Dosimetric evaluation of a novel polymer gel dosimeter for proton therapy.

PURPOSE: The aim of this study is to evaluate the dosimetric performance of a newly developed proton-sensitive polymer gel formulation for proton therapy dosimetry. METHODS: Using passive scattered modulated and nonmodulated proton beams, the dose response of the gel was assessed. A next-generation optical CT scanner is used as the readout mechanism of the radiation-induced absorbance in the gel medium. Comparison of relative dose profiles in the gel to ion chamber profiles in water is performed. A simple and easily reproducible calibration protocol is established for routine gel batch calibrations. Relative stopping power ratio measurement of the gel medium was performed to ensure accurate water-equivalent depth dose scaling. Measured dose distributions in the gel were compared to treatment planning system for benchmark irradiations and quality of agreement is assessed using clinically relevant gamma index criteria. RESULTS: The dosimetric response of the gel was mapped up to 600 cGy using an electron-based calibration technique. Excellent dosimetric agreement is observed between ion chamber data and gel. The most notable result of this work is the fact that this gel has no observed dose quenching in the Bragg peak region. Quantitative dose distribution comparisons to treatment planning system calculations show that most (> 97%) of the gel dose maps pass the 3%/3 mm gamma criterion. CONCLUSIONS: This study shows that the new proton-sensitive gel dosimeter is capable of reproducing ion chamber dose data for modulated and nonmodulated Bragg peak beams with different clinical beam energies. The findings suggest that the gel dosimeter can be used as QA tool for millimeter range verification of proton beam deliveries in the dosimeter medium.

Performance evaluation of an improved optical computed tomography polymer gel dosimeter system for 3D dose verification of static and dynamic phantom deliveries.

The performance of a next-generation optical computed tomography scanner (OCTOPUS-5X) is characterized in the context of three-dimensional gel dosimetry. Large-volume (2.2 L), muscle-equivalent, radiation-sensitive polymer gel dosimeters (BANG-3) were used. Improvements in scanner design leading to shorter acquisition times are discussed. The spatial resolution, detectable absorbance range, and reproducibility are assessed. An efficient method for calibrating gel dosimeters using the depth-dose relationship is applied, with photon- and electron-based deliveries yielding equivalent results. A procedure involving a preirradiation scan was used to reduce the edge artifacts in reconstructed images, thereby increasing the useful cross-sectional area of the dosimeter by nearly a factor of 2. Dose distributions derived from optical density measurements using the calibration coefficient show good agreement with the treatment planning system simulations and radiographic film measurements. The feasibility of use for motion (four-dimensional) dosimetry is demonstrated on an example comparing dose distributions from static and dynamic delivery of a single-field photon plan. The capability to visualize three-dimensional dose distributions is also illustrated.

Identification and fine mapping of a region showing a high frequency of allelic imbalance on chromosome 16q23.2 that corresponds to a prostate cancer susceptibility locus.

Linkage to a prostate cancer susceptibility locus was recently reported on chromosome 16q23. We now report a region exhibiting a high frequency of allelic imbalance (AI) corresponding to this locus in tumors from 51 men diagnosed with prostate cancer using the same linked markers. The highest frequency of AI was found at markers D16S3096 (45%) and D16S516 (53%) that map to chromosome 16q23.2. In addition, 19 of the 51 (37%) prostate tumors showed interstitial AI involving one or both of these markers. This result strongly suggests that a candidate prostate cancer tumor suppressor gene maps between markers D16S3096 and D16S516. We estimate that the distance between these markers is approximately 118 kb using a Stanford radiation hybrid panel. We observed a positive association with family history (P = 0.048) when comparing those men showing interstitial AI at markers D16S3096 and/or D16S516 with those without any imbalance at these two markers. Taken together, these data suggest that we have precisely localized a region of chromosome 16q23.2 that may harbor a prostate cancer tumor suppressor gene implicated in the development of non-familial and possibly familial forms of prostate cancer.

Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome.

PURPOSE: To determine if familial prostate cancer patients have a less favorable prognosis than patients with sporadic prostate cancer after treatment for localized disease with either radiotherapy (RT) or radical prostatectomy (RP). PATIENTS AND METHODS: One thousand thirty-eight patients treated with either RT (n = 583) or RP (n = 455) were included in this analysis. These patients were noted as having a positive family history if they confirmed the diagnosis of prostate cancer in a first-degree relative. The outcome of interest was biochemical relapse-free survival (bRFS). We used proportional hazards to analyze the effect of the presence of family history and other potential confounding variables (ie, age, treatment modality, stage, biopsy Gleason sum [GS], and initial prostate-specific antigen [iPSA] levels) on treatment outcome. RESULTS: Eleven percent of all patients had a positive family history. The 5-year bRFS rates for patients with negative and positive family histories were 52% and 29%, respectively (P < .001). The potential confounders with bRFS rates were iPSA levels, biopsy GS, and clinical tumor stage; treatment modality and age did not appear to be associated with outcome. After adjusting for potential confounders, family history of prostate cancer remained strongly associated with biochemical failure. CONCLUSION: This is the first study to demonstrate that the presence of a family history of prostate cancer correlates with treatment outcome in a large unselected series of patients. Our findings suggest that familial prostate cancer may have a more aggressive course than nonfamilial prostate cancer, and that clinical and/or pathologic parameters may not adequately predict this course.

Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer.

PURPOSE: Several studies have defined risk groups for predicting the outcome after external-beam radiotherapy of localized prostate cancer. However, most models formed patient risk groups, and none of these models considers radiation dose as a predictor variable. The purpose of this study was to develop a nomogram to improve the accuracy of predicting outcome after three-dimensional conformal radiotherapy. MATERIALS AND METHODS: This study was a retrospective, nonrandomized analysis of patients treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1998. Clinical parameters of the 1,042 patients included stage, biopsy Gleason score, pretreatment serum prostate-specific antigen (PSA) level, whether neoadjuvant androgen deprivation therapy was administered, and the radiation dose delivered. Biochemical (PSA) treatment failure was scored when three consecutive rises of serum PSA occurred. A nomogram, which predicts the probability of remaining free from biochemical recurrence for 5 years, was validated internally on this data set using a bootstrapping method and externally using a cohort of patients treated at the Cleveland Clinic, Cleveland, OH. RESULTS: When predicting outcomes for patients in the validation data set from the Cleveland Clinic, the nomogram had a Somers' D rank correlation between predicted and observed failure times of 0.52. Predictions from this nomogram were more accurate (P<.0001) than the best of seven published risk stratification systems, which achieved a Somers' D coefficient of 0.47. CONCLUSION: The development process illustrated here produced a nomogram that seems to predict more accurately than other available systems and may be useful for treatment selection by both physicians and patients.

Declining rates of extracapsular extension after radical prostatectomy: evidence for continued stage migration.

PURPOSE: Prostate-specific antigen (PSA)-based screening is responsible for a profound clinical stage migration in newly detected prostate cancers. Extracapsular extension (ECE) is an important predictor of outcome after radical prostatectomy (RP). We examined trends in the rate of ECE for cancers detected by PSA screening in 731 RP specimens between 1987 and 1997, when screening became routine urologic practice in the United States. METHODS: The rates of ECE were examined in 311 prostates with nonpalpable (stage T1c) disease and 420 with palpable but clinically localized (stage T2) disease. Specimens were step-sectioned and examined by a senior pathologist. Rates of ECE were compared with respect to time, and logistic regression was used to identify predictors of ECE. RESULTS: The rate of ECE decreased from 81% to 36% during the 10-year observation period. Multivariateanalysis involving clinical tumor stage, preoperative serum PSA level, and Gleason score demonstrated that year of treatment was an independent predictor of ECE, with a two-fold reduction of risk occurring during the study period (P <. 001; odds ratio, 1.96; 95% confidence interval, 1.37 to 2.78). CONCLUSION: PSA screening has resulted in a downward trend in pathologic stage in clinically localized prostate cancer, independent of preoperative PSA level, tumor stage, and Gleason score. This time-dependent downward stage migration suggests the need for continuous updating of predictive nomograms and caution in interpreting differences in contemporarily treated patients compared with historical controls. Further study is needed to determine whether this trend will translate into improved disease-free survival.

Evaluation of a diode array for QA measurements on a helical tomotherapy unit.

A helical tomotherapy system is used in our clinic to deliver intensity-modulated radiation therapy (IMRT) treatments. Since this machine is designed to deliver IMRT treatments, the traditional field flatness requirements are no longer applicable. This allows the unit to operate without a field flatness filter and consequently the 400 mm wide fan beam is highly inhomogeneous in intensity. The shape of this beam profile is mapped during machine commissioning and for quality assurance purposes the shape of the beam profile needs to be monitored. The use of a commercial diode array for quality assurance measurements is investigated. Central axis beam profiles were acquired at different depths using solid water built-up material. These profiles were compared with ion chamber scans taken in a water tank to test the accuracy of the diode array measurements. The sensitivity of the diode array to variations in the beam profile was checked. Over a seven week period, beam profiles were repeatedly measured. The observed variations are compared with those observed with an on-board beam profile monitor. The diode measurements were in agreement with the ion chamber scans. In the high dose, low gradient region the average ratio between the diode and ion chamber readings was 1.000 +/- 0.005 (+/- 1 standard deviation). In the penumbra region the agreement was poorer but all diodes passed the distance to agreement (DTA) requirement of 2 mm. The trend in the beam profile variations that was measured with the diode array device was in agreement with the on-board monitor. While the calculated amount of variation differs between the devices, both were sensitive to subtle variations in the beam profile. The diode array is a valuable tool to quickly and accurately monitor the beam profile on a helical tomotherapy unit.

Time and PSA threshold model prognosticates long-term overall and disease-specific survival in prostate cancer patients as early as 3 months after external beam radiation therapy.

The specific aim of this analysis was to evaluate the capability of a time and prostate-specific antigen (PSA) threshold model to prognosticate overall survival (OS) and disease-specific survival (DSS) based on early PSA kinetics after radiotherapy for prostate cancer by retrospective review of outcomes in 918 patients. Crossing below analyzed PSA thresholds at specific defined time points reduced disease-specific death hazard ratios to relative to the cohort above threshold. The time and PSA threshold model demonstrates the ability to prognosticate OS and DSS as early as 3 months post-radiotherapy for prostate cancer.

The use of megavoltage CT (MVCT) images for dose recomputations.

Megavoltage CT (MVCT) images of patients are acquired daily on a helical tomotherapy unit (TomoTherapy, Inc., Madison, WI). While these images are used primarily for patient alignment, they can also be used to recalculate the treatment plan for the patient anatomy of the day. The use of MVCT images for dose computations requires a reliable CT number to electron density calibration curve. In this work, we tested the stability of the MVCT numbers by determining the variation of this calibration with spatial arrangement of the phantom, time and MVCT acquisition parameters. The two calibration curves that represent the largest variations were applied to six clinical MVCT images for recalculations to test for dosimetric uncertainties. Among the six cases tested, the largest difference in any of the dosimetric endpoints was 3.1% but more typically the dosimetric endpoints varied by less than 2%. Using an average CT to electron density calibration and a thorax phantom, a series of end-to-end tests were run. Using a rigid phantom, recalculated dose volume histograms (DVHs) were compared with plan DVHs. Using a deformed phantom, recalculated point dose variations were compared with measurements. The MVCT field of view is limited and the image space outside this field of view can be filled in with information from the planning kVCT. This merging technique was tested for a rigid phantom. Finally, the influence of the MVCT slice thickness on the dose recalculation was investigated. The dosimetric differences observed in all phantom tests were within the range of dosimetric uncertainties observed due to variations in the calibration curve. The use of MVCT images allows the assessment of daily dose distributions with an accuracy that is similar to that of the initial kVCT dose calculation.

Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients.

Prostate cancer incidence, clinical presentation, and mortality rates vary among different ethnic groups. A genetic variant of CYP3A4, a gene involved in the oxidative deactivation of testosterone, has been associated recently with prostate cancer development in Caucasians. To further investigate this variant, we evaluated its genotype frequencies in different ethnic groups and its association with clinical presentation of prostate cancer in African Americans. CYP3A4 genotypes were assayed in healthy male Caucasian (n = 117), Hispanic (n = 121), African-American (n = 116), Chinese (n = 46), and Japanese (n = 34) volunteers using the TaqMan assay. The association between CYP3A4 genotype and prostate cancer presentation was determined in 174 affected African-American men. Genotype frequency of the CYP3A4 variant differed substantially across ethnic groups, with African Americans much more likely to carry one or two copies than any other group (two-sided P < 0.0001). Among African Americans, 46% (80 of 174) of men with prostate cancer were homozygous for the CYP3A4 variant, whereas only 28% (32 of 116) of African-American healthy volunteers were homozygous (two-sided P < 0.005). A consistent positive association was observed between being homozygous for the CYP3A4 variant in African-American prostate cancer patients and clinical characteristics. Men homozygous for the CYP3A4 variant were more likely to present with higher grade and stage of prostate cancer in a recessive model [odds ratio (OR), 1.7; 95% confidence interval (CI), 0.9-3.4]. This association was even stronger for men who were >65 years of age at diagnosis (n = 103; OR, 2.4; 95% CI, 1.1-5.4). In summary, the CYP3A4 genotype frequency in different ethnic groups broadly followed trends in prostate cancer incidence, presentation, and mortality in the United States. African-American prostate cancer patients had a higher frequency of being homozygous for the CYP3A4 variant than healthy African-American volunteers who were matched solely based on ethnicity. Among the patients, those who were homozygous for the CYP3A4 variant were more likely to present with clinically more advanced prostate cancer.

Prognostic factors in the treatment of node-negative nonsmall cell lung carcinoma with radiotherapy alone.

PURPOSE: For patients with early stage nonsmall cell lung carcinoma (NSCLC) but medically inoperable, aggressive radiation therapy might impact on survival. METHODS AND MATERIALS: Between 1980 and 1990, 71 patients treated at MDACC by radiation therapy alone for NSCLC because of medical contradindications for surgery were analyzed. All patients had histologic or cytologic confirmation of NSCLC. The median total radiation dose was 63.23 Gy with 79% of patients receiving doses exceeding 60 Gy. The radiographic response was documented at completion of radiation therapy and 6 months after completion of radiation therapy. The median follow-up time was 36 months, ranging from 14-61 months. RESULTS: Overall survival rates at 3 and 5 years were 19 and 12%, respectively. The disease-specific survival (DSS) rates at 3 and 5 years were 44 and 32%, respectively. The DSS rates at 3 years by T-stage were: 49% for T1, 47% for T2, 26% for T3, and 32% for T4. The local control rates at 3 and 5 years were 66 and 56%, respectively. The local control rates at 3 years by T-stage were: 89% for T1, 61% for T2, 42% for T3, and 55% for T4. Univariately, the significant favorable prognostic factors for DSS were a KPS > or = 70, tumor size < or = 5 cm, no chest-wall invasion, and a radiation dose > or = 50 Gy. The significant favorable prognostic factors for local control were tumor size < or = 4 cm, no chest-wall invasion, a radiation dose > 60 Gy, and a complete response confirmed by chest x-ray at 6 months after radiotherapy (p = 0.04). Coverage of nodal drainage areas did not affect survival or local control. No lethal complications were seen, and documented symptomatic radiation pneumonitis occurred in only 7% of cases. Hence, the significant favorable prognostic factors for DSS were a KPS of > or = 70, tumor size < or = 5 cm, no chest-wall invasion, and a radiation dose > or = 50 Gy. The significant favorable prognostic factors for local control were tumor size of < or = 4 cm, no chest-wall invasion, a radiation dose > 60 Gy, and a complete response confirmed by chest x-ray at 6 months after radiotherapy. Multivariate analysis showed that the most important prognostic factor for DSS was KPS, and the most important prognostic factor for local control was radiation dose. CONCLUSIONS: Patients with a KPS of > or = 70, a tumor size < 5 cm, and no chest-wall invasion would benefit most from treatment with radiation alone to doses exceeding 60 Gy. This patient group represents the best sample for studying the benefit of conformal radiotherapy.

Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy.

PURPOSE: Prostate-specific antigen (PSA) is extensively used in case selection and outcome evaluation after treatment of clinically localized prostate cancer. Careful case selection can have a profound impact on pathologic findings and ultimate outcome. In addition, salvage treatment is frequently initiated at the time of biochemical relapse rather than clinical recurrence. Consequently, patterns of failure can be significantly altered compared to previous times when PSA was not available. To better understand the impact of PSA on pathologic findings, outcome, and salvage treatment, we reviewed our experience in the PSA era with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. METHODS AND MATERIALS: Between 1987 and 1993, 423 cases could be identified with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. The distribution of cases by pretreatment PSA levels was as follows: < or = 4 ng/ml (18%), 4-10 ng/ml (42%), 10-20 ng/ml (21%), > 20 ng/ml (14%), and unknown (5%). The median pretreatment PSA level for the entire group was 8.0 ng/ml. Sixteen patients received adjuvant or neoadjuvant androgen suppression and 13 received postoperative radiotherapy. Only 31 patients (7%) had pathologically positive pelvic lymph nodes. The overall margin involvement rate was 46%. Fifty-three percent of patients had surgical Gleason scores > or = 7, and 65% had extracapsular extension. The median follow-up time was 41 months. RESULTS: The projected overall survival at 7 years after surgery was 90%. The 5-year clinical relapse-free survival rate was 84%. At 5 years, the local control and distant failure rates were 92% and 91%, respectively. Biochemical relapse was defined as a detectable or rising PSA level after prostatectomy. The 5-year biochemical relapse-free survival (bRFS) rate was 59%. The 5-year RFS was 88% in patients with preoperative PSA levels < or = 4, 62% for 4-10, 48% for 10-20, and 31% for > 20. Combining the two independent preoperative variables, iPSA and biopsy GS (bGS), two risks groups were defined: low risk [initial PSA (iPSA) levels < or = 10.0 and bGS < or = 6] and high risk (iPSA levels > 10.0 ng/ml or bGS > or = 7). The 5-year bRFS rate for the low-risk cases was 81% vs. 40% for high-risk cases (p < 0.001). On multivariate analysis, three factors independently predicted biochemical relapse: iPSA levels (p = 0.005), Gleason score from the surgical specimen (sGS) (p = 0.002), and positive surgical margins (p < or = 0.001). The 5-year bRFS rates for margin positive vs. margin negative patients were 37% vs. 78%, respectively. The 5-year bRFS rates for GS > or = 7 vs. GS > or = 6 were 42% vs. 80%, respectively. All clinical relapses were accompanied by a rise in PSA. In patients who manifested biochemical failure followed by a clinical failure, the median interval between the PSA rise and clinical failure was 19 months (range 7-71). Margin involvement was the only independent predictor of local failure (p = 0.019). The 5-year local failure-free survival for negative margin cases was 96% vs. 87% for positive margin cases (p = 0.012). Lymph node (LN) involvement and high-risk group were the two independent predictors of distant failure. The 5-year distant failure-free survival for negative LN cases was 94% vs. 67% for positive LN cases (p < 0.001). The 5-year distant failure-free survival for low-risk cases was 97% vs. 85% for high-risk cases (p = 0.005). For the 124 patients failing biochemically, 85 were observed and 39 were treated either with radiation or androgen deprivation. With a median follow-up of 32 months, the clinical disease relapse-free survival was 79% for the treated patients vs. only 32% for the patients observed (p < 0.001). CONCLUSION: Pretreatment PSA is the most potent clinical factor independently predicting biochemical relapse, thereby allowing markedly better case selection. Achieving negative margins, even in relatively advanced disease, provides excellent lon

Short-course intensity-modulated radiotherapy for localized prostate cancer with daily transabdominal ultrasound localization of the prostate gland.

PURPOSE: To present our initial observations on the clinical feasibility of the technique of short-course intensity-modulated radiotherapy (SCIM-RT) in the treatment of localized prostate cancer coupled with daily transabdominal ultrasound localization of the prostate. The proposed regimen consists of a hypofractionated course delivering 70.0 Gy in 28 fractions. METHODS AND MATERIALS: The treatment data of the first 51 patients treated with SCIM-RT at the Cleveland Clinic Foundation are presented in this report. The technique consisted of intensity-modulated radiotherapy using 5 static fields (anterior, 2 laterals, and 2 anterior obliques). Inverse plans were generated by the Corvus treatment-planning system. The treatment delivery was performed with a Varian Dynamic Multileaf Collimator. The target was the prostate only in patients with low-risk disease (stage T1-T2, pretreatment PSA < or =10, and biopsy Gleason < or =6). The target was the prostate and seminal vesicles in patients with high-risk disease (stage T3 or pretreatment PSA > 10 or biopsy Gleason > or =7). In the Corvus planning system, the margins for the planning target volume (PTV) were 4 mm posteriorly, 8 mm laterally, and 5 mm in all other directions. A total of 70.0 Gy (mean prostate dose approximately 75 Gy) was prescribed in all cases at 2.5 Gy per fraction to be delivered in 28 fractions over 5 1/2 weeks. Prior to treatment delivery, the patients were minimally immobilized on the treatment table, only using lasers and skin marks. The location of the prostate gland was verified daily with the BAT transabdominal ultrasound system and patient position adjustments were performed accordingly. Fifty-one patients completed therapy between October 1998 and May 1999. RESULTS: The dose was prescribed to an isodose line ranging from 82.0% to 90.0% (mean: 87.2%). The range of the individual prostate mean doses was 73.5 to 78.5 Gy (average: 75.3 Gy). The range of the maximum doses was 77.4 to 84.5 Gy (average: 80.2 Gy). The range of the minimum doses was 64.3 to 69.2 Gy (average: 67.5 Gy). The average time for the prostate position verification and alignment of the prostate using the BAT system was 5 minutes. The entire localization/alignment process was performed by the radiation therapists. The daily alignment images were automatically saved and reviewed by the radiation oncologist, a process similar to port film checks. The total treatment (beam-on) time was around 6 minutes using the 5 static intensity-modulated fields. The mean and standard deviation (SD) of bladder volumes irradiated to 50, 60, and 70 Gy were as follows: 24 +/- 11 cc, 16 +/- 8 cc, and 8 +/- 6 cc. The mean and SD of rectal volumes irradiated to 50, 60, and 70 Gy were as follows: 22 +/- 11 cc, 15 +/- 8 cc, and 7 +/- 5 cc. The RTOG acute bladder toxicity scores were as follows: 0 in 3 (6%), 1 in 38 (74%), and 2 in 10 (20%). The RTOG acute rectal toxicity scores for SCIM-RT cases were as follows: 0 in 10 (20%), 1 in 33 (65%), and 2 in 8 (16%). No Grade 3 or 4 acute toxicities were observed. CONCLUSION: The delivery of our proposed hypofractionated-schedule SCIM-RT in combination with daily target localization/alignment with the BAT transabdominal ultrasound system is clinically feasible. It is an alternative method of dose escalation in the treatment of localized prostate cancer. The proposed schedule would significantly increase convenience to patients due to the decrease in overall treatment time. Preliminary acute toxicity results are extremely encouraging. Long-term follow-up is needed to assess late complications and treatment efficacy.

Indications for excluding the seminal vesicles when treating clinically localized prostatic adenocarcinoma with radiotherapy alone.

PURPOSE: The indications for treating the seminal vesicles (SV) in patients with clinically localized carcinoma of the prostate are controversial. We sought to define subgroups of patients in whom coverage could be avoided, using pretreatment prostate specific antigen (PSA) values and the Gleason score. Because the rectum is the major dose-limiting structure, we also measured the extent of rectal sparing achieved by excluding the SV from external beam treatment fields. METHODS AND MATERIALS: We retrospectively studied lateral x-ray simulation films of 43 patients treated with standard four-field radiotherapy and dose-volume histograms of eight patients treated with conformal radiotherapy. The rectal surface areas were measured and the volumes were calculated including and excluding the SV. The pathology reports of patients treated with radical prostatectomy alone between 1987 and 1993 were reviewed. Patients without preoperative PSA levels or biopsy Gleason scores, or who received neoadjuvant hormonal therapy were excluded. Of the 368 remaining patients, 66 (18%) had preoperative PSA levels < or = 4, 172 (47%) had PSA levels 4-10, and 130 (35%) had PSA levels > 10. The Gleason score was < or = 6 in 269 (73%), and 99 (27%) had a score > or = 7. RESULTS: The reduction in the total irradiated rectal areas to full doses when the SV were excluded ranged from 5 to 67% in individual patients (median, 44%). The median reduction in the irradiated rectal volumes to 50% of the prescribed dose, as determined by dose-volume histograms, was 51% (range: 37-76%). The median reduction in bladder volumes was 9% (range: 6%-15%). The incidence of SV involvement was 19% (70 out of 368). Patients with normal PSA levels (< or = 4 ng/mL) had a 3% (2 out of 66) rate of SV involvement. Patients with PSA levels between 4-10 ng/mL had a 8% (10 out of 126) rate of SV involvement. All other cases had at least 20% rate of SV involvement, with a combined rate of 33%. Using a cutoff of 15%, two low risk groups were identified: all patients with PSA levels < or = 4, and patients with PSA 4-10 and Gleason score < or = 6. These constituted 52% (192 out of 368) of all patients. Overall, the low-risk patients had a 6% (12 out of 192) incidence of SV involvement vs. 33% (58 out of 176) for the high risk patients (p < or = .001). CONCLUSIONS: Excluding the SV from the treatment field can significantly reduce (40%-50%) the volume of irradiated rectum. Our data confirm that pretreatment PSA levels and Gleason scores can be effectively used to define subgroups of patients in whom SV irradiation can be avoided. We propose excluding the SV in all patients with PSA levels < or = 4, and patients with PSA levels 4-10 and a Gleason score < or = 6.

Treatment of endometrial carcinoma with radiation therapy alone.

PURPOSE: To review the results of treatment with radiotherapy alone in 152 patients with adenocarcinoma of the endometrium who had medical or surgical contraindications to hysterectomy. METHODS AND MATERIALS: We reviewed the records of all patients who were treated with radiotherapy alone for uterine carcinoma at The University of Texas M. D. Anderson Cancer Center between 1960 and 1986. One hundred fifty-two cases were analyzed. Most patients had multiple medical problems. One hundred sixteen patients were treated with intracavitary radiotherapy alone. A combination of external beam and intracavitary radiotherapy was used for 10 patients with Stage I disease who had unusually large cavities, 10 patients with Stage II disease, and 13 of 15 patients with Stage III or IV disease. Histologic material was reviewed in 91 cases. RESULTS: Ten years after treatment, these patients were twice as likely to have died of intercurrent illness as of uterine cancer. The 5-year disease-specific survival rate of patients with Stage I disease was 87%. The disease-specific survival of patients with Stage II disease was 88%, which was not significantly different from that of Stage I patients. Stage III and IV patients had a significantly poorer disease-specific survival rate of 49% at 5 years. Intrauterine recurrence occurred in 14% of the patients with Stage I or II disease. Salvage treatment was attempted in 5 of the 10 patients who had isolated intrauterine recurrences of Stage I disease and was successful in all cases. Extrauterine pelvic recurrence developed in only 3% of Stage I and II patients. Of 82 Stage I and II carcinomas that were available for pathologic review, 17 (21%) were clear-cell or papillary serous variants. The disease-specific survival rate of patients with Stage I or II papillary serous carcinomas was 43%, significantly poorer than that of patients with endometrioid carcinomas. Seven patients experienced acute anesthesia-related complications; none were fatal. Five patients had serious late complications of radiation therapy. CONCLUSION: Radical radiotherapy achieved acceptable DSS and local control rates in patients with medically or surgically inoperable uterine carcinoma. However for patients with localized disease, such treatment is justified only when the operative risk exceeds the 10-15% uterine recurrence rate expected with radiation alone.

Stage T1-2 prostate cancer with pretreatment prostate-specific antigen level < or = 10 ng/ml: radiation therapy or surgery?

PURPOSE: To detect differences in biochemical failure rates by treatment modality (radiation therapy or radical prostatectomy) in patients with early-stage prostate cancer presenting with pretreatment prostatic-specific antigen (PSA) levels < or = 10.0 ng/ml. METHODS AND MATERIALS: A total of 1467 consecutive patients with prostate carcinoma were treated with either radiotherapy (RT) or radical prostatectomy (RP) between January 1987 and June 1996. Patients with the following were excluded from the present study: initial PSA (iPSA) level > 10 ng/ml (n = 444), clinical Stage T3 disease (n = 73), adjuvant or neoadjuvant treatment (n = 173), no available iPSA level (n = 31), no available biopsy Gleason score (GS) (n = 33), incomplete pathologic information (n = 16), and no available follow-up PSA levels (n = 90). The analysis was performed on 607 cases: 354 treated with RP and 253 with RT (median dose 68.4 Gy). The outcome of interest was biochemical relapse-free survival (bRFS), with biochemical relapse being defined as either a detectable PSA level after RP or elevation in PSA levels of > or = 1.0 ng/ml above the nadir after RT. Proportional hazards were used to analyze the effect of treatment modality and confounding variables (i.e., age, stage, biopsy GS, iPSA levels) on treatment outcome. RESULTS: Seventy-nine percent of patients (n = 478) had clinical Stage T1 or T2A disease at presentation (RP vs. RT: 84% vs. 71%, p < 0.001). Twenty-one percent of patients (n = 127) had iPSA levels < or = 4 ng/ml (RP vs. RT: 24% vs. 17%, p = 0.027). Seventy-six percent of patients (n = 460) had biopsy GS < or = 6 (RP vs. RT: 79% vs. 71%, p = 0.014). The median follow-up time was 24 months (range 3-110). For the 607 patients, the 5-year bRFS rate was 76%. The 5-year RFS rates for RP versus RT were 76% versus 75%, respectively (p = 0.09). After adjustment for all confounding variables, iPSA levels (p < 0.001) and biopsy GS (p = 0.001) were the only independent predictors of relapse, whereas age, clinical stage, and treatment modality were not (p = 0.20; p = 0.09; and p = 0.10, respectively). CONCLUSION: In patients with clinical Stage T1-2 prostate cancer and pretreatment PSA < or = 10 ng/ml, there is no difference in biochemical failure rates between those treated with radiation and those treated with surgery.

Radiation dose response in patients with favorable localized prostate cancer (Stage T1-T2, biopsy Gleason < or = 6, and pretreatment prostate-specific antigen < or = 10).

PURPOSE: To study the radiation dose response as determined by biochemical relapse-free survival in patients with favorable localized prostate cancers, i.e., Stage T1-T2, biopsy Gleason score (bGS) < or = 6, and pretreatment prostate-specific antigen (iPSA) < or = 10 ng/mL. METHODS AND MATERIALS: A total of 292 patients with favorable localized prostate cancer were treated with radiotherapy alone between 1986 and 1999. The median age was 69 years. Sixteen percent of cases (n = 46) were African-American. The distribution by clinical T stage was as follows: T1/T2A, 243 (83%); and T2B/T2C, 49 (17%). The distribution by iPSA was as follows: < or = 4 ng/mL, 49 (17%); and > 4 ng/mL, 243 (83%). The mean iPSA level was 6.2 (median, 6.4). The distribution by bGS was as follows: or = 5 in 89 cases (30%) and 6 in 203 cases (70%). The median radiation dose was 70.0 Gy (range, 63.0-78.0 Gy). Doses of < or = 70.0 Gy were delivered in 175 cases, 70.2-72.0 Gy in 24 cases, 74 Gy in 30 cases, and 78 Gy in 63 cases. For patients receiving < 72 Gy, the median dose was 68 Gy, vs. 78 Gy for patients receiving > or = 72 Gy. A conformal technique was used in 129 (44%) of cases. The median follow-up was 43 months (range, 3-153). RESULTS: For the entire cohort, the projected 5- and 8-year biochemical relapse-free survival (bRFS) rates were both 81%. For patients receiving > or = 72 Gy, the 5- and 8-year bRFS rates were both 95% vs. only 77% for patients receiving < 72 Gy, p = 0.010. For patients receiving 74 Gy, the 4-year bRFS rate was 94% vs. 96% for patients receiving 78 Gy, p = 0.90. A multivariate analysis for factors affecting bRFS rates using Cox proportional hazards was performed for all cases using the following variables: age (continuous variable), race (black vs. white), iPSA (continuous variable), bGS (< or = 5 vs. 6), Stage (T1-2A vs. T2B-C), radiation dose (continuous variable), and radiation technique (conformal vs. standard). From the multivariate analysis, only iPSA (p = 0.017, chi(2) = 5.7), and radiation dose (p = 0.021, chi(2) = 5.3) were independent predictors of outcome. Age (p = 0.94), race (p = 0.89), stage (p = 0.45), biopsy GS (p = 0.40), and radiation technique (p = 0.45) were not. CONCLUSION: There is a clear radiation dose response in patients with favorable localized prostate cancers (i.e., Stage T1-T2, biopsy Gleason score < or = 6, and iPSA < or = 10 ng/mL). At least 74 Gy should be delivered to the prostate and periprostatic tissues. With our cohort of patients, longer follow-up will be needed to assess the importance of doses exceeding 74 Gy.

Short-course intensity-modulated radiotherapy (70 GY at 2.5 GY per fraction) for localized prostate cancer: preliminary results on late toxicity and quality of life.

PURPOSE: To present our preliminary observations on the late toxicity and quality of life (QOL) of patients treated with short-course intensity-modulated radiotherapy (SCIM-RT). METHODS AND MATERIALS: Fifty-one patients were treated with SCIM-RT at the Cleveland Clinic Foundation between October 1998 and May 1999. The technique consisted of intensity-modulated radiotherapy using 5 static fields (anterior, 2 laterals, and 2 anterior obliques). Inverse plans were generated by the Corvus treatment-planning system. The treatment delivery was performed with a dynamic multileaf collimator. A total of 70.0 Gy was prescribed in all cases at 2.5 Gy per fraction to be delivered in 28 fractions over 5 and a half weeks. The location of the prostate gland was verified and adjusted daily with the BAT transabdominal ultrasound system. The median follow-up was 18 months (range: 11 to 26 months). The Radiation Therapy Oncology Group (RTOG) scales were used to evaluate late toxicity. The Expanded Prostate Cancer Index Composite (EPIC) was used to evaluate QOL. A total of 24 patients completed the EPIC questionnaire at approximately 2 years after therapy (median time from treatment to questionnaire administration: 24 months; range: 21 to 26 months). The results from the EPIC questionnaires were compared to scores from 46 patients treated during the same time period with conformal radiotherapy (CRT) to 78 Gy at 2 Gy per fraction. RESULTS: The dose was prescribed to an isodose line ranging from 82.0% to 90.0% (mean: 87.2%). The range of the individual prostate mean doses was 73.5 to 78.5 Gy (average: 75.3 Gy). To date, only 1 patient had Grade 1 late urinary toxicity. To date, only 4 patients had Grade 1 late rectal toxicity. No Grade 2 or 3 late urinary or rectal complications have occurred. The actuarial rectal bleeding rate observed at 18 months was 7%. There were no differences in scores from the urinary, bowel, hormonal, and overall QOL domains between SCIM-RT patients and patients treated with CRT. The overall physical and mental QOL scores were also nearly identical to scores reported for the general U.S. population. CONCLUSION: Preliminary late toxicity results up to 2 years after SCIM-RT are encouraging, with a median follow-up of 18 months (range 11 to 26 months). Late toxicity assessed by the physicians using RTOG late toxicity scores has been excellent. QOL reported by the patients using the EPIC questionnaire reveals no difference between patients treated with high-dose CRT at standard fractionation and patients treated with SCIM-RT. SCIM-RT is an alternative method of dose escalation in the treatment of localized prostate cancer. The proposed schedule significantly increases convenience to patients due to the decrease in overall treatment time.

Higher than standard radiation doses (> or =72 Gy) with or without androgen deprivation in the treatment of localized prostate cancer.

PURPOSE: To study the effect on biochemical relapse-free survival (bRFS) and clinical disease-free survival of radiation doses delivered to the prostate and periprostatic tissues for localized prostate cancer. METHODS AND MATERIALS: A total of 1041 consecutive localized prostate cancer cases treated with external beam radiotherapy (RT) at our institution between 7/86 and 2/99 were reviewed. All cases had available pretreatment parameters including pretreatment prostate-specific antigen (iPSA), biopsy Gleason score (bGS), and clinical T stage. The median age was 69 years. Twenty-three percent of cases (n = 238) were African-American. The distribution by clinical T stage was as follows: T1 in 365 cases (35%), T2 in 562 cases (54%), and T3 in 114 cases (11%). The median iPSA level was 10.1 ng/ml (range: 0.4-692.9). The distribution by biopsy Gleason score (bGS) was as follows: < or =6 in 580 cases (56%) and > or =7 in 461 cases (44%). Androgen deprivation (AD) in the adjuvant or neoadjuvant setting was given in 303 cases (29%). The mean RT dose was 71.9 Gy (range: 57.6-78.0 Gy). The median RT dose was 70.2 Gy, with 458 cases (44%) receiving at least 72.0 Gy. The average dose in patients receiving <72 Gy was 68.3 Gy (median 68.4) versus 76.5 Gy (median 78.0) for patients receiving > or =72 Gy. The mean follow-up was 38 months (median 33 months). The number of follow-up prostate-specific antigen (PSA) levels available was 5998. RESULTS: The 5- and 8-year bRFS rates were 61% (95% CI 55-65%) and 58% (95% CI 51-65%), respectively. The 5-year bRFS rates for patients receiving radiation doses > or =72 Gy versus <72 Gy were 87% (95% CI 82-92%) and 55% (95% CI 49-60%), respectively. The 8-year bRFS rates for patients receiving radiation doses > or =72 Gy versus <72 Gy were 87% (95% CI 82-92%) and 51% (95% CI 44-58%), respectively (p < 0.001). A multivariate analysis of factors affecting bRFS was performed using the following parameters: age (continuous variable), race, T-stage (T1-T2 vs. T3), iPSA (continuous variable), bGS (< or =6 vs. > or =7), use of AD (yes vs. no), radiation technique (conformal versus standard), and radiation dose (continuous variable). T-stage (p < 0.001), iPSA (p < 0.001), bGS (p < 0.001), and RT dose (p < 0.001) were independent predictors of outcome. Age (p = 0.74), race (p = 0.96), radiation technique (p = 0.15), and use of AD (p = 0.31) were not. We observed 11% clinical failures (local, distant, or both) at 5 years and 15% at 8 years for the entire cohort. There was a statistically significant improvement with higher radiation doses (p = 0.032). The 5-year clinical relapse rates for patients receiving > or =72 Gy versus <72 Gy were 5% and 12%, respectively. The 8-year clinical relapse rates for patients receiving radiation doses > or =72 Gy versus <72 Gy were 5% and 17%, respectively (p = 0.026). CONCLUSION: Patients receiving radiation doses exceeding 72 Gy had significantly better bRFS and clinical disease-free survival rates. Although results need to be confirmed with longer follow-up, these preliminary results are extremely encouraging. If these results are confirmed by other institutions and by longer follow-up, RT doses exceeding 72 Gy should be considered as standard of care.

Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution.

PURPOSE: To determine the efficacy of definitive surgery and radiation in patients aged 70 years and older with supratentorial glioblastoma multiforme. METHODS AND MATERIALS: We selected elderly patients (> or = 70 years) who had primary treatment for glioblastoma multiforme at our tertiary care institution from 1977 through 1996. The study group (n = 102) included 58 patients treated with definitive radiation, 19 treated with palliative radiation, and 25 who received no radiation. To compare our results with published findings, we grouped our patients according to the applicable prognostic categories developed by the Radiation Therapy Oncology Group (RTOG): RTOG group IV (n = 6), V (n = 70), and VI (n = 26). Patients were retrospectively assigned to prognostic group IV, V, or VI based on age, performance status, extent of surgery, mental status, neurologic function, and radiation dose. Treatment included surgical resection and radiation (n = 49), biopsy alone (n = 25), and biopsy followed by radiation (n = 28). Patients were also stratified according to whether they were optimally treated (gross total or subtotal resection with postoperative definitive radiation) or suboptimally treated (biopsy, biopsy + radiation, surgery alone, or surgery + palliative radiation). Patients were considered to have a favorable prognosis (n = 39) if they were optimally treated and had a Karnofsky Performance Status (KPS) score of at least 70. RESULTS: The median survival for patients according to RTOG groups IV, V, and VI was 9.2, 6.6, and 3.1 months, respectively (log-rank, p < 0.0004). The median overall survival was 5.3 months. The definitive radiation group (n = 58) had a median survival of 7.3 months compared to 4.5 months in the palliative radiation group (n = 19) and 1.2 months in the biopsy-alone group (p < 0.0001). Optimally treated patients had a median survival of 7.4 months compared to 2.4 months in those suboptimally treated (p < 0.0001). The favorable prognosis group had an 8.4-month median survival compared to 2.4 months in the unfavorable group (p < 0.0001). On multivariate analysis, the KPS, RTOG group, favorable/unfavorable prognosis, and optimal treatment/suboptimal treatment were significant predictors of survival. CONCLUSION: Elderly patients with good performance status (> or = 70 KPS) when treated aggressively with maximal resection and definitive radiation had longer survival than those treated with palliative radiation and biopsy. Aggressive treatment in such patients should be considered.