Neutrophil to lymphocyte ratio associated with prognosis of lung cancer

Purpose. Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. Methods. In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. Results. Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). Conclusions. Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial (AU)

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Neutrophil to lymphocyte ratio associated with prognosis of lung cancer.

PURPOSE: Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. METHODS: In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. RESULTS: Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). CONCLUSIONS: Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial.

Implementation and experimental results of 4D tumor tracking using robotic couch.

PURPOSE: This study presents the implementation and experimental results of a novel technique for 4D tumor tracking using a commercially available and commonly used treatment couch and evaluates the tumor tracking accuracy in clinical settings. METHODS: Commercially available couch is capable of positioning the patient accurately; however, currently there is no provision for compensating physiological movement using the treatment couch in real-time. In this paper, a real-time couch tracking control technique is presented together with experimental results in tumor motion compensation in four dimensions (superior-inferior, lateral, anterior-posterior, and time). To implement real-time couch motion for tracking, a novel control system for the treatment couch was developed. The primary functional requirements for this novel technique were: (a) the treatment couch should maintain all previous∕normal features for patient setup and positioning, (b) the new control system should be used as a parallel system when tumor tracking would be deployed, and (c) tracking could be performed in a single direction and∕or concurrently in all three directions of the couch motion (longitudinal, lateral, and vertical). To the authors' best knowledge, the implementation of such technique to a regular treatment couch for tumor tracking has not been reported so far. To evaluate the performance of the tracking couch, we investigated the mechanical characteristics of the system such as system positioning resolution, repeatability, accuracy, and tracking performance. Performance of the tracking system was evaluated using dosimetric test as an endpoint. To investigate the accuracy of real-time tracking in the clinical setting, the existing clinical treatment couch was replaced with our experimental couch and the linear accelerator was used to deliver 3D conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) treatment plans with and without tracking. The results of radiation dose distribution from these two sets of experiments were compared and presented here. RESULTS: The mechanical accuracies were 0.12, 0.14, and 0.18 mm in X, Y, and Z directions. The repeatability of the desired motion was within ±0.2 mm. The differences of central axis dose between the 3D-CRT stationary plan and two tracking plans with different motion trajectories were 0.21% and 1.19%. The absolute dose differences of both 3D tracking plans comparing to the stationary plan were 1.09% and 1.20%. Comparing the stationary IMRT plan with the tracking IMRT plan, it was observed that the central axis dose difference was -0.87% and the absolute difference of both IMRT plans was 0.55%. CONCLUSIONS: The experimental results revealed that the treatment couch could be successfully used for real-time tumor tracking with a high level of accuracy. It was demonstrated that 4D tumor tracking was feasible using existing couch with implementation of appropriate tracking methodology and with modifications in the control system.

SU-E-J-04: Initial Experience with 4D-CBCT for Lung Cancer: Physician Verification of Computed Shifts Remains Necessary.

PURPOSE: Four-dimensional cone-beam CT (4D-CBCT) is a novel imaging technique used to guide treatment setup for patients with pulmonary lesions by providing additional information about tumor motion at the time of treatment. This study aimed to evaluate the efficacy of the 4D-CBCT capability in ensuring accurate patient setup during SBRT. METHODS: Twelve patients with pulmonary lesions were imaged pre-treatment with Elekta XVI4.5 using the Symmetry protocol resulting in a respiratory correlated 4D-CBCT. Reconstruction produced 10 phased-based and one average 3DCT image set. Patient shifts were derived from contour-based(mask) registration driven by the weighted average of shifts from each phased CT(4D shifts). Physicians reviewed registration and manually adjusted shifts based on visual registration. We exported the average 3DCT to MIM Vista Software 5.1.1 in reference volume coordinates and manually fused to the reference CT. All manual fusions were contour-based registrations performed by a single observer. No rotations were permitted in manual fusion to mimic clinical procedure. Translational 3D shifts from manual fusion were compared to 4D(automatic registration) shifts and final physician-corrected shifts. RESULTS: Mean differences between 4D and 3D shifts in lateral, longitudinal, and vertical directions were 1.07mm, 5.92mm, and 1.43mm, respectively. Mean differences between physician-corrected and 3D shifts were 1.41mm, 4.83mm, and 1.61mm. Differences between 4D shifts and 3D shifts increased with increasing tumor motion. One patient had consistently large longitudinal differences between 4D and 3D shifts (mean=3.0cm). Further review revealed poor 4D registration(via mask and clipbox) on the XVI system which was corrected by physician adjustment prior to treatment. CONCLUSIONS: 4D-CBCT is a valuable imaging tool in patient setup. Physician review of contour-based registration is imperative in preventing a geometrical miss. Caution must be employed in tumors that exhibit a large degree of motion. Further research is necessary in determining functional limits of the 4D-CBCT system.

SU-E-J-12: Initial Clinical Experiences in Using 4D-CBCT as Image Guidance for Lung SBRT.

PURPOSE: The authors started to use Symmetry 4D-CBCT as image guidance for lung SBRT in August 2011. Here the authors present the initial clinical experiences with this novel image guidance technique. METHODS: In total 118 4D-CBCT scans have been acquired for 17 lung patients among which 15 received SBRT and the other 2 received hypofractionated treatments. 4D-CBCT scans are acquired with Elekta XVI 4.5 usingSymmetry, a procedure module in XVI that acquires 4D-CBCT, registers daily images to reference 3D-CT and generates shifts for patient setup. RESULTS: Typical thoracic 4D-CBCT scans with Symmetry take 3 minutes with a 200 degree gantry rotation. Symmetry automatically sorts images into 10 phases based on automatic detection of diaphragm position. Then Symmetry generates two independent intensity-based registrations, one according to a pre-defined large volume of interest including the tumor, surrounding tissues and bony structures, the other only according to an expanded target volume. The registrations are obtained by registering each phase image to the reference image and averaging across all phases in a time-weighted manner. Eventually Symmetry provides users the freedom to pick either one of the two registrations, a compromise, or a manual tuning. Compared to regular 3D-CBCT, 4D-CBCT enables physicians to visually place the moving target in the center of PTV, greatly reducing the probability of missing target due to respiratory motion, thus enables possible reduction in PTV margin. 4D-CBCT also provides the ability to repeatedly evaluate the quality of ITV. It is possible that ITV does not fully cover the tumor motion due to a low quality 4D-CT simulation for a patient with difficulties in regular breathing. CONCLUSIONS: 4D-CBCT is a superior image guidance technique for lung SBRT treatments for its ability to visualize moving target. It provides physicians more confidence in tumor targeting and ability to repeatedly evaluate ITV quality during the treatment course.

Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution.

BACKGROUND: Stereotactic radiosurgery (SRS) and, more recently, fractionated stereotactic radiotherapy (SRT) have been recognized as noninvasive alternatives to surgery for the treatment of acoustic schwannomas. We review our experience of acoustic tumor treatments at one institution using a gamma knife for SRS and the first commercial world installation of a dedicated linac for SRT. METHODS: Patients were treated with SRS on the gamma knife or SRT on the linac from October 1994 through August 2000. Gamma knife technique involved a fixed-frame multiple shot/high conformality single treatment, whereas linac technique involved daily conventional fraction treatments involving a relocatable frame, fewer isocenters, and high conformality established by noncoplanar arc beam shaping and differential beam weighting. RESULTS: Sixty-nine patients were treated on the gamma knife, and 56 patients were treated on the linac, with 1 NF-2 patient common to both units. Three patients were lost to follow-up, and in the remaining 122 patients, mean follow-up was 119 +/- 67 weeks for SRS patients and 115 +/- 96 weeks for SRT patients. Tumor control rates were high (> or =97%) for sporadic tumors in both groups but lower for NF-2 tumors in the SRT group. Cranial nerve morbidities were comparably low in both groups, with the exception of functional hearing preservation, which was 2.5-fold higher in patients who received conventional fraction SRT. CONCLUSION: SRS and SRT represent comparable noninvasive treatments for acoustic schwannomas in both sporadic and NF-2 patient groups. At 1-year follow-up, a significantly higher rate of serviceable hearing preservation was achieved in SRT sporadic tumor patients and may therefore be preferable to alternatives including surgery, SRS, or possibly observation in patients with serviceable hearing.

Assessment of lung cancer response after nonoperative therapy: tumor diameter, bidimensional product, and volume. A serial CT scan-based study.

PURPOSE: Tumor response after nonoperative lung cancer therapy is traditionally evaluated by bidimensional measurement of maximum tumor diameters. The purpose of this analysis is to investigate whether tumor largest dimension (based on RECIST [Response Evaluation Criteria In Solid Tumors]), bidimensional tumor product, and volume correlate with each other in evaluating tumors of patients with locally advanced non-small-cell lung cancer (NSCLC). In addition, the pace of locally advanced NSCLC volumetric response over time, as well as the prognostic value of tumor size, was assessed in this report with software-assisted evaluation of sequential tumor measurement. METHODS AND MATERIALS: Patients with locally advanced NSCLC treated with thoracic radiotherapy (RT) with or without chemotherapy were included, if the following were available: a pretreatment computed tomography (CT) simulation and at least two follow-up diagnostic thoracic CT scans taken at our institution after 1996 that were available in Dicom format for electronic transfer of images from diagnostic radiology to a computer terminal with commercial statistics software (AcQsim/CMS Focus). Primary lung tumor and grossly involved lymph nodes were contoured manually on pre-RT axial images and on all follow-up CT scans. Tumor/lymph node largest dimensions, bidimensional products (BP), and volumes were measured using the same software. Data were presented as percent change in volume or unidimensional and bidimensional measurements, with the CT simulation measurements serving as baseline. RESULTS: A total of 22 patients were evaluated. The median thoracic RT dose was 62.4 Gy (range: 50.0-69.6), and all patients had a Karnofsky performance status > or =80. Chemotherapy (mostly carboplatin/paclitaxel) was given to 17 patients. Nineteen patients had Stage III NSCLC; 1 patient was in Stage I, 1 was in Stage IV, and 1 was recurrent. A total of 107 thoracic CT scans (22 pretreatment and 85 follow-up), averaging 4.9 scans per patient, were analyzed. Tumors reached the smallest volume at a median of 11.0 months from RT completion in all patients, 8.5 months in patients who subsequently failed locally (n = 8), and 11.9 months in those who did not fail locally. Failure rates were as follows: in-field, 36% (8/22); intrathoracic (lung nodules, effusion, pleura), 55% (12/22); and distant, 50% (11/22). Eleven patients are still alive, 4 free of disease. Overall median survival time (MST) is 27.3 months. The median initial tumor volume was 88.0 cc (range: 3.8-218) for all patients; median BP was 33.0 cm(2) (range: 3.1-112.1), and median tumor largest dimension was 7.6 cm (range: 2.2-13.5). The MST of patients with initial tumor volume < or =63.0 cc (n = 9) was >53.0 months and of those with tumor volume > 63.0 cc was 17.3 months. The MST of patients (n = 6) with initial bidimensional tumor product < or =16 cm(2) was >53.0 months and of those with tumor product >16 cm(2) was 17.3 months. The MST of patients with largest initial dimension < or =4 cm was >53.1 months and of those with largest dimension > 4 cm was 25.0 months. At 24 months, 79% of patients with a tumor volume < or =124.0 cc (n = 18) had locally controlled tumors, vs. 0% of patients with tumor volumes >124.0 cc. At the same time point, 93% of patients with BP < or =40 cm(2) were locally controlled, vs. 0% of those with BP > 40 cm(2); 100% of patients with tumor dimensions < or =7.5 cm were locally controlled, vs. 40% of those with dimensions >7.5 cm. The partial responses in our series (assessed as the best response obtained during observation period) were as follows: 4 patients assessed based on either dimension only, product only, or volume only; 15 partial responses based on dimension or product; 16 partial responses based on volume alone; 3 cases of no tumor response, based on dimension or product; and 2 cases based on tumor volume alone. That represents good to excellent agreement among all three methods of measurement. CONCLUSIONS: (1) The response of locally advanced NSCLC to nonoperative therapy is a slow process, with tumor volumes reaching their nadir several months after treatment. (2) Smaller initial tumor size, as measured by largest tumor dimension, bidimensional product, or tumor volume, is associated with better local control and survival than larger initial measurements. (3) Any of the three tumor measurements (largest dimension, bidimensional product, or volume) can be used as a reliable tool in assessing lung cancer response to nonoperative therapy. This confirms further the validity of RECIST and does not suggest that tumor volume is significantly superior for response evaluation.

Preliminary report on reduction of esophagitis by amifostine in patients with non-small-cell lung cancer treated with chemoradiotherapy.

Esophagitis is a major toxicity of chemoradiotherapy for lung cancer. Twenty-four patients with non-small-cell lung cancer received induction chemotherapy (paclitaxel/carboplatin) followed by concurrent thoracic irradiation (RT) and weekly paclitaxel. Acute esophagitis was scored weekly. Since a high rate of grade 3 esophagitis was noted in the initial group of 12 patients, amifostine (AMI) 500 mg intravenously twice weekly was added to the regimen in the subsequent 12 patients. Esophagitis Index (EI) was calculated as an area under the curve reflecting esophagitis grade over time. Median number of AMI doses was 12 per patient. AMI was well tolerated. Two patients were not evaluable for esophagitis. The incidence of grade 3 esophagitis was 18% in the initial 11 patients versus 9% in the AMI-treated patients (P = not significant). Mean EI was numerically lower in the AMI-treated patients than in the initial group (5.1 vs. 11.6, P = 0.14). The product of RT dose and length of esophagus in the RT field was larger in the AMI group (934 vs. 761, P = 0.035). Median survival time for all patients was 12.4 months. Esophagitis Index, a novel measure of the severity and duration of acute esophagitis, may be reduced in lung cancer patients receiving twice-weekly AMI with thoracic RT and paclitaxel. Twice weekly AMI did not eliminate grade 3 esophagitis; therefore, dose escalation of AMI is planned. The effect of AMI was not due to the shorter irradiated esophageal length. A phase III randomized trial is now open to assess AMI's effect on esophagitis.

Clinical applications of radioprotectors.

Patients with malignant or benign tumors who receive radiation therapy--frequently in combination with chemotherapy--are likely to experience side effects, either acutely or chronically. After several decades of preclinical and clinical research efforts, a first approved radioprotective drug, amifostine, has been introduced into the clinic. Although thus far it has been demonstrated to be effective only for the prevention of dry mouth following radiotherapy, it has the potential to be applied in many other oncologic situations.

Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): identification of five groups with different survival.

PURPOSE: Survival of patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) is predicted by the stage of the disease and other characteristics. This analysis was undertaken to identify these characteristics in a large cooperative group patient population, as well as to define subgroups of the population with differing outcomes. PATIENTS AND METHODS: Analysis included 1,999 patients treated in 9 RTOG trials between 1983 and 1994 with thoracic irradiation (RT) with (n = 355) or without chemotherapy (CT). RESULTS: In univariate analysis, the following characteristics were significantly associated with an improved survival: use of CT, CT delivered without major deviation, abnormal pulmonary function tests, normal hemoglobin, protein, LDH and BUN, presence of dyspnea, hemoptysis, cough or hoarseness, uninvolved lymph nodes, T1 or T2 stage, no malignant pleural effusion (PE), weight loss of < 8%, Karnofsky performance status (KPS) of at least 90, adenocarcinoma histology, female gender, and age less than 70 years. Recursive partitioning analysis (RPA) was subsequently applied to identify 5 patient subgroups with significantly different median survival times (MST): Group I, KPS of > or = 90, who received chemotherapy (MST 16.2 months); Group II, KPS of > or = 90, who received no CT, but had no PE (MST 11.9 months); Group III, KPS < 90, younger than 70 years, with non-large cell histology (MST 9.6 months); Group IV, KPS > or = 90, but with PE, or KPS < 90, younger than 70 years, and with large cell histology, or older than 70 years, but without PE (MST 5.6-6.4 months); Group V, older than 70, with PE (MST 2.9 months). CONCLUSION: Cisplatinum-based CT improves survival, for excellent prognosis of LA-NSCLC patients, over RT alone. The presence of a malignant pleural effusion is a major negative prognostic factor for survival. The identification of RPA prognostic groups among patients with LA-NSCLC provides prognostic information and may serve as a basis of stratification in future trials.

Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: a multivariate analysis of patients with lung cancer treated with nonoperative therapy.

PURPOSE: To identify in a multivariate analysis treatment-related factors predisposing patients (pts) with lung cancer to acute esophagitis, expressed as a severity grade or Esophagitis Index (EI). METHODS AND MATERIALS: Acute esophagitis is prospectively scored as an RTOG Grade in our institution during and after thoracic radiotherapy. Charts, toxicity forms and digitally reconstructed radiographs (DRRs) of all pts with lung cancer who received thoracic radiotherapy (RT) between 11/95 and 1/99 were reviewed. Esophagitis grades for each time point were verified by review of weekly physician and nursing treatment notes, hospital discharge summaries and referring physician notes and then plotted on graph against time. The area under the curve was calculated for each patient's graph and was defined as an Esophagitis Index. The length of esophagus was measured on each anterior DRR while assuming that esophagus overlies the vertebral bodies on the anterior films and projects over the edge of the vertebral body on the oblique DRRs. This assumption was confirmed in 10 pts by digitizing esophagus on CT simulator-derived slices and visualizing its position on DRRs. To compare RT doses delivered with different fractionation schemes to standard fractionated doses, the equivalent RT doses were calculated using the linear-quadratic formula and alpha/beta ratio of 10. Univariate and multivariate analyses of several factors potentially influencing the maximum esophagitis grade, as well as EI, were performed. RESULTS: A total of 277 pts were identified. Pts were included in the analysis (n = 105) if they fulfilled the following criteria: chart, toxicity form and DRRs were all available; parallel opposed fields (no multiple fields) were used for both the initial and off cord/cone down fields; and an equivalent dose of 45.0 Gy or more was delivered. Seventy-eight pts had Stage III; 32, Stage IV, and the remainder, Stages I, II, or recurrent lung cancer (85 non-small cell and 18, small cell). Seventy-four pts were treated with definitive intent. Chemotherapy was given concurrently with RT in 58 pts (in 7 pts, with twice daily, or b.i.d., RT) and as induction treatment, in 11. Only 2 pts required a treatment break of more than 1 week. Median total and equivalent RT doses, fraction size, and anterior esophageal length were as follows: 59.9 Gy, 59.9 Gy, 2.0 Gy, and 14 cm (range, 4.2-21). The following maximum grades of esophagitis were recorded: 1, in 54 pts; 2, in 17 pts; 3, in 13 pts, and 4, in 1 pt. The mean EI for all pts; pts treated with standard RT alone; induction chemotherapy and standard RT; concurrent chemotherapy and standard (QD) RT; and b.i.d. RT with concurrent chemotherapy, was 41. 5 (range, 0-317); 13.6; 24.5; 52.4; and 132.1, respectively (p < 0. 001). Three pts developed an esophageal stricture within 3 months beginning RT. In multivariate analysis, the following factors were significantly associated with increasing EI: concurrent chemotherapy with QD RT and concurrent chemotherapy with b.i.d. RT (p < 0.001, considered jointly). Both factors were also associated with increasing maximum esophagitis grade (p = 0.011). Esophageal length was not associated with increasing EI or esophagitis grade in either univariate or multivariate analyses. CONCLUSION: Concurrent chemotherapy and twice daily radiotherapy, especially if combined together, were associated with the highest acute maximum esophagitis grade and esophagitis index in pts with lung cancer. The duration of acute esophagitis was also longest in the concurrent chemotherapy/twice daily radiotherapy group. Esophagitis Index appeared to be a more sensitive measure of acute esophagitis than the maximum esophagitis grade. The increasing length of esophagus in the radiation field did not predict for the severity of acute esophagitis.

Standard off-cord lung oblique fields do not include the entire mediastinum: a computed tomography simulator study.

The routinely recommended target volume for off-cord lung oblique fields in the treatment of postoperative bronchogenic carcinoma includes the entire mediastinum, as defined by coverage of the contralateral mainstem bronchus and subcarinal space. However, this may be difficult to accomplish with the field angles of 20 degrees to 40 degrees, recommended in the recently completed Intergroup Trial (Radiation Therapy Oncology Group 91-05). This project was undertaken to define the oblique angle necessary to encompass the entire mediastinum as determined by computerized tomography simulator verification. Axial computerized tomography simulation images of 25 patients with non-small-cell lung cancer were used in this study. Ten patients had prior lobectomy or pneumonectomy as part of their management. The contralateral mainstem bronchus, subcarinal space (SS), and the spinal cord were each contoured as separate volumes. The length of the contralateral mainstem bronchus was defined as extending from the carina to the bifurcation of the lobar bronchi. The subcarinal space was defined as a triangular space (in a coronal plane) with the carina at the apex, the mainstem bronchi superiorly, and a horizontal line 5 cm below the carina as the base of the triangle. The minimal angle to encompass the contralateral mainstem bronchus and subcarinal space, and to exclude the spinal cord was determined for each patient. The contoured volumes did not have additional margin added. The position of the carina was scored as "midline" if located in the midsagittal plane, or "off-midline" if deviated to either side from midline. Midline deviation was determined at the level of the carina to evaluate possible anatomical distortion relating to the tumor or prior surgery, and its effect on the minimal angle was assessed. The median minimal angle measured was 45 degrees (range: 28-65 degrees) for the entire group, and in 64% of those evaluated, this oblique angle was significantly greater than the 40 degrees recommended in Radiation Therapy Oncology Group guidelines (p = 0.017). In patients without midline deviation (n = 17), the median minimal angle was 45 degrees (range: 28-60 degrees), and in patients with midline deviation (n = 8), it was determined to be 44 degrees (range: 27-65 degrees), with no statistical difference noted between the two groups (p = NS). Although midline deviation was present in 4 of 10 patients previously resected, the above relationship remained unchanged. Based on computerized tomography simulation verification, off-cord oblique field angles of 20 degrees to 40 degrees do not adequately cover the entire mediastinum in most patients. To adequately encompass the entire mediastinum as defined in the Intergroup Trial (Radiation Therapy Oncology Group 91-05) with off-cord oblique fields, treatment angles greater than 40 degrees are necessary. Whether the potential increase in lung volume exposed to radiation from these larger angles results in a poorer therapeutic ratio requires further investigation.

Thoracic reirradiation for symptomatic relief after prior radiotherapeutic management for lung cancer.

Limited information is available in the medical literature on thoracic reirradiation for patients with recurrent/persistent lung carcinoma or new primary lung tumors. Controversy exists regarding the retreatment because of concerns regarding the risk of radiation toxicity. The medical and radiotherapeutic records of more than 1,500 patients with lung cancer seen in the Department of Radiation Oncology at Thomas Jefferson University Hospital from 1982 through 1997 were searched. Twenty-three patients with history of previous thoracic radiation therapy underwent thoracic reirradiation for either biopsy-proven and/or radiographically evident tumor recurrence, metastasis, or second lung primary. Most patients were reirradiated because of progressive dyspnea, cough, thoracic pain, or hemoptysis. Each of these symptoms was evaluated separately with regard to the subjective response to reirradiation. The median follow-up time from completion of reirradiation to last correspondence with the patient and/or family was 3.2 months, with a range of 0 to 17.5 months. In six patients with hemoptysis, a decrease or resolution of this symptom was noted. Of five patients with thoracic pain attributed to carcinoma, four noted an improvement in pain after reirradiation. Of 15 patients with cough, 9 had an improvement in cough, and of 15 patients with dyspnea, 11 had an improvement. Thoracic reirradiation is an effective modality in patients with hemoptysis, thoracic pain, cough, and dyspnea attributed to a radiographically defined recurrence and/or progression of lung cancer.

Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme.

PURPOSE: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model. PATIENTS AND METHODS: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m(2). A second dose level, 260 mg/m(2), was opened, and 69 patients were entered. RESULTS: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m(2) dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m (2) dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m(2) were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m(2) were 16.2 months (class III), 10.3 months (class IV), 5. 1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m(2) dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level. CONCLUSION: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m(2) dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.

Combining stereotactic angiography and 3D time-of-flight magnetic resonance angiography in treatment planning for arteriovenous malformation radiosurgery.

PURPOSE: This study was initiated to evaluate the advantages of using three-dimensional time-of-flight magnetic resonance angiography (3D TOF MRA), as an adjuvant to conventional stereotactic angiography, in obtaining three-dimensional information about an arteriovenous malformation (AVM) nidus and in optimizing radiosurgical treatment plans. METHODS AND MATERIALS: Following angiography, contrast-enhanced MRI and MRA studies were obtained in 22 consecutive patients undergoing Gamma Knife radiosurgery for AVM. A treatment plan was designed, based on the angiograms and modified as necessary, using the information provided by MRA. The quantitative analysis involved calculation of the ratio of the treated volume to the MRA nidus volume (the tissue volume ratio [TVR]) for the initial and final treatment plans. RESULTS: In 12 cases (55%), the initial treatment plans were modified after including the MRA information in the treatment planning process. The mean TVR for the angiogram-based plans was 1.63 (range 1.17-2.17). The mean coverage of the MRA nidus by the angiogram-based plans was 93% (range 73-99%). The mean MRA nidus volume was 2.4 cc (range 0. 6-5.3 cc). The MRA-based modifications resulted in increased conformity with the mean TVR of 1.46 (range 1.20-1.74). These modifications were caused by MRA revealing irregular nidi and/or vascular components superimposed on the angiographic projections of the nidi. In a number of cases, the information from MRA was essential in defining the nidus when the projections of the angiographic outlines showed different superior and/or inferior extent of the nidus. In two cases, MRA revealed irregular nidi, correlating well with the angiograms and showed that the angiographically acceptable plans undertreated 27% of the MRA nidus in one case and 18% of the nidus in the other case. In the remaining 10 cases (45%), both MRI and MRA failed to detect the nidus due to surgical clip artifacts and the presence of embolizing glue. CONCLUSIONS: The 3D TOF MRA provided information on irregular AVM shape, which was not visualized by angiography alone, and it was superior to MRI for defining the AVM nidus. However, when imaging artifacts obscured the AVM nidus on MRI and MRA, angiography permitted detection of AVM. Utilizing MRA as a complementary imaging modality to angiography increased accuracy of the AVM radiosurgery and allowed for optimal dose planning.

Changes in the size and location of kidneys from the supine to standing positions and the implications for block placement during total body irradiation.

PURPOSE: The use of total body irradiation (TBI) as a conditioning regimen for bone marrow transplantation often calls for partial transmission kidney blocks. These blocks are frequently designed based on the location of the kidneys during the abdominal computerized tomography (CT) scan. At our institution, TBI patients are treated in the standing position. As the kidneys can shift with different patient positions, a study was undertaken to evaluate the magnitude of the changes in the size and location of the kidneys from the supine CT position to the upright treatment position. METHODS AND MATERIALS: Intravenous contrast was administered to 15 patients. The patients were initially positioned supine on a simulator table and then positioned upright immediately in front of the image intensifier. PA radiographs were obtained with the patients in both positions. Changes in the size of the kidneys and their location relative to the vertebral bodies were noted. RESULTS: In going from the supine to upright position, all the kidneys shifted inferiorly between 0.5 cm and 7.5 cm with an average of 3.6 cm. Most of the kidneys also shifted in the transverse dimension and incurred a change in width. The range of the transverse shift was from 0.9 cm in the lateral direction to 4.9 cm medially. The maximum width broadening was 1.2 cm and the maximum decrease in width was 1.8 cm. CONCLUSIONS: When compared to the supine position, patients in the upright position show a dramatic inferior shift of the kidneys with other obvious, but less predictable, changes. For TBI treatments delivered in the upright position, kidney blocks should not be designed on the basis of supine abdominal CT scans.

Future development of amifostine as a radioprotectant.

Animal data and clinical trials document the efficacy of amifostine (WR-2721, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) in decreasing the effects of radiation on normal tissues without decreasing the cytotoxic effects on malignant tumors. The selection of the optimal dose may depend on the intensity of the regimen to be administered as well as on the normal tissues to be protected. Also of important consideration is the question of how to sequence amifostine infusion. The optimal amifostine schedule during the course of the combined-modality treatment may require shortening the duration of chemotherapy infusion or giving amifostine in two split doses (before and after chemotherapy). Wide application of amifostine in once-daily/multiple-daily fractionated radiotherapy regimens may be facilitated by the availability of other, nonintravenous delivery routes, which are being explored. Although efforts are currently directed at amifostine-mediated modification of acute or late mucosal reactions associated with radiation therapy, there are many other radiation-induced toxicities. Further randomized studies are necessary to document the effects of amifostine on nonmucosal damage. Amifostine has the potential to protect a broad range of normal tissues from the toxicities of radiation and from certain forms of chemotherapy.

A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma.

PURPOSE: A phase I dose escalation of hypofractionated stereotactic radiotherapy (H-SRT) in recurrent or persistent malignant gliomas as a means of increasing the biologically effective dose and decreasing the high rate of reoperation due to toxicity associated with single-fraction stereotactic radiosurgery (SRS) and brachytherapy. MATERIALS AND METHODS: From November 1994 to September 1996, 25 lesions in 20 patients with clinical and/or imaging evidence of malignant glioma persistence or recurrence received salvage H-SRT. Nineteen patients at the time of initial diagnosis had glioblastoma multiforme (GBM) and one patient had an anaplastic astrocytoma. All of these patients with tumor persistence or recurrence had received initial fractionated radiation therapy (RT) with a mean and median dose of 60 Gy (44.0-72.0 Gy). The median time from completion of initial RT to H-SRT was 3.1 months (0.7-45.5 months). Salvage H-SRT was delivered using daily 3.0-3.5 Gy fractions (fxs). Three different total dose levels were sequentially evaluated: 24.0 Gy/3.0 Gy fxs (five lesions), 30.0 Gy/3.0 Gy fxs (10 lesions), and 35.0 Gy/3.5 Gy fxs (nine lesions). Median treated tumor volume measured 12.66 cc (0.89-47.5 cc). The median ratio of prescription volume to tumor volume was 2.8 (1.4-5.0). Toxicity was judged by RTOG criteria. Response was determined by clinical neurologic improvement, a decrease in steroid dose without clinical deterioration, and/or radiologic imaging. RESULTS: No grade 3 toxicities were observed and no reoperation due to toxicity was required. At the time of analysis, 13 of 20 patients had died. The median survival time from the completion of H-SRT is 10.5 months with a 1-year survival rate of 20%. Neurological improvement was found in 45% of patients. Decreased steroid requirements occurred in 60% of patients. Minor imaging response was noted in 22% of patients. Using Fisher's exact test, response of any kind correlated strongly to total dose (p = 0.0056). None of six lesions treated with 21 Gy or 24 Gy responded, whereas there was a 79% response rate among the 19 lesions treated with 30 or 35 Gy. Tumor volumes < or =20 cc were associated with a higher likelihood of response (p = 0.053). CONCLUSIONS: H-SRT used in this cohort of previously irradiated patients with malignant glioma was not associated with the need for reoperation due to toxicity or grade 3 toxicity. This low toxicity profile and encouraging H-SRT dose-related response outcome justifies further evaluation and dose escalation.

Immediate side effects of stereotactic radiotherapy and radiosurgery.

PURPOSE: Despite increased utilization of fractionated stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS), the incidence and nature of immediate side effects (ISE) associated with these treatment techniques are not well defined. We report immediate side effects from a series of 78 patients. MATERIALS AND METHODS: Intracranial lesions in 78 adult patients were treated with SRT or SRS, using a dedicated linear accelerator. Those lesions included 13 gliomas, 2 ependymomas, 19 metastatic tumors, 15 meningiomas, 12 acoustic neuromas, 4 pituitary adenomas, 1 optic neuroma, 1 chondrosarcoma, and 11 arteriovenous malformations (AVM). SRT was used in 51 and SRS in 27 patients. Mean target volume was 9.0 cc. Eleven patients received prior external-beam radiation therapy within 2 months before SRT/SRS. Any side effects occurring during and up to 2 weeks after the course of radiation were defined as ISE and were graded as mild, moderate, or severe. The incidence of ISE and the significance of their association with several treatment and pretreatment variables were analyzed. RESULTS: Overall, 28 (35%) of 78 patients experienced one or more ISE. Most of the ISE (87%) were mild, and consisted of nausea (in 5), dizziness/vertigo (in 5), seizures (in 6), and new persistent headaches (in 17). Two episodes of worsening neurological deficit and 2 of orbital pain were graded as moderate. Two patients experienced severe ISE, requiring hospitalization (1 seizure and 1 worsening neurological deficit). ISE in 6 cases prompted computerized tomography of the brain, which revealed increased perilesional edema in 3 cases. The incidence of ISE by diagnosis was as follows: 46% (6 of 13) for gliomas, 50% (6 of 12) for acoustic neuromas, 36% (4 of 11) for AVM, 33% (5 of 15) for meningiomas, and 21% (4 of 19) for metastases. A higher incidence of dizziness/vertigo (4 of 12 = 33%) was seen among acoustic neuroma patients than among other patients (p< 0.01). There was no significant association of dizziness/vertigo with either a higher average and maximum brainstem dose (p = 0.74 and 0.09, respectively) or with 2-Gy equivalents of the average and maximum brainstem doses (p = 0.28 and 0.09, respectively). Higher RT dose to the margin and higher maximum RT dose were associated with a higher incidence of ISE (p = 0.05 and 0.01, respectively). However, when RT dose to the margin was converted to a 2-Gy dose-equivalent, it lost its significance as predictor of ISE (p = 0.51). Recent conventional external-beam radiation therapy, target volume, number of isocenters, collimator size, dose inhomogeneity, prescription isodose, pretreatment edema, dose of prior radiation, fraction size (2.0-7.0 Gy with SRT and 13.0-21.0 Gy with SRS), fractionation schedule, and dose to brainstem were not significantly associated with ISE. ISE occurred in 26% (8) of 31 patients taking corticosteroids prior to SRT/SRS and in 20 (42%) of 47 patients not taking them (p = 0.15). CONCLUSION: ISE occur in one third of patients treated with SRT and SRS and are usually mild or moderate and self-limited. Dizziness/vertigo are common and unique for patients with acoustic neuromas and are not associated with higher brainstem doses. We are unable to detect a relationship between ISE and higher margin or maximum RT doses. No specific conclusion can be drawn with regard to the effect of corticosteroids, used prior to SRS/SRT, on the occurrence of ISE.