Estimation of the Incidence of Late Bladder and Rectum Complications After High-Dose (70–78 Gy) Conformal Radiotherapy for Prostate Cancer,Using Dose–Volume Histograms

Purpose: To investigate whether Dose–Volume Histogram (DVH) parameters can be used to identify risk groups for developing late gastrointestinal (GI) and genitourinary (GU) complications after conformal radiotherapy for prostate cancer.Methods and Materials: DVH parameters were analyzed for 130 patients with localized prostate cancer, treated with conformal radiotherapy in a dose-escalating protocol (70–78 Gy, 2 Gy per fraction). The incidence of late (>6 months) GI and GU complications was classified using the RTOG/EORTC and the SOMA/LENT scoring system. In addition, GI complications were divided in nonsevere and severe (requiring one or more laser treatments or blood transfusions) rectal bleeding. The median follow-up time was 24 months. We investigated whether rectal and bladder wall volumes, irradiated to various dose levels, correlated with the observed actuarial incidences of GI and GU complications, using volume as a continuous variable. Subsequently, for each dose level in the DVH, the rectal wall volumes were dichotomized using different volumes as cutoff levels. The impact of the total radiation dose, and the maximum radiation dose in the rectal and bladder wall was analyzed as well.Results: The actuarial incidence at 2 years for GI complications ≥Grade II was 14% (RTOG/EORTC) or 20% (SOMA/LENT); for GU complications ≥Grade III 8% (RTOG/EORTC) or 21% (SOMA/LENT). Neither for GI complications ≥Grade II (RTOG/EORTC or SOMA/LENT), nor for GU complications ≥Grade III (RTOG/EORTC or SOMA/LENT), was a significant correlation found between any of the DVH parameters and the actuarial incidence of complications. For severe rectal bleeding (actuarial incidence at 2 years 3%), four consecutive volume cutoff levels were found, which significantly discriminated between high and low risk. A trend was observed that a total radiation dose ≥ 74 Gy (or a maximum radiation dose in the rectal wall >75 Gy) resulted in a higher incidence of severe rectal bleeding (p = 0.07).Conclusions: These data show that dose escalation up to 78 Gy, using a conformal technique, is feasible. However, these data have also demonstrated that the incidence of severe late rectal bleeding is increased above certain dose–volume thresholds.     

Grading-system-dependent volume effects for late radiation-induced rectal toxicity after curative radiotherapy for prostate cancer

PURPOSE: To assess the association between the dose distributions in the rectum and late Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer (RTOG/EORTC), Late Effects of Normal Tissue SOMA, and Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 graded rectal toxicity among patients with prostate cancer treated with RT. METHODS AND MATERIALS: Included in the study were 124 patients who received three-dimensional conformal RT for prostate cancer to a total dose of 70 Gy in 2-Gy fractions. All patients completed questionnaires regarding rectum complaints before RT and during long-term follow-up. Late rectum Grade 2 or worse toxicity, according to RTOG/EORTC, LENT SOMA, and CTCAE v3.0 criteria, was analyzed in relation to rectal dose and volume parameters. RESULTS: Dose-volume thresholds (V40>or=65%, V50>or=55%, V65>or=45%, V70>or=20%, and a rectum volumeor=70 Gy (V70) was most predictive for late Grade 2 or worse rectal toxicity with each of the grading systems. The associations were strongest, however, with use of the LENT SOMA system. CONCLUSIONS: Volume effects for late radiation-induced rectal toxicity are present, but their clinical significance depends on the grading system used. This should be taken into account in the interpretation of studies reporting on radiation-induced rectal toxicity.     

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.

: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74–78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24–102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity.

: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm³ of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons).

: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.     

Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response

PURPOSE: The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. METHODS AND MATERIALS: Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. RESULTS: A dose response for >/= Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1) smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to these five factors, acute rectal toxicity was also significantly correlated (p = 0.05) with late rectal bleeding when patients from both dose groups were combined in multivariate analysis. CONCLUSION: A multivariate logistic regression model is presented which describes the probability of developing late rectal bleeding after conformal irradiation of prostate cancer. Late rectal bleeding correlated with factors which may indicate that a greater fractional volume of rectal wall was exposed to high dose, such as smaller rectal wall volume, inclusion of the rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).     

Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT

PURPOSE: To predict acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) and Subjective Objective Signs Management and Analysis/Late Effect of Normal Tissue (SOMA/LENT) toxicities of the lower gastrointestinal (LGI) syndrome in patients with prostate cancer undergoing three-dimensional conformal radiotherapy using a tool (nomogram) that takes into account clinical and dosimetric variables that proved to be significant in the Italian Association for Radiation Oncology (AIRO) Group on Prostate Cancer (AIROPROS) 0102 trial. METHODS AND MATERIALS: Acute rectal toxicity was scored in 1,132 patients by using both the RTOG/EORTC scoring system and a 10-item self-assessed questionnaire. Correlation between clinical variables/dose-volume histogram constraints and rectal toxicity was investigated by means of multivariate logistic analyses. Multivariate logistic analyses results were used to create nomograms predicting the symptoms of acute LGI syndrome. RESULTS: Mean rectal dose was a strong predictor of Grade 2-3 RTOG/EORTC acute LGI toxicity (p = 0.0004; odds ratio (OR) = 1.035), together with hemorrhoids (p = 0.02; OR = 1.51), use of anticoagulants/antiaggregants (p = 0.02; OR = 0.63), and androgen deprivation (AD) (p = 0.04; OR = 0.65). Diabetes (p = 0.34; OR = 1.28) and pelvic node irradiation (p = 0.11; OR = 1.56) were significant variables to adjust toxicity prediction. Bleeding was related to hemorrhoids (p = 0.02; OR = 173), AD (p = 0.17; OR = 0.67), and mean rectal dose (p = 0.009; OR = 1.024). Stool frequency was related to seminal vesicle irradiation (p = 0.07; OR = 6.46), AD administered for more than 3 months (p = 0.002; OR = 0.32), and the percent volume of rectum receiving more than 60 Gy (V60Gy) V60 (p = 0.02; OR = 1.02). Severe fecal incontinence depended on seminal vesicle irradiation (p = 0.14; OR = 4.5) and V70 (p = 0.033; OR = 1.029). CONCLUSIONS: To the best of our knowledge, this work presents the first set of nomograms available in the literature specific to symptoms of LGI syndrome and provides clinicians with a tailored probability of the specific outcome. Validation of the tool is in progress.     

Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy

PURPOSE: To compare acute and late gastrointestinal (GI) and genitourinary (GU) side effects in prostate cancer patients randomized to receive 68 Gy or 78 Gy. METHODS AND MATERIALS: Between June 1997 and February 2003, 669 prostate cancer patients were randomized between radiotherapy with a dose of 68 Gy and 78 Gy, in 2 Gy per fraction and using three-dimensional conformal radiotherapy. All T stages with prostate-specific antigen (PSA) <60 ng/mL were included, except any T1a and well-differentiated T1b-c tumors with PSA < or =4 ng/mL. Stratification was done for four dose-volume groups (according to the risk of seminal vesicles [SV] involvement), age, hormonal treatment (HT), and hospital. The clinical target volume (CTV) consisted of the prostate with or without the SV, depending on the estimated risk of SV invasion. The CTV-planning target volume (PTV) margin was 1 cm for the first 68 Gy and was reduced to 0.5 cm (0 cm toward the rectum) for the last 10 Gy in the 78 Gy arm. Four Dutch hospitals participated in this Phase III trial. Evaluation of acute and late toxicity was based on 658 and 643 patients, respectively. For acute toxicity (<120 days), the Radiation Therapy Oncology Group (RTOG) scoring system was used and the maximum score was reported. Late toxicity (>120 days) was scored according to the slightly adapted RTOG/European Organization for Research and Treatment of Cancer (EORTC) criteria. RESULTS: The median follow-up time was 31 months. For acute toxicity no significant differences were seen between the two randomization arms. GI toxicity Grade 2 and 3 was reported as the maximum acute toxicity in 44% and 5% of the patients, respectively. For acute GU toxicity, these figures were 41% and 13%. No significant differences between both randomization arms were seen for late GI and GU toxicity, except for rectal bleeding requiring laser treatment or transfusion (p = 0.007) and nocturia (p = 0.05). The 3-year cumulative risk of late RTOG/EORTC GI toxicity grade > or =2 was 23.2% for 68 Gy, and 26.5% for 78 Gy (p = 0.3). The 3-year risks of late RTOG/EORTC GU toxicity grade > or =2 were 28.5% and 30.2% for 68 Gy and 78 Gy, respectively (p = 0.3). Factors related to acute GI toxicity were HT (p < 0.001), a higher dose-volume group (p = 0.01), and pretreatment GI symptoms (p = 0.04). For acute GU toxicity, prognostic factors were: pretreatment GU symptoms (p < 0.001), HT (p = 0.003), and prior transurethral resection of the prostate (TURP) (p = 0.02). A history of abdominal surgery (p < 0.001) and pretreatment GI symptoms (p = 0.001) were associated with a higher incidence of late GI grade > or =2 toxicity, whereas HT (p < 0.001), pretreatment GU symptoms (p < 0.001), and prior TURP (p = 0.006) were prognostic factors for late GU grade > or =2. CONCLUSIONS: Raising the dose to the prostate from 68 Gy to 78 Gy resulted in higher incidences of acute and late GI and GU toxicity, but these differences were not significant, except for late rectal bleeding requiring treatment and late nocturia. Other factors than the studied dose levels appeared to be important in predicting toxicity after radiotherapy, especially previous surgical interventions (abdominal surgery or TURP), hormonal therapy, and the presence of pretreatment symptoms.     

Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study

PURPOSE: To determine dosimetric factors for lung, lung subregions, and heart that correlate with radiation pneumonitis (Radiation Therapy Oncology Group Grade 3 or more) in the 78 evaluable patients from a Phase I dose escalation study (1991-2003) of three-dimensional conformal radiation therapy (3D-CRT) of non-small-cell lung cancer. METHODS AND MATERIALS: There were 10 > or = Grade 3 pneumonitis cases within 6 months after treatment. Dose-volume factors analyzed for univariate correlation with > or = Grade 3 pneumonitis were mean dose (MD), effective uniform dose (d(eff)), normal tissue complication probability (NTCP), parallel model f(dam) and V(D) for 5 < or = D < or = 60 Gy for whole, ipsilateral, contralateral, upper and lower halves of the lungs and heart D05, and mean and maximum doses. RESULTS: The most significant variables (0.005 < p < 0.006) were ipsilateral lung V(D) for D < 20 Gy. Also significant (p < 0.05) for ipsilateral lung were V(D) for D < 50 Gy, MD, f(dam) and d(eff); for total lung V(D) (D < 50 Gy), MD, f(dam), d(eff) and NTCP; for lower lung V(D) (D < 60 Gy), MD, f(dam) and d(eff). All variables for upper and contralateral lung were insignificant, as were heart variables. CONCLUSIONS: Previously reported correlations between severe pneumonitis and whole lung V13 and with other dose-volume factors of total lung and lower lung are confirmed. The most significant correlations were for (V05-V13) in ipsilateral lung.     

Acute toxicity in definitive versus postprostatectomy image-guided radiotherapy for prostate cancer

PURPOSE: To assess the incidence of acute gastrointestinal (GI) and genitourinary (GU) injury and the dose-volume response in patients with clinically localized prostate cancer treated with image-guided radiotherapy using helical tomotherapy. METHODS AND MATERIALS: Between November 2004 and March 2007, 146 consecutive patients with localized prostate cancer were treated with helical tomotherapy at the City of Hope Medical Center. Of the 146 patients, 70 had undergone prostatectomy. Acute GI and GU toxicities were evaluated using the Radiation Therapy Oncology Group/European Organization for Research and Cancer of Medical scoring system. Events were scored for patients developing Grade 2 or greater morbidity within 90 days after the end of radiotherapy (RT). The dosimetric parameters included the minimal dose received by the highest 10%, 20%, 50%, 80%, and 90% of the target volume, the mean rectal dose, minimal rectal dose, maximal rectal dose, and the volume receiving > or =45, > or =65, and > or =70 Gy. These variables, plus the status of radical prostatectomy, hormonal therapy, RT techniques, and medical conditions, were included in a multivariate logistic regression analysis. A goodness-of-fit evaluation was done using the Hosmer-Lemeshow statistic. RESULTS: A dose-response function for acute GI toxicity was elicited. The acute GI Grade 2 or greater toxicity was lower in the definitive RT group than in the postoperative RT group (25% vs. 41%, p <0.05). Acute GU Grade 2 or greater toxicity was comparable between the two groups. No grade 3 or greater complications were observed. No dosimetric variable was significant for GU toxicity. For acute GI toxicity, the significant dosimetric parameters were the minimal dose received by 10%, 20%, and 50% of the target volume and the mean rectal dose; the most predictive parameter was the minimal dose received by 10% of the target volume. The dose-modifying factor was 1.2 for radical prostatectomy. CONCLUSION: The results of our study have shown that acute rectal symptoms are dose-volume related. Postprostatectomy RT resulted in a greater incidence of acute GI toxicity than did definitive RT. For postoperative RT, it would be prudent to use different dose-volume limits.     

Significant reduction of acute toxicity following pelvic irradiation with helical tomotherapy in patients with localized prostate cancer.

PURPOSE: To assess and quantify the possible benefit deriving from IMRT with Helical Tomotherapy (HTT) delivery to the pelvic nodal area in patients with prostate cancer in terms of reduction of acute and late toxicities. METHODS AND MATERIALS: Thirty-five patients candidate to radical or postoperative RT on whole pelvis (WPRT) were treated with HTT, while receiving a concomitant boost to the prostate or the prostatic bed (median 74.2 and 72 Gy, respectively) within a moderately hypofractionated (28-33 fractions; median HTT duration 44 days) regimen. Median and mean doses to whole pelvis were 52 and 54 Gy, respectively. One of the major goals of planning optimisation was to minimize the dose received by the intestinal cavity (IC) outside the nodal PTV. RESULTS: HTT resulted to be very efficient in sparing the IC even at dose levels below 30-35 Gy and guaranteed a significant sparing of bladder and rectum even at intermediate-low doses (V20-V40). No acute Grade 3 RTOG toxicity was recorded. Eighteen G1 and two G2 GU acute toxicities, 13 G1 upper GI acute toxicities, 8 G1 and 1 G2 acute proctitis were observed; no patient experienced G2 upper GI toxicity. After a median FU of 11.5 months (>10 in 18 patients) one case of late G3 GU toxicity was reported in one post-prostatectomy treated patient; no G2 late rectal bleeding or other GI toxicity was recorded. CONCLUSIONS: WPRT with HTT resulted in a very low incidence of acute Grade 2 and in the disappearance of acute Grade 3 toxicities.     

Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose-volume analysis

PURPOSE: To report acute toxicity and to evaluate the relationship between dose-volume effects and acute toxicity in patients with localized prostate cancer, treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Acute toxicity (both lower gastrointestinal [GI] and genito-urinary [GU]) in 100 patients treated with IMRT definitively to a prescribed dose of 70 Gy were assessed using RTOG scoring criteria. A rectal balloon was used for prostate immobilization. Mean doses to seminal vesicles, prostate, bladder, and rectum were recorded. Average irradiated bladder and rectal volumes above 65, 70, and 75 Gy were assessed. A relationship between dose volume and clinical toxicity was evaluated. All patients completed the full duration of acute toxicity assessment. RESULTS: Mean doses to the prostate and seminal vesicles were 75.8 and 73.9 Gy. This represents a moderate dose escalation. Acute GI toxicity profile was very favorable. Eleven percent and 6% of the patients had grade 1 and 2 GI toxicity, respectively, while 83% had no GI complaint. For GU complaints, 38% and 35% had grade 1 and 2 toxicity, respectively, while 27% had no complaints. There was no grade 3 or higher acute GI or GU toxicity. Mean doses to the bladder were 22.8, 23.4, and 26.1 Gy for grade 0, 1, and 2 GU toxicity, respectively (p = 0.132). There is no statistically significant relationship between acute GU toxicity and the bladder volume receiving > 65 Gy, > 70 Gy, or > 75 Gy. In evaluating acute GI toxicity, there are very few grade 1 and 2 events. No relationship was found between acute rectal toxicity and mean rectal dose or irradiated rectal volumes receiving more than 65, 70, and 75 Gy. CONCLUSION: The findings are important with regard to the safety of IMRT, especially in reducing acute GI toxicity. Dose escalation with IMRT using a prostate immobilization technique is feasible. The findings are also important because they contribute to the clinical and dosimetric correlation aspect in the use of IMRT to treat prostate cancer. A larger cohort may be needed to determine if there is a relationship between acute GU toxicity and (a) mean bladder dose and (b) irradiated bladder volume receiving > 65 Gy, > 70 Gy, or > 75 Gy. A larger cohort of patients treated to a higher dose may be needed to show a relationship between dose volume and acute GI toxicity.     

Three-dimensional conformal radiation therapy for non-small-cell lung cancer: a phase I/II dose escalation clinical trial

PURPOSE: A prospective Phase I/II dose escalation study was conducted to determine the maximum tolerated dose (MTD) in three-dimensional conformal radiation therapy (3D-CRT) for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: MTD would be reached via a dose escalation study. After 42 Gy/21 fractions, 4.2 weeks by conventional fractionated irradiation through anteroposterior/posteroanterior fields, the 3D-CRT technique was used as boost. The planned total dose escalation depended on lung volume irradiated. According to the percentage of lung volume receiving >20 Gy, the patients were divided into three subgroups (i.e., <25%, 25%-37%, and >37%). The scheduled dose escalation began with 69 Gy and continued to 78 Gy. The boost doses were delivered at 3 Gy per fraction, once per day, five fractions per week. Each dose level includes 5 patients. Besides radiotherapy, all patients received neoadjuvant and adjuvant chemotherapy with MVP regimen (Mitomycin, Vindesine, cis-platium). The criterion for stopping further dose escalation was > or =20% of patients with > or =RTOG Grade 3 radiation pneumonitis. RESULTS: Between June 1999 and February 2001, 50 patients had been enrolled in this study, including 4 with Stage II disease, 31 with Stage IIIa disease, and 15 with Stage IIIb disease. The dose escalation plan has been completed. All subgroups reached the highest predetermined dose levels (i.e., 78 Gy for the <25% subgroup, 78 Gy for the 25-37% subgroup, and 75 Gy for the >37% subgroup). Although none of the subgroups developed more than 20% of >/=Grade 3 acute pneumonitis, dose escalation was terminated because long-term follow-up was needed to observe late complications. Median follow-up time (MFT) for the entire group was 18 months (6-37 months). The most common acute complication was esophagitis in 56% of patients with RTOG Grade 1-2, and in 4% with Grade 3. Acute radiation pneumonitis developed in 36% of patients with RTOG Grade 1-2. Only 1 patient had Grade 3 pneumonitis, which was in the 25-37% subgroup at 75 Gy. The hematopoietic toxicity appeared in 58% of patients with Grade 1-2, and 8% with Grade 3. As to late complications, only 30% of patients developed pulmonary fibrosis of RTOG Grade 1-2. The median survival time for the entire group was 18 months. Two-year overall survival, locoregional progression-free rate, and distant metastasis rate were 44%, 40%, and 41%, respectively. CONCLUSIONS: Although MFT was 18 months, it had not yet been declared because a longer follow-up was needed to observe the late complications. The 2-year overall survival of 44% was very encouraging and implied that 3D-CRT combined with chemotherapy would improve the outcome for locally advanced NSCLC.     

Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy)

PURPOSE: A prospective Phase I dose escalation study was conducted to determine the maximally tolerated radiation dose in men treated with three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. This is a preliminary report of toxicity at Level III (79.2 Gy) on 3D Oncology Group/Radiation Therapy Oncology Group (RTOG) 9406. METHODS AND MATERIALS: Between November 26, 1996 and October 1, 1998, 173 patients with clinically organ-confined prostate cancer (T1 and T2) were accrued to a Level III dose of 79.2 Gy. One hundred sixty-nine patients were available for analysis of toxicity. Patients were registered to two groups according to the risk of seminal vesicle invasion (SVI) on the basis of presenting PSA and Gleason score. Group 1 patients had a calculated risk of SVI <15%, and Group 2 patients had a risk of SVI > or = 15%. For Group 1 patients, the planning target volume (PTV) margins were 5-10 mm around the prostate only. For Group 2 patients, the same margins were applied to the prostate and seminal vesicles (PTV(1)) for the initial 55.8 Gy; then treatment volume was reduced to the prostate only (PTV(2)). To reduce the rectal dose on dose Level III, the minimum PTV dose was limited to 73.8 Gy, whereas the minimum gross target volume dose was 79.2 Gy, both in 44 fractions. The incidence of > or = 3 Grade late effects was compared to that in a similar group of patients treated on RTOG 7506 and 7706 studies. RESULTS: Acute tolerance to 79.2 Gy was excellent with no patients experiencing > or = Grade 3 acute toxicity. The acute toxicity rate was comparable to that reported for previous lower dose levels. With the median follow-up of 3.3 years (range: 0.4-4.4 years), a total of 4 patients (2.4%) experienced Grade 3 late toxicity, three cases of which were related to the bladder, and one related to the rectum. There were no Grade 4 or 5 late complications noted during the period of observation. These results are also comparable to those reported at dose Levels I and II. The expected incidence of > or = 3 Grade 3 late toxicity was calculated using historical data from two previous RTOG prostate cancer trials, 7506 and 7706. The calculated risk accounted for the difference in follow-up duration between patients in this study and the historical experience. The observed rate of > or = Grade 3 late effects for Group 1 (two cases) is significantly lower (p = 0.0002) than the 17.6 cases that would have been expected from the historical control. The observed rate for Group 2 (two cases) was also significantly lower (p = 0.0037) than the 12.1 cases expected. CONCLUSION: Based on excellent tolerance of 3D-CRT for stages T1 and T2 prostate cancer, further biological dose escalation has been pursued to Levels IV and V, 74 Gy and 78 Gy, respectively, at 2 Gy per day, in an attempt to reduce the total treatment duration. This trial has closed. A Phase III comparative RTOG trial is being developed to determine whether high-dose 3D-CRT improves efficacy.     

Spinal cord tolerance to high-dose fractionated 3D conformal proton-photon irradiation as evaluated by equivalent uniform dose and dose volume histogram analysis

PURPOSE: To evaluate cervical spinal cord tolerance using equivalent uniform dose (EUD) and dose volume histogram (DVH) analysis after proton-photon radiotherapy. METHODS AND MATERIAL: The 3D dose distributions were analyzed in 85 patients with cervical vertebral tumors. Mean follow-up was 41.3 months. The mean prescribed dose was 76.3 Cobalt Gray Equivalent (CGE = proton dose x RBE 1.1). Dose constraints to the center and the surface of the cervical cord were 55-58 CGE and 67-70 CGE, respectively. Dose parameters, DVH and EUD, were calculated for each patient. The spinal cord toxicity was graded using the European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) late effects scoring system. RESULTS: Thirteen patients experienced Grade 1-2 toxicity. Four patients had Grade 3 toxicity. For the dose range used in this study, none of the dosimetric parameters was found to be associated with the observed distribution of cord toxicities. The only factor significantly associated with cord toxicity was the number of surgeries before irradiation. CONCLUSION: The data and our analysis suggest that the integrity of the normal musculoskeletal supportive tissues and vascular supply may be important confounding factors of toxicity at these dose levels. The results also indicate that the cervical spinal cord dose constraints used in treating these patients are appropriate for conformal proton-photon radiotherapy.     

Rectal sequelae after conformal radiotherapy of prostate cancer: dose-volume histograms as predictive factors.

PURPOSE: To identify clinically relevant parameters predictive of late rectal bleeding derived from cumulative dose-volume histograms (DVHs) of the rectum after conformal radiotherapy of prostate cancer. MATERIALS AND METHODS: One hundred and nine patients treated with 3D conformal radiotherapy between 1/1994 and 1/1996 for localized prostate cancer (clinical stage T1-T3) were available for analysis. All patients received a total dose of 66 Gy/2 Gy per fraction (specified at the International Commission on Radiation Units and Measurements ICRU reference point). DVHs of the contoured rectum were analyzed by defining the absolute (aV) and relative (rV) rectum volume that received more than 30% (V30), 50% (V50), 70% (V70), 80% (V80), 90% (V90) and 100% (V100) of the prescribed dose. Additionally, a new aspect of DVH analysis was investigated by calculation of the area under the DVH-curve between several dose levels (area under the curve (AUC)-DVH). DVH-variables were correlated with radiation side effects evaluated in 3-6 months intervals and graded according to the EORTC/RTOG score. The median follow-up was 30 months (12-60 months). RESULTS: Univariate and multivariate stepwise Cox-Regression analysis including age, PTV, rectum size, rV100, rV90, rV80, rV70, rV50 rV30 and aV30 to aV100 were calculated. Late rectal bleeding (EORTC/RTOG grade 2) was significantly correlated with the percentage of rectum volume receiving > or = 90% of the prescribed dose (rV90) (P = 0.007) and inversely correlated in a significant way with the size of contoured rectum (P = 0.006) in multivariate analysis. In our series, a proportion of the rectum volume > or = 57% were included in the 90%-isodose (rV90 > or = 57%) in one half of the patients, with an actuarial incidence of 31% of late rectal bleeding at 3 years. In the other half of the patients, when rV90 < 57%, the 3-year actuarial incidence was 11% (P < 0.03). CONCLUSION: Our data demonstrate a dose-volume relationship at the reference dose of 60 Gy ( approximately 90% of the prescribed dose) with respect to late rectal toxicity. The rV90 seems to be the most useful and easily obtained parameter when comparing treatment plans to evaluate the risk of rectal morbidity.     

Conformal radiotherapy for prostate cancer--longer duration of acute genitourinary toxicity in patients with prior history of invasive urological procedure

The incidence and predictors of acute toxicity were evaluated in patients treated with three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. Between December 1997 and November 1999, 116 patients with T1-T3 prostatic carcinoma were enrolled in the study. Ninety patients were treated with 70 Gy and 26 patients with T3 tumors received 74 Gy. Of the 116 patients 42 (36.2%) had a prior history of invasive urological procedure (IUP) (transurethral resection of the prostate or transvesical prostatectomy for benign prostatic hyperplasia). Acute gastrointestinal (GI) and genitourinary (GU) symptoms were graded according to the EORTC/RTOG scoring system. Toxicity duration after the completion of 3D-CRT was recorded. The majority of patients experienced only mild or no (Grade 1) acute toxicities. Medications for GI and GU symptoms (Grade 2) were required by 28.4% and 12.9% of patients, respectively. Only one case of Grade 3 GI toxicity (0.9%) was observed. Seven patients (6.1%) experienced severe GU toxicity (Grade 3 or 4). No correlation was found between acute toxicity and age, stage, dose (70 Gy vs. 74 Gy), IUP and pelvic lymphadenectomy. A significant relationship was observed between the duration of acute GU toxicity and prior IUP. Symptoms persisted for more than 4 weeks in 51.9% and 26.0% of patients with and without a prior history of IUP, respectively (p = 0.02). The incidence of acute complications, associated with 3D-CRT for prostate cancer, was acceptable in our cohort of patients. A prior history of IUP resulted in a significantly longer duration of acute GU toxicity.     

Dose-volume relationship for acute side effects during high dose conformal radiotherapy for prostate cancer.

PURPOSE: To determine acute and late complications for bladder and rectum and to determine dose-volume correlations. METHODS AND MATERIALS: Sixty-four patients received definitive treatment for prostate cancer between January 1995 and December 1998 using conformal three-dimensional radiotherapy. Doses ranged from 72 to 80Gy. The acute and late side effects were gathered retrospectively, and graded according to Radiotherapy and Oncology Group criteria (RTOG). The patients were divided into two groups: or=76Gy (Group B) and had a mean follow-up of 32 and 22 months, respectively. RESULTS: No grades 3-4 acute, urinary or rectal toxicity was reported. Acute grade 2 rectal complications were seen in 10 and 18% of the patients in Groups A and B, respectively. They were observed at a mean dose of 38Gy. Acute grade 2 urinary symptoms were 33 and 47% for Groups A and B, respectively. They were seen at a mean dose of 43Gy. Acute rectal symptoms were dose-volume related. Patients without diarrhea had a mean rectal volume receiving a dose of 70Gy or more of 8.5 cm(3). However, patients with RTOG 2 diarrhea had a volume of 16.5 cm(3) (P=0.042). No dose-volume relationship for acute bladder symptoms or late complications were seen. Grades 1-2 late rectal and bladder complications were seen in 11 and 8% of the patients, respectively. None required hospital admission or transfusion. CONCLUSION: Radiotherapy to the prostate can be given at 80Gy. No grades 3-4 acute, urinary or rectal toxicity was reported. Acute rectal symptoms are dose-volume related.     

Unique role of proximal rectal dose in late rectal complications for patients with cervical cancer undergoing high-dose-rate intracavitary brachytherapy

PURPOSE: To investigate the correlation of the radiation dose to the upper rectum, proximal to the International Commission of Radiation Units and Measurements (ICRU) rectal point, with late rectal complications in patients treated with external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary brachytherapy (ICRT) for carcinoma of the uterine cervix. METHODS AND MATERIALS: Between June 1997 and February 2001, 75 patients with cervical carcinoma completed definitive or preoperative RT and were retrospectively reviewed. Of the 75 patients, 62 with complete dosimetric data and a minimal follow-up of at least 1 year were included in this analysis. Of the 62 patients, 36 (58%) also received concurrent chemotherapy, mainly with cisplatin during EBRT. EBRT consisted of a mean of 50.1 +/- 1.3 Gy of 18-MV photons to the pelvis. A parametrial boost was given to 55 patients. Central shielding was used after 40-45 Gy of pelvic RT. HDR ICRT followed EBRT, with a median dose of 5 Gy/fraction given twice weekly for a median of four fractions. The mean dose to point A from HDR ICRT was 23.9 +/- 3.0 Gy. In addition to the placement of a rectal tube with a lead wire during ICRT, 30-40 mL of contrast medium was instilled into the rectum to demonstrate the anterior rectal wall up to the rectosigmoid junction. Late rectal complications were recorded according to the Radiation Therapy Oncology Group grading system. The maximal rectal dose taken along the rectum from the anal verge to the rectosigmoid junction and the ICRU rectal dose were calculated. Statistical tests were used for the correlation of Grade 2 or greater rectal complications with patient-related variables and dosimetric factors. Correlations among the point A dose, ICRU rectal dose, and maximal proximal rectal dose were analyzed. RESULTS: Fourteen patients (23%) developed Grade 2 or greater rectal complications. Patient-related factors, definitive or preoperative RT, and the use of concurrent chemotherapy were not associated with the occurrence of rectal complications. The maximal rectal dose during ICRT was at the proximal rectum rather than at the ICRU rectal point in 55 (89%) of 62 patients. Patients with Grade 2 or greater rectal complications had received a significantly greater total maximal proximal rectal dose from ICRT (25.6 Gy vs. 19.2 Gy, p = 0.019) and had a greater maximal proximal rectal dose/point A dose ratio (1.025 vs. 0.813, p = 0.024). In contrast, patients with and without rectal complications had a similar dose at point A (25.0 Gy vs.23.6 Gy, p = 0.107). The differences in the ICRU rectal dose (17.8 Gy vs.15.4 Gy, p = 0.065) and the ICRU rectal dose/point A dose ratio (0.71 vs. 0.66, p = 0.210) did not reach statistical significance. Patients with >62 Gy of a direct dose sum from EBRT and ICRT to the proximal rectum (12 of 29 vs. 2 of 33, p = 0.001) and >110 Gy of a total maximal proximal rectal biologic effective dose (13 of 40 vs. 1 of 22, p = 0.012) presented with a significantly increased frequency of Grade 2 or greater rectal complications. The correlations between the maximal proximal rectal dose and the ICRU rectal dose were less satisfactory (Pearson coefficient 0.375). Moreover, 11 of the 14 patients with rectal complications had colonoscopic findings of radiation colitis at the proximal rectum, the area with the maximal rectal dose. CONCLUSION: Eighty-nine percent of our patients had a maximal rectal dose from ICRT at the proximal rectum instead of the ICRU rectal point. The difference between patients with and without late rectal complications was more prominent for the proximal rectal dose than for the ICRU rectal dose. It is important and useful to contrast the whole rectal wall up to the rectosigmoid junction and to calculate the dose at the proximal rectum for patients undergoing HDR ICRT.     

适形放射治疗Ⅱ-Ⅲ期非小细胞肺癌初步报道

目的：研究三维适形放射治疗非小细胞肺癌(NSCLC)的疗效、副反应及患者的耐受性。方法：2000年10月～2001年7月，25例不能手术的Ⅱ-Ⅲ期非小细胞肺癌采用常规全纵隔或半纵隔 患侧肺门 原发病灶前后两野对穿外照射，照射肿瘤的剂量达8MV-X DT40～41．4Gy／20～23次／4～4．4周后，由CMS公司FOCUS2．6．1三维治疗计划系统设计、DVHs评价和优化适形治疗计划。计划靶区为临床靶区外放1．0～1．5cm，计划适形照射总剂量为25～30Gy，2．5～3Gy／次，1次／天，5天／周，肺作不均质密度校正，照射方法均为非共面野。按RTOG和WHO标准观察急性放射反应及近期疗效，评价患者的耐受性。结果：25例患者均顺利完成治疗，肿瘤中位剂量70．12Gy(62．45Gy～71．40Gy)。近期疗效为CR16．0％(4／25)，PR56．0％(14／25)，NC20．0％(5／25)，PD8．0％(2／25)，总有效率为72．0％(18／25)。根据RTOG分级，急性放射性食管炎1～2级24．0％(6／25)，3级4．0％(1／25)；急性放射性肺炎1～2级16．0％(4／25)，3级4．0％(1／25)；骨髓抑制1～2级16．0％(4／25)；心脏损伤1～2级12．0％(3／25)；随访至2002年7月，死亡7例，一年生存率75．15％。25例患者的中位随访期为14个月(6～18个月)，随访率为96％。结论：由于提高了分割量及总剂量，三维适形放射治疗不能手术的非小细胞肺癌可取得较好的近期疗效，并且经剂量-体积直方图(DVHs)优化治疗计划，减少了正常组织的照射剂量，使治疗能为患者耐受。由于样本较小，病例仍在进一步累积中，晚期并发症的发生率及远期疗效有待进一步观察。     

Significant correlation between rectal DVH and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy (66.6-70.2 Gy)

PURPOSE: Investigating the correlation between dosimetric/clinical parameters and late rectal bleeding in patients treated with adjuvant or salvage radiotherapy after radical prostatectomy. METHODS AND MATERIALS: Data of 154 consecutive patients, including three-dimensional treatment planning and dose-volume histograms (DVHs) of the rectum (including filling), were retrospectively analyzed. Twenty-six of 154 patients presenting a (full) rectal volume >100 cc were excluded from the analysis. All patients considered for the analysis (n = 128) were treated at a nominal dose equal to 66.6-70.2 Gy (ICRU dose 68-72.5 Gy; median 70 Gy) with conformal (n = 76) or conventional (n = 52) four-field technique (1.8 Gy/fr). Clinical parameters such as diabetes mellitus, acute rectal bleeding, hypertension, age, and hormonal therapy were considered. Late rectal bleeding was scored using a modified Radiation Therapy Oncology Group scale, and patients experiencing >or=Grade 2 were considered bleeders. Median follow-up was 36 months (range 12-72). Mean and median rectal dose were considered, together with rectal volume and the % fraction of rectum receiving more than 50, 55, 60, and 65 Gy (V50, V55, V60, V65, respectively). Median and quartile values of all parameters were taken as cutoff for statistical analysis. Univariate (log-rank) and multivariate (Cox hazard model) analyses were performed. RESULTS: Fourteen of 128 patients experienced >or=Grade 2 late bleeding (3-year actuarial incidence 10.5%). A significant correlation between a number of cutoff values and late rectal bleeding was found. In particular, a mean dose >or=54 Gy, V50 >or=63%, V55 >or=57%, and V60 >or=50% was highly predictive of late bleeding (p or=63% and those with V50 <63% (DVH grouping), data were fitted with a Cox regression hazard model using DVH grouping, rectal volume, and the main clinical parameters as independent variables. Results of the analysis showed that DVH grouping (relative risk 3.3; p = 0.04) and acute bleeding (relative risk 7.1; p = 0.001) are independently predictive of late bleeding. CONCLUSIONS: DVHs of the rectum are significantly correlated with late bleeding for patients irradiated at 66.6-70.2 Gy after radical prostatectomy.