Eugene Huang

PROSTATE CANCER RADIATION DOSE RESPONSE: RESULTS OF THE M. D. ANDERSON PHASE III RANDOMIZED TRIAL

PURPOSEnA randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer.nnnMETHODS AND MATERIALSnA total of 305 Stage T1-T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis.nnnRESULTSnThere was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA <or=10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy.nnnCONCLUSIONnAn increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives >or=70 Gy to <25% should be used.

Intrafraction prostate motion during IMRT for prostate cancer.

PURPOSEnAlthough the interfraction motion of the prostate has been previously studied through the use of fiducial markers, CT scans, and ultrasound-based systems, intrafraction motion is not well documented. In this report, the B-mode, Acquisition, and Targeting (BAT) ultrasound system was used to measure intrafraction prostate motion during 200 intensity-modulated radiotherapy (IMRT) sessions for prostate cancer.nnnMETHODS AND MATERIALSnTwenty men receiving treatment with IMRT for clinically localized prostate cancer were selected for the study. Pre- and posttreatment BAT ultrasound alignment images were collected immediately before and after IMRT on 10 treatment days for a total of 400 BAT alignment procedures. Any ultrasound shifts of the prostate borders in relation to the planning CT scan were recorded in 3 dimensions: right-left (RL), anteroposterior (AP), and superior-inferior (SI). Every ultrasound procedure was evaluated for image quality and alignment according to a 3-point grading scale.nnnRESULTSnAll the BAT images were judged to be of acceptable quality and alignment. The dominant directions of intrafraction prostate motion were anteriorly and superiorly. The mean magnitude of shifts (+/-SD) was 0.01 +/- 0.4 mm, 0.2 +/- 1.3 mm, and 0.1 +/- 1.0 mm in the left, anterior, and superior directions, respectively. The maximal range of motion occurred in the AP dimension, from 6.8 mm anteriorly to 4.6 mm posteriorly. The percentage of treatments during which prostate motion was judged to be <or=5 mm was 100%, 99%, and 99.5% in the RL, AP, and SI directions, respectively. Three of the measurements were >5 mm. The extent of intrafraction motion was much smaller than that of interfraction motion. Linear regression analysis showed very little correlation between the two types of motion (r = 0.014, 0.029, and 0.191, respectively) in the RL, AP, and SI directions.nnnCONCLUSIONnUsing an ultrasound-based system, intrafraction prostate motion occurred predominantly in the anterior and superior directions, but was clinically insignificant. Intrafraction motion was much smaller than interfraction motion, and the two types of movement did not correlate.

Experience of ultrasound-based daily prostate localization

PURPOSEnThe NOMOS (Sewickley, PA) B-mode Acquisition and Targeting System (BAT) ultrasound system provides a rapid means of correcting for interfraction prostate positional variation. In this investigation, we report our experience on the clinical issues relevant to the daily use of the BAT system and the analysis of combined setup error and organ motion for 3509 BAT alignment procedures in 147 consecutive patients treated with IMRT for prostate cancer.nnnMETHODS AND MATERIALSnAfter setup to external skin marks, therapists performed the BAT ultrasound alignment procedure before each IMRT treatment. In this study, a single physician (A.C.) reviewed all BAT images and classified image quality and accuracy of image alignment by the therapist. On a scale of 1-3, near-perfect image quality or alignment was given a 1, fair image quality or misalignment > or = 5 mm (likely within the PTV) was given a 2, and unacceptable image quality or misalignment >5 mm (potential to violate the PTV) was given a value of 3. The distribution of shifts made was analyzed in each dimension and for all patients. The time required to perform the BAT alignment was also assessed in 17 patients.nnnRESULTSnAmong the 3509 attempted BAT procedures, the image quality was judged to be poor or unacceptable in 5.1% (181). Of the remaining 3328 BAT images, with quality scores of 1-2, alignments were unacceptable (>5 mm misalignment as judged by the reviewing physician) in 3% (100). The mean shift in each direction, averaged over all patients, was 0.5-0.7 mm. Interfraction standard deviation (1 SD) of prostate position based on combined setup error and internal organ motion is 4.9 mm, 4.4 mm, and 2.8 mm in the anteroposterior (AP), superior-inferior (SI), and lateral (RL) dimensions, respectively. The distribution of the shifts was a near-random Gaussian-type in all three major axes, with greater variations in AP and SI directions. The percent of BAT procedures in which the shift was >5 mm was 28.6% in AP, 23% in SI, and 9% in RL directions. The average BAT procedure took extra 5 min out of a 20-min time slot in a typical eight-field IMRT treatment.nnnCONCLUSIONSnThe quality of the daily ultrasound images was deemed acceptable in 95%. Major alignment errors by therapists were only 3%. The BAT system is clinically effective and feasible in a matter of 5 min. Although the accuracy of the BAT was not addressed in this investigation, we found a significant percentage of large shifts being made from the initial alignment position.

HAZARDS OF DOSE ESCALATION IN PROSTATE CANCER RADIOTHERAPY

PURPOSEnTo assess the benefit of escalating the dose in definitive prostate cancer radiotherapy vs. the associated risk of complications.nnnMATERIALS AND METHODSnBetween 1987 and 1999, 1087 patients with clinical Stage T1b-T3 adenocarcinoma of the prostate were definitively irradiated without hormonal therapy and had a pretreatment serum prostate-specific antigen (PSA) and Gleason score recorded. The median follow-up was 65 months. Doses ranged from 64 to 78 Gy, with the treatment techniques corresponding to the year of therapy and the prescribed dose. A total of 301 patients were treated on a randomized protocol to either 70 or 78 Gy. Also, 163 patients were treated with three-dimensional conformal therapy and had dose-volume histograms available for review.nnnRESULTSnTumor stage, grade, pretreatment PSA level, and radiation dose were all independent predictors of PSA disease-free survival (PSA-DFS) in multivariate analysis. The hazard rate for biochemical failure peaked at 1.5-3 years after radiotherapy. Although a statistically significant dose effect on PSA-DFS was found in the pretreatment PSA levels of those with both < or =10 ng/mL and >10 ng/mL, in those with a pretreatment PSA < or =10 ng/mL, the improvement in outcome was only seen going from a dose level of 64-66 Gy to 68-70 Gy with a 5-year PSA-DFS rate of 66% vs. 81% (p <0.0001). This was also confirmed by the data from the randomized patients who showed no difference in outcome whether treated to 70 Gy or 78 Gy. In patients with a pretreatment PSA level >10 ng/mL, a statistically significant improvement was found in disease-free outcome among the 64-66-Gy, 68-70-Gy, and 78-Gy levels. PSA-DFS was approximately 50% better at each higher dose level at 5 and 8 years after treatment. The dose had a statistically significant impact in both intermediate- and high-risk groups. Rectal morbidity was both dose and volume related. Although at 5 years after therapy, the Grade 2-3 rectal complication rate was twice as high for patients treated to 78 Gy than to 70 Gy, 26% vs. 12%, this risk could be markedly diminished by adhering to dose-volume constraints.nnnCONCLUSIONSnIn intermediate- and high-risk prostate cancer patients, although it appears that radiation-dose escalation may improve PSA-DF outcome, the price paid in treatment morbidity can be high without adequate attention to dose-volume constraints of normal tissue. Care must be taken to consider not only the hazard of tumor recurrence but also that of complications.

Locoregional treatment outcomes for inoperable anthracycline-resistant breast cancer

PURPOSEnTo assess the therapeutic outcomes and treatment-related morbidity of patients treated with radiation for inoperable breast cancer resistant to anthracycline-containing primary chemotherapy.nnnMETHODS AND MATERIALSnWe analyzed the medical records of breast cancer patients treated on five consecutive institutional trials who had been designated as having inoperable locoregional disease after completion of primary chemotherapy, without evidence of distant metastases at diagnosis. The cohort for this analysis was 38 (4.4%) of 867 patients enrolled in these trials. Kaplan-Meier statistics were used for survival analysis, and prognostic factors were compared using log-rank tests. The median follow-up of surviving patients was 6.1 years.nnnRESULTSnThirty-two (84%) of the 38 patients were able to undergo mastectomy after radiotherapy. For the whole group, the overall survival rate at 5 years was 46%, with a distant disease-free survival rate of 32%. The 5-year survival rate for patients who were inoperable because of primary disease extent was 64% compared with 30% for those who were inoperable because of nodal disease extent (p = 0.0266). The 5-year rate of locoregional control was 73% for the surgically treated patients and 64% for the overall group. Of the 32 who underwent mastectomy, the 5-year rate of significant postoperative complications was 53%, with 4 (13%) requiring subsequent hospitalization and additional surgical revision. Preoperative radiation doses of >or=54 Gy were significantly associated with the development of complications requiring surgical treatment (70% vs. 9% for doses <54 Gy, p = 0.0257).nnnCONCLUSIONnDespite the poorer prognosis of patients with inoperable disease after primary chemotherapy, almost one-half remained alive at 5 years and one-third were free of distant disease after multidisciplinary locoregional management. These patients have high rates of locoregional recurrence after preoperative radiotherapy and mastectomy, and the morbidity associated with this approach may limit dose-escalation strategies. Alternative therapeutic strategies such as novel systemic agents, use of planned myocutaneous repair for closure, or radiation combined with radiosensitizing agents, should be considered in this class of patients.