiotherapy were converted to the equivalent doses given in fractions of 2 Gy for a range of alpha/beta ratios (1 Gy to infinity) according to the LQ(L) model. For the LQL model, different cut-off values between the LQ model and the linear component were used. The Lyman model parameters were fitted to the events of RP grade 2 or higher to derive the normal tissue complication probability (NTCP). The lung dose was calculated as the mean lung dose and the percentage of lung volume (V) receiving doses higher than a threshold dose of xGy (V(x)). RESULTS: The best NTCP fit was found if the mean lung dose, or V(x), was calculated with an alpha/beta ratio of 3 Gy. The NTCP fit of other alpha/beta ratios and the LQL model were worse but within the 95% confidence interval of the NTCP fit of the LQ model with an alpha/beta ratio of 3 Gy. The V(50) NTCP fit was better than the NTCP fit of lower threshold doses. CONCLUSIONS: For high fraction doses, the LQ model with an alpha/beta ratio of 3 Gy was the best method for converting the physical lung dose to predict RP.

Radiation dose-volume effects in the lung.

The three-dimensional dose, volume, and outcome data for lung are reviewed in detail. The rate of symptomatic pneumonitis is related to many dosimetric parameters, and there are no evident threshold "tolerance dose-volume" levels. There are strong volume and fractionation effects.

Urinary obstruction in prostate cancer patients from the Dutch trial (68 Gy vs. 78 Gy): relationships with local dose, acute effects, and baseline characteristics.

PURPOSE: To investigate the relationship between late urinary obstruction and the details of the dose distribution of irradiated prostate cancer patients, taking into account their baseline symptoms and acute complaints. PATIENTS AND METHODS: We selected patients from the Dutch multicenter trial randomized between 68 Gy and 78 Gy, for whom toxicity data and dose data were available (n = 557). The absolute dose surface parameters of the delineated bladder were calculated. Next, we constructed three-dimensional dose maps of the area around the prostate, providing an approximate identification of the corresponding anatomic locations. The dose difference maps were constructed by subtracting the mean dose maps of the patients with and without late urinary obstruction. Selected local dose points were analyzed using Cox regression analysis. RESULTS: Urinary obstruction was scored for 40 patients, including 19 of 296 patients who received 68-72 Gy and 21 of 261 patients who received 76-78 Gy. A total of 19 events occurred within 2 years after irradiation and 21 events after 2 years. The bladder surface receiving >or=80 Gy predicted (p <.01) the occurrence of obstruction within 2 years. The dose difference map indicated highly significant differences in the bladder neck situated in the trigonal region (p < .001) that were especially predictive of obstruction after 2 years and of the diagnosis of bladder neck obstruction. Baseline complaints and transurethral resection of the prostate and acute complaints were mainly predictive for obstruction within 2 years. CONCLUSION: Relatively early events of urinary obstruction were associated with urinary problems existing before RT, acute toxicity, previous transurethral resection of the prostate, and hotspots in the bladder. Events after 2 years were associated with the local dose in the trigonal area.

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.

Relating dose outside the prostate with freedom from failure in the Dutch trial 68 Gy vs. 78 Gy.

PURPOSE: For prostate cancer patients at risk for subclinical spread of the disease, we investigated whether incidental dose outside the target was associated with tumor control. METHODS AND MATERIALS: We selected 352 intermediate-risk (mainly T2b-T3a) and high-risk (mainly T3b) patients treated in a randomized trial. Target volume was prostate (68-78 Gy) and seminal vesicles (50-78 Gy). Failure (clinical or biochemical) was evaluated at 4 years. To compare three-dimensional dose distributions, an automated mapping procedure was introduced. Between patients, these maps provide an approximate identification of corresponding anatomical locations. Maps of the dose difference between patients with and without failure were constructed. Univariate and multivariate analyses were performed including the dose in selected points. RESULTS: Dose differences were mainly found in the obturatorial region for the high-risk patients, and in the presacral region for the intermediate risk group (>7 Gy, p < 0.01). Univariate hazard ratios per 10 Gy for selected dose points were 0.83 (p = 0.01, obturatorial) and 0.72 (p = 0.002, presacral). These hazard ratios were stable under multivariate analysis correcting for established prognostic factors, hospital, and dose to the prostate. CONCLUSIONS: Patients without failure have received on average a higher dose to regions where regional cancer spread could be expected.