Howard Amols

HIGH-DOSE INTENSITY MODULATED RADIATION THERAPY FOR PROSTATE CANCER: EARLY TOXICITY AND BIOCHEMICAL OUTCOME IN 772 PATIENTS

Purpose To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT). Methods and materials Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6-60 months). Results Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of >/= late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of >/= late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively. Conclusions These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.

INCIDENCE OF LATE RECTAL AND URINARY TOXICITIES AFTER THREE- DIMENSIONAL CONFORMAL RADIOTHERAPY AND INTENSITY-MODULATED RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER

PURPOSE To report the incidence and predictors of treatment-related toxicity at 10 years after three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for localized prostate cancer. METHODS AND MATERIALS Between 1988 and 2000, 1571 patients with stages T1-T3 prostate cancer were treated with 3D-CRT/IMRT with doses ranging from 66 to 81 Gy. The median follow-up was 10 years. Posttreatment toxicities were all graded according to the National Cancer Institutes Common Terminology Criteria for Adverse Events. RESULTS The actuarial likelihood at 10 years for the development of Grade>or=2 GI toxicities was 9%. The use of IMRT significantly reduced the risk of gastrointestinal (GI) toxicities compared with patients treated with conventional 3D-CRT (13% to 5%; p<0.001). Among patients who experienced acute symptoms the 10-year incidence of late toxicity was 42%, compared with 9% for those who did not experience acute symptoms (p<0.0001). The 10-year incidence of late Grade>or=2 genitourinary (GU) toxicity was 15%. Patients treated with 81 Gy (IMRT) had a 20% incidence of GU symptoms at 10 years, compared with a 12% for patient treated to lower doses (p=0.01). Among patients who had developed acute symptoms during treatment, the incidence of late toxicity at 10 years was 35%, compared with 12% (p<0.001). The incidence of Grade 3 GI and GU toxicities was 1% and 3%, respectively. CONCLUSIONS Serious late toxicity was unusual despite the delivery of high radiation dose levels in these patients. Higher doses were associated with increased GI and GU Grade 2 toxicities, but the risk of proctitis was significantly reduced with IMRT. Acute symptoms were a precursor of late toxicities in these patients.

Ultra-High Dose (86.4 Gy) IMRT for Localized Prostate Cancer: Toxicity and Biochemical Outcomes

PURPOSE To report toxicity and preliminary biochemical outcomes with high-dose intensity-modulated radiation therapy (IMRT) to a dose of 86.4 Gy for localized prostate cancer. METHODS AND MATERIALS Between August 1997 and March 2004, 478 patients were treated with 86.4 Gy using a 5- to 7-field IMRT technique. To adhere to normal tissue constraints, the mean D95 and V100 for the planning target volume were 83 Gy and 87%, respectively. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse was calculated. The median follow-up was 53 months. RESULTS Thirty-seven patients (8%) experienced acute Grade 2 gastrointestinal (GI) toxicity. There was no acute Grade 3 or 4 GI toxicity. One hundred and five patients (22%) experienced acute Grade 2 genitourinary (GU) toxicity and three patients (0.6%) had Grade 3 GU toxicity. There was no acute Grade 4 GU toxicity. Sixteen patients (3%) developed late Grade 2 GI toxicity and two patients (<1%) developed late Grade 3 GI toxicity. Sixty patients (13%) had late Grade 2 GU toxicity and 12 (<3%) experienced late Grade 3 GU toxicity. The 5-year actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low, intermediate, and high risk NCCN prognostic groups. CONCLUSION This report represents the largest data set of patients treated to ultra-high radiation dose levels of 86.4 Gy using IMRT for localized prostate cancer. Our findings indicate that this treatment is well tolerated and the early excellent biochemical control rates are encouraging.

Results of a Phase I Dose-Escalation Study using Three-Dimensional Conformal Radiotherapy in the Treatment of Inoperable Nonsmall Cell Lung Carcinoma

The objective of this study was to report the results of a Phase I dose‐escalation study using three‐dimensional conformal radiation therapy (3D‐CRT) for the treatment of patients with nonsmall cell lung carcinoma (NSCLC).

Intensity-modulated radiotherapy

Intensity-modulated radiotherapy represents a recent advancement in conformal radiotherapy. It employs specialized computer-driven technology to generate dose distributions that conform to tumor targets with extremely high precision. Treatment planning is based on inverse planning algorithms and iterative computer-driven optimization to generate treatment fields with varying intensities across the beam section. Combinations of intensity-modulated fields produce custom-tailored conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal tissues. Thus far, data have demonstrated improved precision of tumor targeting in carcinomas of the prostate, head and neck, thyroid, breast, and lung, as well as in gynecologic, brain, and paraspinal tumors and soft tissue sarcomas. In prostate cancer, intensity-modulated radiotherapy has resulted in reduced rectal toxicity and has permitted tumor dose escalation to previously unattainable levels. This experience indicates that intensity-modulated radiotherapy represents a significant advancement in the ability to deliver the high radiation doses that appear to be required to improve the local cure of several types of tumors. The integration of new methods of biologically based imaging into treatment planning is being explored to identify tumor foci with phenotypic expressions of radiation resistance, which would likely require high-dose treatments. Intensity-modulated radiotherapy provides an approach for differential dose painting to selectively increase the dose to specific tumor-bearing regions. The implementation of biologic evaluation of tumor sensitivity, in addition to methods that improve target delineation and dose delivery, represents a new dimension in intensity-modulated radiotherapy research.

Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging

PURPOSE Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. METHODS MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. RESULTS The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using (125)I seeds. The preset dose bounds of 100-150% to the prostate and 100-120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. CONCLUSIONS Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for (125)I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: The Memorial Sloan-Kettering Cancer Center (MSKCC) experience

INTRODUCTION Intensity-modulated radiation therapy (IMRT) is an advanced treatment delivery technique that can improve the therapeutic dose ratio. Its use in the treatment of inoperable non-small cell lung cancer (NSCLC) has not been well studied. This report reviews our experience with IMRT for patients with inoperable NSCLC. METHODS AND MATERIALS We performed a retrospective review of 55 patients with stage I-IIIB inoperable NSCLC treated with IMRT at our institution between 2001 and 2005. The study endpoints were toxicity, local control, and overall survival. RESULTS With a median follow-up of 26 months, the 2-year local control and overall survival rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, 2-year local control and overall survival rates were 58% and 58%, respectively, with a median survival time of 25 months. Six patients (11%) experienced grade 3 acute pulmonary toxicity. There were no acute treatment-related deaths. Two patients (4%) had grade 3 or worse late treatment-related pulmonary toxicity. CONCLUSIONS IMRT treatment resulted in promising outcomes for inoperable NSCLC patients.

Validation of GATE Monte Carlo simulations of the GE Advance/Discovery LS PET scanners

The recently developed GATE (GEANT4 application for tomographic emission) Monte Carlo package, designed to simulate positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanners, provides the ability to model and account for the effects of photon noncollinearity, off-axis detector penetration, detector size and response, positron range, photon scatter, and patient motion on the resolution and quality of PET images. The objective of this study is to validate a model within GATE of the General Electric (GE) Advance/Discovery Light Speed (LS) PET scanner. Our three-dimensional PET simulation model of the scanner consists of 12 096 detectors grouped into blocks, which are grouped into modules as per the vendors specifications. The GATE results are compared to experimental data obtained in accordance with the National Electrical Manufactures Association/Society of Nuclear Medicine (NEMA/SNM), NEMA NU 2-1994, and NEMA NU 2-2001 protocols. The respective phantoms are also accurately modeled thus allowing us to simulate the sensitivity, scatter fraction, count rate performance, and spatial resolution. In-house software was developed to produce and analyze sinograms from the simulated data. With our model of the GE Advance/Discovery LS PET scanner, the ratio of the sensitivities with sources radially offset 0 and 10 cm from the scanners main axis are reproduced to within 1% of measurements. Similarly, the simulated scatter fraction for the NEMA NU 2-2001 phantom agrees to within less than 3% of measured values (the measured scatter fractions are 44.8% and 40.9 +/- 1.4% and the simulated scatter fraction is 43.5 +/- 0.3%). The simulated count rate curves were made to match the experimental curves by using deadtimes as fit parameters. This resulted in deadtime values of 625 and 332 ns at the Block and Coincidence levels, respectively. The experimental peak true count rate of 139.0 kcps and the peak activity concentration of 21.5 kBq/cc were matched by the simulated results to within 0.5% and 0.1% respectively. The simulated count rate curves also resulted in a peak NECR of 35.2 kcps at 10.8 kBq/cc compared to 37.6 kcps at 10.0 kBq/cc from averaged experimental values. The spatial resolution of the simulated scanner matched the experimental results to within 0.2 mm.

Cone-beam CT with megavoltage beams and an amorphous silicon electronic portal imaging device: potential for verification of radiotherapy of lung cancer.

We investigate the potential of megavoltage (MV) cone-beam CT with an amorphous silicon electronic portal imaging device (EPID) as a tool for patient position verification and tumor/organ motion studies in radiation treatment of lung tumors. We acquire 25 to 200 projection images using a 22 x 29 cm EPID. The acquisition is automatic and requires 7 minutes for 100 projections; it can be synchronized with respiratory gating. From these images, volumetric reconstruction is accomplished with a filtered backprojection in the cone-beam geometry. Several important prereconstruction image corrections, such as detector sag, must be applied. Tests with a contrast phantom indicate that differences in electron density of 2% can be detected with 100 projections, 200 cGy total dose. The contrast-to-noise ratio improves as the number of projections is increased. With 50 projections (100 cGy), high contrast objects are visible, and as few as 25 projections yield images with discernible features. We identify a technique of acquiring projection images with conformal beam apertures, shaped by a multileaf collimator, to reduce the dose to surrounding normal tissue. Tests of this technique on an anthropomorphic phantom demonstrate that a gross tumor volume in the lung can be accurately localized in three dimensions with scans using 88 monitor units. As such, conformal megavoltage cone-beam CT can provide three-dimensional imaging of lung tumors and may be used, for example, in verifying respiratory gated treatments.

Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer.

The relative inability of conventional radiotherapy to control localized prostate cancer results from resistance of subpopulations of tumor clonogens to dose levels of 65 to 70 Gy, the maximum feasible with traditional two-dimensional (2D) treatment planning and delivery techniques. Several technological advances have enhanced the precision and improved the outcome of external-beam radiotherapy. The three-dimensional conformal radiotherapy (3D-CRT) approach has permitted significant increases in the tumor dose to levels beyond those feasible with conventional techniques. Intensity-modulated radiotherapy (IMRT), an advanced form of conformal radiotherapy, has resulted in reduced rectal toxicity, permitting tumor dose escalation to previously unattainable levels with a concomitant improvement in local tumor control and disease-free survival. The combination of androgen deprivation and conventional-dose radiotherapy, tested mainly in patients with locally advanced disease, has also produced significant outcome improvements. Whether androgen deprivation will preclude the need for dose escalation or whether high-dose radiotherapy will obviate the need for androgen deprivation remains unknown. In some patients, both approaches may be necessary to maximize the probability of cure. In view of the favorable benefit-risk ratio of high-dose IMRT, the design of clinical trials to resolve these critical questions is essential.