Multicenter Trial of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer: Survival and Toxicity Endpoints.

PURPOSE: The radiobiology of prostate cancer may favor the extreme hypofractionation inherent in stereotactic body radiation therapy (SBRT); however, data from a large multicenter study are lacking. We therefore examined the hypothesis that dose-escalated SBRT can be safely administered across multiple institutions, with favorable 5-year disease-free survival (DFS) rates compared with historical controls. METHODS AND MATERIALS: Twenty-one centers enrolled 309 patients with prostate adenocarcinoma: 172 with low-risk (LR) and 137 with intermediate-risk (IR) disease. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. The prostate was prescribed 40 Gy in 5 fractions of 8 Gy. We assessed toxicities using Common Terminology Criteria for Adverse Events (CTCAE) version 3 and biochemical failure using the "nadir + 2" definition. The study population yielded 90% power to identify excessive (>10%) rates of grade ≥3 genitourinary (GU) or gastrointestinal toxicities and, in the LR group, 80% power to show superiority in DFS over a 93% historical comparison rate. RESULTS: At a median follow-up of 61 months, 2 LR patients (1.2%) and 2 IR patients (1.5%) experienced grade 3 GU toxicities, far below the 10% toxicity rate deemed excessive (upper limits of 95% confidence interval, 3.5% and 4.3%, respectively). No grade 4 or 5 toxicities occurred. All grade 3 toxicities were GU, occurring 11 to 51 months after treatment. For the entire group, the actuarial 5-year overall survival rate was 95.6% and the DFS rate was 97.1%. The 5-year DFS rate was 97.3% for LR patients (superior to the 93% DFS rate for historical controls; P = .0008; lower limit of 95% confidence interval, 94.6%) and 97.1% for IR patients. CONCLUSIONS: Dose-escalated prostate SBRT was administered with minimal toxicity in this multi-institutional study. Relapse rates compared favorably with historical controls. SBRT is a suitable option for LR and IR prostate cancer.

Short-term and long-term reproducibility of lung tumor position using active breathing control (ABC).

PURPOSE: To evaluate the short-term and long-term reproducibility of lung tumor position for scans acquired using an active breathing control (ABC) device. METHODS AND MATERIALS: Ten patients with lung cancer were scanned over three sessions during the course of treatment. For each session, two scans were acquired at deep inhale, and one scan each at half of deep inhale and at exhale. Long-term reproducibility was evaluated by comparing the same breathing state scans from two sessions, with setup variation removed by skeletal alignment. Tumor alignment was based on intensity matching of a small volume around the tumor. For short-term reproducibility, the two inhale volumes from the same session were compared. RESULTS: For the short-term reproducibility, the mean and the standard deviation (SD) of the displacement of the center of tumor were 0.0 (1.5) mm in anteroposterior (AP), 0.3 (1.4) mm in superior/inferior (SI), and 0.2 (0.7) mm in right/left (RL) directions. For long-term reproducibility, the mean (SD) were -1.3 (3.1) mm AP, -0.5 (3.8) mm SI, and 0.3 (1.6) mm RL for inhale and -0.2 (2.8) mm AP, 0.2 (2.1) mm SI, and -0.7 (1.1) mm RL for exhale. CONCLUSION: The ABC device demonstrates very good short-term and long-term reproducibility. Increased long-term variability in position, primarily in the SI and AP directions, indicates the role of tumor-directed localization in combination with breath-held immobilization.

Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer.

BACKGROUND AND PURPOSE: The University of Michigan lung dose escalation study has increased the dose of external beam radiation for non-small cell lung cancer based on the volume of normal lung irradiated. The results of patients treated to either 92.4 or 102.9 Gy are reported. MATERIALS AND METHODS: Seventeen patients have completed treatment to 92.4 or 102.9 Gy and have been followed for at least 6 months. The treatment planning goal was to minimize the effective volume (V(eff)) of total lung irradiated as computed using the Kutcher-Burman DVH reduction scheme. Dose was escalated independently within each of five V(eff) bins. Toxicity, freedom from local progression (FFLP), overall survival (OS) and cause specific survival (CSS) are reported. RESULTS: Thirteen patients were Stage I, one was Stage II and three were Stage III. V(eff) ranged from 0.06 to 0.21. The median pretreatment FEV(1) was 1.24 L or 44% of predicted. Median follow-up for survivors was 37.9 months. No patient had significant pulmonary toxicity. One patient each had grades 2 and 3 esophagitis. Median percent change in FEV1 was -11%. Two- and three-year actuarial FFLP and OS rates for the entire group were 68 and 58% and 51 and 26%, respectively. For Stage I patients, the 2 and 3 year FFLP, OS and CSS rates were 82 and 68%, 54 and 33%, 76 and 48% respectively. CONCLUSIONS: These results suggest that doses of radiation of 92.4 and 102.9 Gy can be delivered safely to limited lung volumes with minimal toxicity.

Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability.

PURPOSE: To compare different normal tissue complication probability (NTCP) models to predict the incidence of radiation pneumonitis on the basis of the dose distribution in the lung. METHODS AND MATERIALS: The data from 382 breast cancer, malignant lymphoma, and inoperable non-small-cell lung cancer patients from two centers were studied. Radiation pneumonitis was scored using the Southwestern Oncology Group criteria. Dose-volume histograms of the lungs were calculated from the dose distributions that were corrected for dose per fraction effects. The dose-volume histogram of each patient was reduced to a single parameter using different local dose-effect relationships. Examples of single parameters were the mean lung dose (MLD) and the volume of lung receiving more than a threshold dose (V(Dth)). The parameters for the different NTCP models were fit to patient data using a maximum likelihood analysis. RESULTS: The best fit resulted in a linear local dose-effect relationship, with the MLD as the resulting single parameter. The relationship between the MLD and NTCP could be described with a median toxic dose (TD(50)) of 30.8 Gy and a steepness parameter m of 0.37. The best fit for the relationship between the V(Dth) and the NTCP was obtained with a D(th) of 13 Gy. The MLD model was found to be significantly better than the V(Dth) model (p <0.03). However, for 85% of the studied patients, the difference in NTCP calculated with both models was <10%, because of the high correlation between the two parameters. For dose distributions outside the range of the studied dose-volume histograms, the difference in NTCP, using the two models could be >35%. For arbitrary dose distributions, an estimate of the uncertainty in the NTCP could be determined using the probability distribution of the parameter values of the Lyman-Kutcher-Burman model. CONCLUSION: The maximum likelihood method revealed that the underlying local dose-effect relation for radiation pneumonitis was linear (the MLD model), rather than a step function (the V(Dth) model). Thus, for the studied patient population, the MLD was the most accurate predictor for the incidence of radiation pneumonitis.

Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma.

PURPOSE: This study was performed to evaluate the outcome of patients with gallbladder cancer who received postoperative concurrent chemotherapy and radiation therapy. METHODS AND MATERIALS: Curative resection followed by adjuvant combined modality therapy with external beam radiation therapy (EBRT) and chemotherapy was attempted in 21 consecutive gallbladder carcinoma (GBC) patients at the Mayo Clinic from 1985 through 1997. All patients received concurrent 5-fluorouracil during EBRT. EBRT fields encompassed the tumor bed and regional lymph nodes (median dose of 54 Gy in 1.8-2.0-Gy fractions). One patient received 15 Gy intraoperatively after EBRT. A retrospective analysis was performed for the end points of local control, distant failure, and overall survival. RESULTS: After maximal resection, 12 patients had no residual disease on pathologic evaluation, 5 had microscopic residual disease, and 4 had gross residual disease. One patient had Stage I disease, and 20 had Stage III-IV disease. With median follow-up of 5 years (range: 2.6-11.5 years), 5-year survival for the entire cohort was 33%. The 5-year survival rate of patients with Stage I-III disease was 65% vs. 0% for those with Stage IV disease (p < 0.02). For patients with no residual disease, 5-year survival was 64% vs. 0% for those with residual disease (p = 0.002). The median survival was 0.6, 1.4, and 5.1 years for patients with gross residual, microscopic residual, and no residual disease, respectively (p = 0.02). The 5-year local control rate for the entire cohort was 73%. Two-year local control rates were 0%, 80%, and 88% for patients with gross residual, microscopic residual, or no residual disease, respectively (p < 0.01). Five-year local control rates were 100% for the 6 patients who received total EBRT doses >54 Gy (microscopic residual, 3 patients; gross residual, 1 patient; negative but narrow margins, 2 patients) vs. 65% for the 15 who received a lower dose (3, gross residual; 2, microresidual; 10, negative margins). CONCLUSION: Patients with completely resected (negative margins) GBC followed by adjuvant EBRT plus 5-fluorouracil chemotherapy had a relatively favorable prognosis, with a 5-year survival rate of 64%. These results seem to be superior to historical surgical controls from the Mayo Clinic and other institutions, which report 5-year survival rates of approximately 33% with complete resection alone. Both tumor stage and extent of resection seemed to influence survival and local control. More aggressive measures using current cancer therapies and integration of new cancer treatment modalities will be required to favorably impact on the poor prognosis of patients with Stage IV or subtotally resected GBC. Additional investigation leading to earlier diagnosis is warranted, because most patients with GBC present with advanced disease.