Frequentist rules for regulatory approval of subgroups in phase III trials: A fresh look at an old problem.

BACKGROUND: The number of Phase III trials that include a biomarker in design and analysis has increased due to interest in personalised medicine. For genetic mutations and other predictive biomarkers, the trial sample comprises two subgroups, one of which, say B+ is known or suspected to achieve a larger treatment effect than the other B-. Despite treatment effect heterogeneity, trials often draw patients from both subgroups, since the lower responding B- subgroup may also gain benefit from the intervention. In this case, regulators/commissioners must decide what constitutes sufficient evidence to approve the drug in the B- population. METHODS AND RESULTS: Assuming trial analysis can be completed using generalised linear models, we define and evaluate three frequentist decision rules for approval. For rule one, the significance of the average treatment effect in B- should exceed a pre-defined minimum value, say ZB->L. For rule two, the data from the low-responding group B- should increase statistical significance. For rule three, the subgroup-treatment interaction should be non-significant, using type I error chosen to ensure that estimated difference between the two subgroup effects is acceptable. Rules are evaluated based on conditional power, given that there is an overall significant treatment effect. We show how different rules perform according to the distribution of patients across the two subgroups and when analyses include additional (stratification) covariates in the analysis, thereby conferring correlation between subgroup effects. CONCLUSIONS: When additional conditions are required for approval of a new treatment in a lower response subgroup, easily applied rules based on minimum effect sizes and relaxed interaction tests are available. Choice of rule is influenced by the proportion of patients sampled from the two subgroups but less so by the correlation between subgroup effects.

Atypical presentation of invasive meningococcal disease caused by serogroup W meningococci.

Neisseria meningitidis, a gram-negative diplococcus, is typically an asymptomatic coloniser of the oropharynx and nasopharynx. Passage of N. meningitidis into the bloodstream can cause invasive meningococcal disease (IMD), a potentially life-threatening illness with rapid onset that generally presents as meningitis, septicemia or both. Serogroup W IMD has been increasing in prevalence in recent years, and observations suggest that it may present with atypical signs and symptoms. Herein, a literature search was performed to identify trends in atypical serogroup W IMD presentation in order to review those that are most prevalent. Findings indicate that the most prevalent atypical presentations of serogroup W IMD include acute gastrointestinal (GI) symptoms, septic arthritis and bacteremic pneumonia or severe upper respiratory tract infection, notably epiglottitis. Atypical clinical presentation is associated with higher case fatality rates and can lead to misdiagnoses. Such risks highlight the need for clinicians to consider IMD in their differential diagnoses of patients with acute GI symptoms, septic arthritis or bacteremic pneumonia, primarily in regions where serogroup W is prevalent.

SU-E-T-545: Dose Comparison between Intravenous Contrast-Enhanced CT and Non Contrast CT in Treatment Planning.

PURPOSE: With increasing concern for patient dose from CT scan, we are trying to reduce CT scan and use intravenous contrast-enhanced CT (contrast CT) in treatment planning. This study is to investigate dose calculation accuracy using contrast CT in treatment planning for lung, esophagus and pancreas cancer. METHODS: We analyzed treatment plans for 8 patients for whom CT simulation was performed both with and without intravenous contrast agent (CA) (non-contrast CT). IMRT/3D plans were generated with inhomogeneity correction on the non-contrast CT scan. Contrast CTs were fused to the non-contrast studies and all contours and plans were copied to the contrast CT scans. For each patient, we analyzed dose-volume histograms (DVH) for planning volumes (PTV) and the organs-at-risk (OAR), comparing the doses generated on non-contrast CT scans with those generated on contrast CT scans. RESULTS: Maximum doses ratio Dmax(contrast)/Dmax (non-contrast) in PTVs was 1.0009±0.0013. The ratio of D05 (contrast)/D05 (non-contrast) was 0.996±0.005. The ratio of mean PTV dose Dmean(contrast)/Dmean(non-contrast) was 0.990±0.005%. The ratio of minimum dose Dmin(contrast)/Dmin(non-contrast) and D95(contrast)/D95(non-contrast) were 0.970±0.030 and 0.984±0.009, respectively. Contrast CT raised cord dose slightly. The ratio of cord Dmax was 1.005±0.026. However there were two cases the ratio of cord Dmax were 1.035. CONCLUSIONS: The PTV D95 is usually normalized to prescription dose and the D95 differences between contrast and regular CT were within 2%. In most cases, the contrast CT could be used to treatment planning clinically. However more attention should be paid to maximum cord dose if it is already close to criteria limit.

SU-E-J-14: Evaluation of Mechanical Accuracy of Electronic Portal Imaging Devise on Its Use in Patient Specific IMRT QA.

PURPOSE: Electronic portal imaging devices (EPID) have been used for both in vivo dosimetry and in vitro dose verification in intensity modulated radiotherapy (IMRT). This study is to investigate the effect of EPID mechanical precision on the accuracy of measured dose distribution. METHODS: EPID energy fluences (dicom images) of H&N IMRT fields were collected daily on two Varian LINACs (Clinac-iX & Trilogy) over 4-week period. The energy fluences were converted to doses using EPIDoseTM (Sun Nuclear Corp). Mechanical deviations of EPIDs could be divided into two components: one with inherent detector center misalignment from the beam central axis, another caused by the 'sagging effect' from gantry rotation. The first component was detected by 'best matching' of the measured and calculated dose at zero gantry angle (G=0). The second component was computed by 'best matching' the 10×10cm field defined by MLC at G=0, 90,180, and 270, separately. A 'shift' was generated by the combination of these two components and then applied to correct the measured dose at the corresponding gantry angle for the IMRT field. RESULTS: Inherent misalignment of the detector's center and the 'sagging' deviation were found to be 1-2 mm and 1-5 mm, respectively for both LINACs. Each component was found very stable (change < 1mm) over the 4-week observational period. Using a Gamma index of 2%/2mm (DD/DTA), the 'shift' increased the average passing rate from 59% to more than 92%. On the other hand, blindly applying 'auto-shift' from commercially available software to obtain the best match would compound true QA issues with units' misalignments. CONCLUSIONS: A false 'mismatch' between measured and calculated dose distribution caused by mechanical inaccuracies of EPID could be avoided by measuring the two components identified in this study. One should examine the mechanical precision of equipment prior to clinical use of EPID dosimetry.

SU-E-T-170: A Viable Approach to Patient Specific QA for Spine VMAT SRS Using EPID-Based Dosimetry.

PURPOSE: VMAT involves multi-parameter modulations, thus presenting multi-dimensional challenges. Here, we present a viable approach to VMAT patient specific QA using EPID-based dosimetry for spine VMAT SRS casesMethods: Our spine VMAT SRS plans consisted of two full arcs and were optimized with 6 MV photons for a Varian Trilogy LINAC. The QA plans were computed by resetting all control points to 0° gantry angle while keeping the MLC apertures and corresponding MU weights intact. The dose distribution at the depth of clinical significance was calculated in a solid water phantom. EPIDose (Sun Nuclear Corp) was used to convert MV EPID images into absolute dose in a plane of interest in a homogeneous medium. During measurements, the source-to-detector distance (SDD) was set to 105 cm and the VMAT QA plan was delivered with 600 MU/min. For each QA plan, three measurements were made. The average pass rate (thresholds: 2%/2 mm) was then calculated. In addition, the dose at the isocenter or other points of clinical significance was also measured and the mean was calculated. RESULTS: Our current institutional QA acceptance criteria for VMAT plans are: pass rate 90% for 2%/2mm with a dose threshold of 10% and the discrepancy between the measured and planned doses at the isocenter or other points of clinical significance 2%. Our preliminary investigation indicated that the pass rate was normally greater than 95.0% with a total number of valid detection points of ∼30000. The dose difference at the point of interest was, in general, around ±1.0 %. Sharp dose gradients were accurately detected at the PTV-cord interface. CONCLUSIONS: EPID- based dosimetry is real-time and financially viable. It can achieve sub- millimeter dosimetry accuracy without extensive inter-diode interpolations. We believe that EPID-based VMAT dosimetry offers a competitive alternative to other competing dosimetry technologies.

Evaluation of imaging performance of major image guidance systems.

PURPOSE: The imaging characteristics of two popular kV cone-beam CT (CBCT) and two MVCT systems utilised in image-guided radiation therapy (IGRT) were evaluated. MATERIALS AND METHODS: The study was performed on Varian Clinac iX, Elekta Synergy S, Siemens Oncor, and Tomotherapy. A CT phantom (Catphan-504, Phantom Laboratory, Salem, NY) was scanned for measurements of image quality including image noise, uniformity, density accuracy, spatial resolution, contrast linearity, and contrast resolution. The measurement results were analysed using in-house image analysis software. Reproducibility, position correction, and geometric accuracy were also evaluated with markers in a smaller alignment phantom. The performance evaluation compared volumetric image properties from these four systems with those from a conventional diagnostic CT (CCT). RESULTS: It was shown that the linearity of the two kV CBCT was fairly consistent with CCT. The Elekta CBCT with half-circle 27-cm FOV had higher CT numbers than the other three systems. The image noises of the Elekta kV CBCT, Siemens MV CBCT, and Tomotherapy fan-beam CT (FBCT) are about 2-4 times higher than that of the Varian CBCT. The spatial resolutions of two kV CBCTs and two MV CBCTs were 8-11 lp/cm and 3-5 lp/cm, respectively. CONCLUSION: Elekta CBCT provided a faster image reconstruction and low dose per scan for half-circle scanning. Varian CBCT had relatively lower image noise. Tomotherapy FBCT had the best uniformity.

Evaluation of imaging performance of major image guidance systems

Purpose: The imaging characteristics of two popular kV cone-beam CT (CBCT) and two MVCT systems utilised in image-guided radiation therapy (IGRT) were evaluated. Materials and methods: The study was performed on Varian Clinac iX, Elekta Synergy S, Siemens Oncor, and Tomotherapy. A CT phantom (Catphan-504, Phantom Laboratory, Salem, NY) was scanned for measurements of image quality including image noise, uniformity, density accuracy, spatial resolution, contrast linearity, and contrast resolution. The measurement results were analysed using in-house image analysis software. Reproducibility, position correction, and geometric accuracy were also evaluated with markers in a smaller alignment phantom. The performance evaluation compared volumetric image properties from these four systems with those from a conventional diagnostic CT (CCT). Results: It was shown that the linearity of the two kV CBCT was fairly consistent with CCT. The Elekta CBCT with half-circle 27-cm FOV had higher CT numbers than the other three systems. The image noises of the Elekta kV CBCT, Siemens MV CBCT, and Tomotherapy fan-beam CT (FBCT) are about 2-4 times higher than that of the Varian CBCT. The spatial resolutions of two kV CBCTs and two MV CBCTs were 8-11 lp/cm and 3-5 lp/cm, respectively. Conclusion: Elekta CBCT provided a faster image reconstruction and low dose per scan for half-circle scanning. Varian CBCT had relatively lower image noise. Tomotherapy FBCT had the best uniformity.

A recycling framework for the construction of Bonferroni-based multiple tests.

In this paper we describe Bonferroni-based multiple testing procedures (MTPs) as strategies to split and recycle test mass. Here, 'test mass' refers to (parts of) the nominal level alpha at which the family-wise error rate is controlled. Briefly, test mass is split between different null hypotheses, and whenever a null hypothesis is rejected, the part of alpha allocated to it may be recycled to the testing of other hypotheses. These recycling MTPs are closed testing procedures based on raw p-values associated with testing the individual null hypotheses, and the class of such MTPs includes, for example, serial and parallel gatekeeping, fallback and Holm procedures. Graphical displays and a concise algebraic notation are provided for such MTPs. This recycling approach has pedagogical advantages and may facilitate the tailoring of MTPs for different purposes.

Advances in 4D medical imaging and 4D radiation therapy.

This paper reviews recent advances in 4D medical imaging (4DMI) and 4D radiation therapy (4DRT), which study, characterize, and minimize patient motion during the processes of imaging and radiotherapy. Patient motion is inevitably present in these processes, producing artifacts and uncertainties in target (lesion) identification, delineation, and localization. 4DMI includes time-resolved volumetric CT, MRI, PET, PET/CT, SPECT, and US imaging. To enhance the performance of these volumetric imaging techniques, parallel multi-detector array has been employed for acquiring image projections and the volumetric image reconstruction has been advanced from the 2D to the 3D tomography paradigm. The time information required for motion characterization in 4D imaging can be obtained either prospectively or retrospectively using respiratory gating or motion tracking techniques. The former acquires snapshot projections for reconstructing a motion-free image. The latter acquires image projections continuously with an associated timestamp indicating respiratory phases using external surrogates and sorts these projections into bins that represent different respiratory phases prior to reconstructing the cyclical series of 3D images. These methodologies generally work for all imaging modalities with variations in detailed implementation. In 4D CT imaging, both multi-slice CT (MSCT) and cone-beam CT (CBCT) are applicable in 4D imaging. In 4D MR imaging, parallel imaging with multi-coil-detectors has made 4D volumetric MRI possible. In 4D PET and SPECT, rigid and non-rigid motions can be corrected with aid of rigid and deformable registration, respectively, without suffering from low statistics due to signal binning. In 4D PET/CT and SPECT/CT, a single set of 4D images can be utilized for motion-free image creation, intrinsic registration, and attenuation correction. In 4D US, volumetric ultrasonography can be employed to monitor fetal heart beating with relatively high temporal resolution. 4DRT aims to track and compensate for target motion during radiation treatment, minimizing normal tissue injury, especially critical structures adjacent to the target, and/or maximizing radiation dose to the target. 4DRT requires 4DMI, 4D radiation treatment planning (4D RTP), and 4D radiation treatment delivery (4D RTD). Many concepts in 4DRT are borrowed, adapted and extended from existing image-guided radiation therapy (IGRT) and adaptive radiation therapy (ART). The advantage of 4DRT is its promise of sparing additional normal tissue by synchronizing the radiation beam with the moving target in real-time. 4DRT can be implemented differently depending upon how the time information is incorporated and utilized. In an ideal situation, the motion adaptive approach guided by 4D imaging should be applied to both RTP and RTD. However, until new automatic planning and motion feedback tools are developed for 4DRT, clinical implementation of ideal 4DRT will meet with limited success. However, simplified forms of 4DRT have been implemented with minor modifications of existing planning and delivery systems. The most common approach is the use of gating techniques in both imaging and treatment, so that the planned and treated target localizations are identical. In 4D planning, the use of a single planning CT image, which is representative of the statistical respiratory mean, seems preferable. In 4D delivery, on-site CBCT imaging or 3D US localization imaging for patient setup and internal fiducial markers for target motion tracking can significantly reduce the uncertainty in treatment delivery, providing improved normal tissue sparing. Most of the work on 4DRT can be regarded as a proof-of-principle and 4DRT is still in its early stage of development.

Use of EPID for leaf position accuracy QA of dynamic multi-leaf collimator (DMLC) treatment.

We describe in this paper an alternative method for routine dynamic multi-leaf collimator (DMLC) quality assurance (QA) using an electronic portal imaging device (EPID). Currently, this QA is done at our institution by filming an intensity-modulated radiotherapy (IMRT) test field producing a pattern of five 1-mm bands 2 cm apart and performing a visual spot-check for leaf alignment, motion lags, sticking and any other mechanical problems. In this study, we used an amorphous silicon aS500 EPID and films contemporaneously for the DMLC QA to test the practicality and efficacy of EPID vis-à-vis film. The EPID image was transformed to an integrated dose map by first converting the reading to dose using a calibration curve, and then multiplying by the number of averaged frames. The EPID dose map was then back-projected to the central axis plane and was compared to the film measurements which were scanned and converted to dose using a film dosimetry system. We determined the full-width half-maximum (FWHM) of each band for both images, and evaluated the dose to the valley between two peaks. We also simulated mechanical problems by increasing the band gap to 1.5 mm for some leaf pairs. Our results show that EPID is as good as the film in resolving the band pattern of the IMRT test field. Although the resolution of the EPID is lower than that of the film (0.78 mm/pixel vs 0.36 mm/pixel for the film), it is high enough to faithfully reproduce the band pattern without significant distortion. The FWHM of the EPID is 2.84 mm, slightly higher than the 2.01 mm for the film. The lowest dose to the valley is significantly lower for the EPID (15.5% of the peak value) than for the film (28.6%), indicating that EPID is less energy independent. The simulated leaf problem can be spotted by visual inspection of both images; however, it is more difficult for the film without being scanned and contrast-enhanced. EPID images have the advantage of being already digital and their analysis can easily be automated to flag leaf pairs outside tolerance limits of set parameters such as FWHM, peak dose values, peak location, and distance between peaks. This automation is a new feature that will help preempt MLC motion interlocks and decrease machine downtime during actual IMRT treatment. We conclude that since EPID images can be acquired, analyzed and stored much more conveniently than film, EPID is a good alternative to film for routine DMLC QA.

Impact of Helicobacter pylori eradication on heartburn in patients with gastric or duodenal ulcer disease -- results from a randomized trial programme.

BACKGROUND: Helicobacter pylori infection has been proposed as a protective factor against the development of gastro-oesophageal reflux disease. AIM: To study heartburn and endoscopic findings before and after H. pylori eradication therapy in patients with peptic ulcer disease. METHODS: In a multicentre trial programme, patients (n = 1497) were randomized to the omeprazole triple therapy group or to the control group, and were followed for 1-6 months after treatment. Patients in whom the infection was eradicated were compared with those in whom infection persisted. The severity of heartburn was measured at baseline and at each return visit. Endoscopy was performed 6 months after therapy in two of the five studies. RESULTS: In patients with duodenal ulcer, there was a significantly lower prevalence of heartburn after successful eradication of H. pylori relative to that after failed eradication (estimated odds ratio, 0.48). The reduction in the prevalence of heartburn in patients with gastric ulcer was independent of the post-treatment H. pylori status. In studies in which ulcer relapse was included in the model, this factor emerged as a significant factor for heartburn. The observed incidence of oesophagitis at the last visit was not influenced by H. pylori status. CONCLUSIONS: Eradication of H. pylori in patients with peptic ulcer disease was associated with a reduced prevalence of heartburn. Prevention of ulcer relapse could be the true cause of this reduction.

A parameter optimization algorithm for intensity-modulated radiotherapy prostate treatment planning.

An iterative algorithm has been developed to analytically determine patient specific input parameters for intensity-modulated radiotherapy prostate treatment planning. The algorithm starts with a generic set of inverse planning parameters that include dose and volume constraints for the target and surrounding critical structures. The overlap region between the target volume and the rectum is used to determine the optimized target volume coverage goal. Sequential iterations are performed to vary the numerous parameters individually or in sets while other parameters remain fixed. A coarse grid search is first used to avoid convergence on a local maximum. Linear interpolation is then used to define a region for a fine grid search. Selected parameters are also tested for possible improvements in target coverage. In several representative test cases investigated the coverage of the planning target volume improved with the use of the algorithm while still meeting the clinical acceptability criteria for critical structures. The algorithm avoids time-consuming random trial and error variations that are often associated with difficult cases and also eliminates lengthy user learning curves. The methodology described in this paper can be applied to any treatment planning system that requires the user to select the input optimization parameters.

The treatment of large extraskeletal chondrosarcoma of the leg: comparison of IMRT and conformal radiotherapy techniques.

Extraskeletal chondrosarcoma of the leg is a rare, malignant neoplasm with very few cases having been reported in the literature. In this study we investigate the possibility of using intensity modulated radiotherapy (IMRT) for this type of disease and demonstrate its advantages over conventional three-dimensional (3D) conformal treatment. A case was presented of a patient with extraskeletal chondrosarcoma of the lateral compartment of the leg in which the target volume was 50 cm in length and twisted around the surrounding bones. Both the 3D conformal plan and IMRT plan were designed using the Memorial Sloan-Kettering Cancer Center planning system. The IMRT plan produced a superior dose distribution to the patient as compared to the 3D conformal plan both in terms of dose conformity and homogeneity in the target volumes, and reduction of the maximum dose to the bone. The planning time of the IMRT plan was about 3-5 times shorter than that of the 3D conformal plan. It was demonstrated that the IMRT technique can be used not just for small tumors, but also for large and spiral-shaped tumors close to critical organs. The IMRT method requires less planning time, and provides better target coverage with more sparing of critical structures. When planning patients with multiple target volumes receiving different prescribed doses, the IMRT technique can more easily meet this requirement.

Pharmacologic considerations in the neonate with congenital heart disease.

Advances in knowledge about the developing cardiovascular system and compensatory physiologic changes that occur in infants with congenital heart disease have led to new approaches in the management of cardiac failure and arrhythmias. Information about the pharmacologic effects, pharmacokinetics, and pharmacodynamics of newer agents used in the management of congenital heart disease have led to more appropriate use of these medications to prolong survival and improve outcomes.

Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms.

PURPOSE AND OBJECTIVE: Late rectal bleeding is a potentially dose limiting complication of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. The frequency of late rectal bleeding has been shown to increase as the prescription dose rises above 70 Gy. The purpose of this study is to identify features of the cumulative dose-volume histogram (DVH) for the rectal wall that correlate with late rectal bleeding after 3D-CRT for prostate cancer. METHODS AND MATERIALS: Follow-up information on rectal bleeding is available for 261 and 315 patients treated using 3D-CRT at Memorial Sloan-Kettering Cancer Center for Stage T1c-T3 prostate cancer with minimum target doses of 70.2 and 75.6 Gy, respectively. All patients in this study were treated with a coplanar 6-field technique (2 lateral and 4 oblique fields). Patients were classified as having rectal bleeding if they bled (> or = Grade 2) before 30 months, and nonbleeding (< or = Grade 1) if they were without bleeding at 30 months, using the RTOG morbidity scale. Rectal bleeding was observed in 13 and 38 of the patients treated at 70.2 and 75.6 Gy, respectively. Treatment plans were analyzed for 39 nonbleeding and 13 bleeding patients receiving 70.2 Gy, and 83 nonbleeding and 36 bleeding patients receiving 75.6 Gy. Dose-volume histograms (DVHs) for the anatomic rectal wall were calculated. Average DVHs of the bleeding and nonbleeding patients were generated, and a permutation test was used to assess the significance of differences between them, for each dose group. The confounding effect of total rectal wall volume (V(RW)) was removed by calculating the average differences in DVHs between all combinations of bleeding and nonbleeding patients with similar V(RW)s. Finally, multivariate analysis using logistic regression was performed to test the significance of the DVH variables in the presence of anatomic, geometric, and medical variables previously found to correlate with rectal bleeding in a companion analysis of the same patients. RESULTS: The area under the average percent volume DVH for the rectal wall of patients with bleeding was significantly higher than those of patients without bleeding in both dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy). However, small V(RW)s were associated with rectal bleeding (p = 0.06, 70.2 Gy; p < 0.01, 75.6 Gy), resulting in an increase in average percent volumes exposed to all doses for patients with rectal bleeding. For patients with similar V(RW)s, rectal bleeding was significantly correlated with the volumes exposed to 46 Gy in both dose groups (p = 0.02, 70.2 Gy; p = 0.005, 75.6 Gy, tolerance in V(RW): 5 ccs). For the 75.6 Gy dose group, the percent volume receiving 77 Gy was significantly correlated with rectal bleeding (p < 0.005). Bivariate analysis using logistic regression, including V(RW) together with a single DVH variable, showed good agreement with the above analysis. Multivariate analysis revealed a borderline significant correlation of the percent volume receiving 71 Gy in the 70.2 Gy dose group. It also showed that the DVH variables were highly correlated with geometric and dosimetric variables previously found to correlate with rectal bleeding in multivariate analysis. CONCLUSION: Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.

Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer.

PURPOSE AND OBJECTIVE: Three-dimensional conformal radiotherapy (3D-CRT) is a mode of high-precision radiotherapy designed to increase the tumor dose and decrease the dose to normal tissues. This study reports the final results of the first two dose levels (70.2 Gy and 75.6 Gy) of a phase I dose-escalation study using 3D-CRT for the treatment of non-small cell lung cancer. PATIENTS AND METHODS: Fifty-two patients were treated with 3D-CRT without chemotherapy. The median age was 67 years (range, 39-82 years). The majority of patients had locally advanced cancer. Tumor was staged as I/II in 10%, IIIA in 40%, and IIIB in 50%. Radiation was delivered in daily fractions of 1.8 Gy, 5 days a week. A radiation dose level was considered complete when 10 patients received the intended dose without unacceptable acute morbidity. Toxicity was scored according to the Radiation Therapy Oncology Group grading scheme. RESULTS: Twenty patients were initially assigned to the 70.2-Gy level; 14 of them received the intended dose. Three patients experienced severe acute toxicity, two with grade 3 (requiring steroids or oxygen) and a third with grade 5 (fatal) acute radiation pneumonitis. Because of the grade 5 pulmonary toxicity, the protocol was modified, and only patients with a calculated risk of normal tissue complication of less than 25% were eligible for dose escalation. Patients who had a normal tissue complication probability (NTCP) of greater than 25% received a lower dose of radiation. An additional 18 patients were entered on the modified study; 11 of them received 70.2 Gy. One patient experienced grade 3 acute pneumonitis. Despite dose reduction in four patients because of an unacceptably high NTCP, two additional patients developed grade 3 pulmonary toxicity. Fourteen patients were accrued to the 75.6-Gy dose level, and 10 received the intended dose. One of the 10 patients experienced grade 3 pulmonary toxicity and one developed grade 3 esophageal toxicity. Three patients were treated to lower doses as a result of their calculated NTCP without toxicity, and one patient refused treatment. The 2-year local control, disease-free survival, and overall survival rates were 37%, 12%, and 24%, respectively. The median survival time was 11 months. DISCUSSION: Treatment to 70.2 Gy and 75.6 Gy using 3D-CRT was delivered with acceptable morbidity when NTCP constraints were observed. Local control was encouraging in these patients with locally advanced disease. Patients are currently being accrued to the 81-Gy level of the study.

The deep inspiration breath-hold technique in the treatment of inoperable non-small-cell lung cancer.

PURPOSE: Conventional radiotherapeutic techniques are associated with lung toxicity that limits the treatment dose. Motion of the tumor during treatment requires the use of large safety margins that affect the feasibility of treatment. To address the control of tumor motion and decrease the volume of normal lung irradiated, we investigated the use of three-dimensional conformal radiation therapy (3D-CRT) in conjunction with the deep inspiration breath-hold (DIBH) technique. METHODS AND MATERIALS: In the DIBH technique, the patient is initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100% vital capacity, and simulation, verification, and treatment take place during this phase of breath-holding. RESULTS: Seven patients have received a total of 164 treatment sessions and have tolerated the technique well. The estimated normal tissue complication probabilities decreased in all patients at their prescribed dose when compared to free breathing. The dose to which patients could be treated with DIBH increased on average from 69.4 Gy to 87.9 Gy, without increasing the risk of toxicity. CONCLUSIONS: The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of toxicity.

Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer.

PURPOSE: To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale. RESULTS: Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001). CONCLUSIONS: The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.

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).

The HOMER Study: the effect of increasing the dose of metronidazole when given with omeprazole and amoxicillin to cure Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori eradication with omeprazole, amoxycillin, and metronidazole is both effective and inexpensive. However, eradication rates with different dosages and dosing vary, and data on the impact of resistance are sparse. In this study, three different dosages of omeprazole, amoxycillin, and metronidazole were compared, and the influence of metronidazole resistance on eradication was assessed. METHODS: Patients (n = 394) with a positive H. pylori screening test result and endoscopy-proven duodenal ulcer in the past were enrolled into a multicenter study performed in four European countries and Canada. After baseline endoscopy, patients were randomly assigned to treatment for 1 week with either omeprazole, 20 mg twice daily, plus amoxycillin, 1,000 mg twice daily, plus metronidazole, 400 mg twice daily (low M); or omeprazole, 40 mg once daily, plus amoxycillin, 500 mg three times daily, plus metronidazole, 400 mg three times daily (medium M); or omeprazole, 20 mg twice daily, plus amoxycillin, 1,000 mg twice daily, plus metronidazole, 800 mg twice daily (high M). H. pylori status at entry was assessed by a 13C urea breath test and a culture. Eradication was defined as two negative 13C-urea breath test results 4 and 8 weeks after therapy. Susceptibility testing using the agar dilution method was performed at entry and in patients with persistent infection after therapy. RESULTS: The eradication rates, in terms of intention to treat (ITT) (population n = 379) (and 95% confidence interval [CI]) were as follows: low M 76% (68%, 84%), medium M 76% (68%, 84%), and high M 83% (75%, 89%). By per-protocol analysis (population n = 348), the corresponding eradication rates were: low M 81%, medium M 80%, and high M 85%. No H. pylori strains were found to be resistant to amoxycillin. Prestudy resistance of H. pylori strains to metronidazole was found in 72 of 348 (21%) of the cultures at entry (range, 10%-39% in the five countries). The overall eradication rate in prestudy metronidazole-susceptible strains was 232 of 266 (87%) and, for resistant strains, it was 41 of 70 (57%; p <.001). Within each group, the results were as follows (susceptible/resistant): low M, 85%/54%; medium M, 86%/50%; and high M, 90%/75%. There were no statistically significant differences among the treatment groups. 23 strains susceptible to metronidazole before treatment were recultured after therapy failed; 20 of these had now developed resistance. CONCLUSIONS: H. pylori eradication rates were similar (approximately 80%) with all three regimens. Metronidazole resistance reduced efficacy; increasing the dose of metronidazole appeared not to overcome the problem or significantly improve the outcome. Treatment failure was generally associated with either prestudy or acquired metronidazole resistance. These findings are of importance when attempting H. pylori eradication in communities with high levels of metronidazole resistance.