Patterns of missing mini mental status exam (MMSE) in radiation therapy oncology group (RTOG) brain cancer trials.

The Mini Mental Status Exam (MMSE) instrument has been commonly used in the Radiation Therapy Oncology Group (RTOG) to assess mental status in brain cancer patients. Evaluating patient factors in relation to patterns of incomplete MMSE assessments can provide insight into predictors of missingness and optimal MMSE collection schedules in brain cancer clinical trials. This study examined eight RTOG brain cancer trials with ten treatment arms and 1,957 eligible patients. Patient data compliance patterns were categorized as: (1) evaluated at all time points (Complete), (2) not evaluated from a given time point or any subsequent time points but evaluated at all the previous time points (Monotone drop-out), (3) not evaluated at any time point (All missing), and (4) all other patterns (Mixed). Patient characteristics and reasons for missingness were summarized and compared among the missing pattern groups. Baseline MMSE scores and change scores after radiation therapy (RT) were compared between these groups, adjusting for differences in other characteristics. There were significant differences in frequency of missing patterns by age, treatment type, education, and Zubrod performance status (ZPS; P < 0.001). Ninety-two percent of patients were evaluated at least once: seven percent of patients were complete pattern, 49% were Monotone pattern, and 36% were mixed pattern. Patients who received RT only regimens were evaluated at a higher rate than patients who received RT + other treatments (49-64% vs. 27-45%). Institutional error and request to not be contacted were the most frequent known reasons for missing data, but most often, reasons for missing MMSE was unspecified. Differences in baseline mean MMSE scores by missing pattern (Complete, Monotone dropout, Mixed) were statistically significant (P < 0.001) but differences were small (<1.5 points) and significance did not persist after adjustment for age, ZPS, and other factors related to missingness. Post-RT change scores did not differ significantly by missing pattern. While baseline and change scores did not differ widely by missing pattern for available measurements, incomplete data was common and of unknown reason, and has potential to substantially bias conclusions. Higher compliance rates may be achievable by addressing institutional compliance with assessment schedules and patient refusal issues, and further exploration of how educational and health status barriers influence compliance with MMSE and other tools used in modern neurocognitive batteries.

Morphologic magnetic resonance imaging features of therapy-induced cerebral necrosis.

To describe the morphologic magnetic resonance imaging (MRI) findings in histologically proven therapy-induced cerebral necrosis. We retrospectively reviewed the morphologic MRI findings in patients with therapy-induced cerebral necrosis. Images were reviewed for size, location, and characteristics of signal intensity abnormalities and T1-contrast enhancement. Images were also assessed for mass effect, necrosis, cyst, atrophy, cortical thinning, and leukoencephalopathy. The individual imaging characteristics were correlated with clinical and treatment variables. There were 44 patients. Seventy percent had a glioma, all patients had received radiation, and 57% had received chemotherapy in close proximity to radiation. All images demonstrated contrast enhancement, predominantly in the white matter. Enhancement was present in the periventricular/subependymal region in 50% of cases and the corpus callosum in 27%. The most common pattern of lesion peripheral enhancement was "spreading wavefront" and of interior enhancement was "Swiss cheese/soap bubble." The enhancing lesion was single in 60% of cases. Mass effect was present in 93% of patients. Location and patterns of enhancement were significantly associated with the interval from brain radiation to the diagnosis of therapy-induced cerebral necrosis, tumor histology, patient age, type of radiation, and administration of systemic chemotherapy. This is the largest study of the morphologic conventional MRI findings in pathologically confirmed therapy-induced cerebral necrosis. We characterized the imaging findings in a variety of tumor types following a variety of radiation treatments and other antineoplastic therapy. These findings may be of value in identifying therapy-induced cerebral necrosis in patients treated for a brain tumor.

Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of radiation therapy oncology group trial 93-12.

PURPOSE: The combination of cisplatin, ifosfamide, and oral etoposide (PIEo) given concurrently with accelerated hyperfractionated thoracic radiation was studied in patients with limited small-cell lung cancer in a phase II trial to assess response, survival, and toxicity. PATIENTS AND METHODS: Sixty-seven patients were accrued between March 1994 and April 1996. Chemotherapy doses were cisplatin 20 mg/m(2) and ifosfamide 1,200 mg/m(2) on days 1 to 3 and etoposide 40 mg/m(2) administered orally days 1 through 14. Radiation consisted of accelerated hyperfractionated thoracic radiation (AHTRT) 1.5 Gy bid x 30 fractions (total 45 Gy) days 1 through 19, concurrent with cycle 1 of chemotherapy. Three additional cycles of chemotherapy were given every 4 weeks after completion of chemoradiation. Prophylactic cranial radiation (25 Gy in 10 fractions) was offered to patients for whom complete response (CR) after completion of chemotherapy was achieved. RESULTS: An overall objective response rate of 78% (41 CRs [67%] and seven partial responses [11%]) was seen in 61 patients whose disease response could be evaluated. Median progression-free and overall survival estimates were 12.7 and 23.7 months, respectively. Two- and 3-year survival rates were estimated at 50% and 39%, respectively. Major toxic effects included grade 4 granulocytopenia in 34 (55%), grade 4 thrombocytopenia in 16 (26%), grade 3 to 5 fever/infection in six (10%; with one death resulting from sepsis), and grade 3/4 esophagitis in 27 patients (43%). Other nonhematologic toxic greater than grade 2 occurred in 11 patients (18%). CONCLUSION: Relative to conventional etoposide/cisplatin and concurrent AHTRT, chemoradiation with PIEo produced similar median and 2-year survival rates and a higher rate of acute esophageal toxicity. However, the locoregional control rate with a minimum follow-up of 2 years is excellent at 80%. It is conceivable that longer follow-up will prove this regimen more promising. Research efforts should focus on other methods to improve disease control in all potential sites of recurrence.

Radiotherapy patterns of care study in lung carcinoma.

PURPOSE: For the first time, a lung Patterns of Care Study was conducted to determine the national patterns of radiation (RT) practice in patients treated for nonmetastatic lung cancer in 1998 to 1999. MATERIALS AND METHODS: A national survey of randomly selected RT institutions in the United States was conducted using two-stage cluster sampling, stratified by practice type. Patients with nonmetastatic lung cancer (Karnofsky performance score [KPS] > or = 60), who received RT as definitive or adjuvant therapy, were randomly selected. To determine national estimates, sample size was weighted by the relative number of institutions per strata and the number of patient records reviewed per the number of patients eligible. Accordingly, 42,335 patient records from 58 institutions were reviewed by trained research associates. The unweighted sample size (or number of patients) was 541. RESULTS: The histologies were small-cell lung cancer (SCLC) in 14.5% of patients versus non-small-cell lung cancer (NSCLC) in 85.5% of patients. The median age was 67 years (range, 29 to 92 years); 61% of patients were male, and 38% were current smokers. Bone scans and brain imaging were not obtained in 34% and 52% of clinical stage (CS) III NSCLC patients, respectively. Regarding treatment strategies, for SCLC and CS III NSCLC, chemotherapy plus RT was used significantly more than RT alone (P <.05); in CS I NSCLC, RT alone was the primary treatment (P <.05). Overall, 58% of patients received systemic therapy. On multivariate analysis, factors correlating with increased use of chemotherapy included younger age, histology (SCLC > NSCLC), increasing CS, increasing KPS, and lack of comorbidities. Only 3% of all patients were treated on prospective clinical trials. CONCLUSION: This study establishes the general patterns of care for lung carcinoma in RT facilities within the United States. As supported by clinical trials, patients with limited-stage SCLC and CS III NSCLC received chemotherapy plus RT more than they received RT alone. Further improvements in staging, smoking cessation, and increased accrual to clinical trials must be encouraged.

A method for repositioning of stereotactic brain patients with the aid of real-time CT image guidance.

This note presents a method that recalculates the coordinates of the isocentre for patients undergoing stereotactic radiotherapy to the brain with a relocatable head frame based on a pre-treatment CT scan. The method was evaluated by comparing initial stereotactic coordinates of the isocentre with the recalculated coordinates for eight single-fraction patients. These patients had the Brown-Roberts-Wells (BRW) frame fixed to the outer table of the skull, and therefore the coordinates of any anatomical point should be identical between the initial scan and the pre-treatment scan. The differences between the two sets of coordinates were attributed to errors in the method. The results showed that the systematic errors in the recalculated coordinates were less than 0.05 mm, and they were not statistically significant. The random errors (one standard deviation) were from 0.35 mm (lateral) to 0.58 mm (vertical). The average value of the combined 3D difference was 0.75 mm.

Induction paclitaxel and carboplatin followed by concurrent chemoradiotherapy in patients with unresectable, locally advanced non-small cell lung carcinoma: report of Fox Chase Cancer Center study 94-001.

The paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/carboplatin combination has demonstrated promising activity in patients with incurable non-small cell lung cancer (NSCLC). Our exploratory study is designed to evaluate the efficacy of this combination as induction therapy in patients with locally advanced NSCLC, to determine the maximally tolerated doses of paclitaxel and carboplatin administered every 3 weeks during radical thoracic radiation after induction treatment, and to determine the efficacy of granulocyte colony-stimulating factor (G-CSF) priming before induction treatment, followed by conventional G-CSF, compared with conventional G-CSF alone. Eligibility stipulated Karnofsky performance status > or =70%, < or =5% weight loss, and stages IIIB or bulky IIIA NSCLC. Induction treatment consisted of two cycles of paclitaxel 175 to 225 mg/m2 infused over 3 hours combined with carboplatin (target area under the concentration-time curve of 7.5) given on days 1 and 22. On days 2 through 15 and 23 through 36, all patients received G-CSF 5 microg/kg; half were randomized to receive priming G-CSF daily for 5 days before day 1 of treatment. On day 43, thoracic radiation (60 Gy in 30 2-Gy fractions daily, 5 days a week for 6 weeks) was initiated. At dose level 1, patients received carboplatin dosed to a target area under the concentration-time curve of 3.75 and paclitaxel 67.5 mg/m2 over 3 hours on days 43 and 64. In the absence of dose-limiting toxicity, phase I escalation in three-patient cohorts proceeded to a maximum carboplatin area under the concentration-time curve of 5.0 and a paclitaxel dose of 175 mg/m2, delivered over 3 hours. To date, 35 patients (83% stage IIIB) have received induction treatment, 29 of whom are evaluable for response. Myelosuppression and neurotoxicity have been mild during induction treatment, prompting a paclitaxel dose increase to 225 mg/m2 on days 1 and 22 after the first seven patients were accrued. The phase III portion of the study evaluating G-CSF priming remains coded. Sixteen patients have received concurrent thoracic radiation and chemotherapy and are evaluable for response and toxicity. In sequential cohorts, the paclitaxel dose on days 43 and 64 has been escalated to 175 mg/m2 with only one episode each of grade 4 granulocytopenia and grade 3 anemia. In the first 13 patients evaluated, the severity of esophagitis corresponded to the length of the esophagus in the radiation treatment field: grade 1 in all six patients with esophageal exposure < or =16 cm and grade > or =2 in six of seven patients with > or =16 cm of the esophagus irradiated. Three episodes of grade > or =2 steroid-responsive pulmonary toxicity have occurred 2 to 6 months after the conclusion of concurrent thoracic radiation and chemotherapy. The major response rate is 38% to induction treatment and 59% to combined-modality treatment. Of the first 21 patients accrued, 62% survived 1 year. Induction paclitaxel/carboplatin therapy is active and well tolerated by patients with locally advanced NSCLC. The maximum tolerated doses of paclitaxel and carboplatin during concurrent thoracic radiation and the role of G-CSF priming are not yet established. Severity of esophagitis corresponds to the extent of esophagus irradiated during concurrent thoracic radiotherapy and chemotherapy.

Long-term visual changes following pituitary irradiation.

PURPOSE: To analyze possible long-term effects of pituitary irradiation on visual fields and acuity. METHODS AND MATERIALS: Eighty-six patients were treated with radiotherapy for pituitary tumors at the National Cancer Institute between 1980 and 1991. Twenty-one patients had baseline preradiation and long-term follow-up visual fields. Eyes were followed with serial Goldmann or Humphrey visual field testing. Neuroradiologic correlation was made with the available brain scans. There were 12 females and 9 males with an median age of 44. Eighteen patients had hormone-secreting tumors and three had chromophobe adenomas. All but one patient with an inoperable invasive macroadenoma were irradiated after one or more transphenoidal resections or a craniotomy. The indications for radiation in the operable patients were: nine patients, partial tumor resection; nine patients, tumor recurrence; and two patients, persistent hormonal elevation after surgery. The median dose delivered was 50 Gy (45-59.4 Gy). The average field size was 6 x 6 cm (5 x 5 cm to 10 x 12.5 cm). RESULTS: With a median follow-up of 48 months (14-128) after radiotherapy, 1 out of 21 patients has recurred (at 8 months) and all patients are alive. Of the 38 sighted eyes, 27 had normal visual fields before and after radiation, 7 eyes showed improvement, and 4 eyes had a stable defect, mostly in the superior temporal region. There were no cases of radiation-induced visual field or acuity deterioration. Six out of 21 patients (29%) had neurologic symptoms in follow-up, most of which appeared vascular in nature. Four patients complained of atypical migranous-like headaches that first began 1.5-3 years following treatment. One patient complained of recurrent vertical diplopia and one patient had a cerebral vascular accident 7 years following therapy. A dose-related association with these neurovascular symptoms approached statistical significance. Only 1 out of 11 (9%) patients who received doses less than or equal to 50 Gy developed these symptoms, whereas 5 out of 10 (50%) patients who received doses greater than 50 Gy developed symptoms (p2 = 0.064). CONCLUSION: Postoperative radiation for partially resected or recurrent pituitary adenomas using megavoltage radiation, as well as modern field arrangements and fractionation, is extremely effective and safe. Ninety-five percent of patients are free of recurrence with not deterioration in the visual fields or acuities. Some patients experienced neurovascular symptoms (mostly vascular headaches) following surgery and radiation. There is a trend (p2 = 0.064) toward increased symptoms following higher radiation doses.

Prostate cancer patient subsets showing improved bNED control with adjuvant androgen deprivation.

PURPOSE: Cooperative groups have investigated the outcome of androgen deprivation therapy combined with radiation therapy in prostate cancer patients with variable pretreatment prognostic indicators. This report describes an objective means of selecting patients for adjuvant hormonal therapy by a retrospective matched case/control comparison of outcome between patients with specific pretreatment characteristics who receive adjuvant hormones (RT+H) vs. patients with identical pretreatment characteristics treated with radiation therapy alone (RT). In addition, this report shows the 5-year bNED control for patients selected by this method for RT+H vs. RT alone. METHODS AND MATERIALS: From 10/88 to 12/93, 517 T1-T3 NXM0 patients with known pretreatment PSA level were treated at Fox Chase Cancer Center. Four hundred fifty-nine of those patients were treated with RT alone while 58 were treated with RT+H. The patients were categorized according to putative prognostic factors indicative of bNED control, which include the palpation stage, Gleason score, and pretreatment PSA. We compared actuarial bNED control rates according to treatment group within each of the prognostic groups. In addition, we devised a retrospective matched case/control selection of RT patients for comparison with the RT+H group. Five-year bNED control was compared for the two treatment groups, excluding the best prognosis group, using 56 RT+H patients and 56 matched (by stage, grade, and pretreatment PSA level) controls randomly selected from the RT alone group. bNED control for the entire group of 517 patients was then analyzed multivariately using step-wise Cox regression to determine independent predictors of outcome. Covariates considered for entry into the model included stage (T1/T2AB vs. T2C/T3), grade (2-6 vs. 7-10), pretreatment PSA (0-15 vs. > 15), treatment (RT vs. RT+H), and center of prostate dose. bNED failure is defined as PSA > or = 1.5 ngm/ml and rising on two consecutive determinations. The median follow-up for the 112 matched case/control patients was 41 months. The median follow-up was 46 months for the RT (range 11-102 months) and 37 months for the RT+H group (range 6-82 months). RESULTS: Univariate analysis according to treatment for the prognostic factors of palpation stage, Gleason score, and pretreatment PSA demonstrates a significant improvement in 3-year bNED control with the addition of hormones for patients with T2C/T3, Gleason score 7-10, or pretreatment PSA > 15 ngm/ml. A comparison of bNED control according to treatment demonstrates improvement in 5-year bNED control of 55% for patients treated with RT+H vs. 31% for those patients treated with RT alone (p = 0.0088), although there is not a survival advantage. Multivariate analysis demonstrates that hormonal treatment is a highly significant independent predictor of bNED control (p = 0.0006) along with pretreatment PSA (p = 0.0001), palpation stage (p = 0.0001), grade (p = 0.0030), and dose (p = 0.0001). CONCLUSIONS: (1) Patients with specific adverse pretreatment prognostic factors (i.e., T2C/T3, Gleason score 7-10, pretreatment PSA > 15) benefit from adjuvant hormonal therapy. (2) Upon multivariate analysis, hormonal therapy is determined to be a highly significant predictor of bNED control, after adjusting for all other covariates. (3) The 5-year bNED control rates of 55% for RT+H vs. 31% for RT alone represents the magnitude of benefit from adjuvant hormone therapy. (4) The bNED control curves are separated by about 20 months, representing a delay in disease progression with adjuvant hormonal therapy, as there is no overall survival difference.

Is there an increased risk of second primaries following prostate irradiation?

PURPOSE: To assess the risk of developing a second primary cancer following prostate irradiation compared to the underlying risk in patients with prostate cancer. METHODS AND MATERIALS: The baseline rate of secondary cancers following prostate cancer was obtained from a study of 18,135 patients from the Connecticut Tumor Registry, of whom only 12.5% received radiotherapy. These patients, with a mean age of 72 and a mean follow-up of 3.9 years, were compared to a cohort of 543 patients (median age 70) with similar follow-up (median 3.9 years), all of whom were treated with definitive radiotherapy at Fox Chase Cancer Center. The possible association between various covariates (age, dose, palpation stage, field size, Gleason score, pretreatment PSA) and the development of a secondary cancer was assessed. RESULTS: 1,053 of 18,135 patients (5.8%) in the Connecticut Tumor Registry developed a second primary cancer compared with 31 of 543 (5.7%) patients treated with prostate radiation (p = 0.99). Although this risk increases gradually over time, it is not significantly different, at any time period, between the two groups of patients. Of the 31 secondary primaries in the irradiated group, 82% had a history of tobacco and/or alcohol use. Only melanomas were significantly increased compared to the expected rate in an age-matched population (p < 0.001). Five of the 31 secondary cancers occurred within the radiation field (four bladder, one colon), four within 3 years and only one occurred 9 years after radiotherapy. No association was found between age (<70 vs. > or =70 and as a continuous variable), dose (<74 vs. > or =74 Gy), palpation stage ( or =T2C), field size (prostate vs. pelvic), radiation technique (conventional vs. conformal), Gleason score (2-6 vs. 7-10), or pretreatment PSA (<15 vs. > or =15 and as a continuous variable) and the risk of developing a second primary. Although a lower radiation dose (as a continuous variable) correlated with an increased risk of developing a secondary cancer (p = 0.04), this phenomenon is likely due to differences in follow-up time. CONCLUSION: Up to at least 10 years, there is no increased risk of developing a second primary cancer following prostate irradiation compared to the baseline rate from prostate cancer itself. This risk is not higher in younger patients with localized disease (

Phase II radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme.

PURPOSE: Fractionated external beam radiotherapy (EBRT) +/- carmustine (BCNU) is the standard of care for patients with glioblastoma multiforme (GBM), but survival results remain poor. Preclinical studies indicate synergy between RT and paclitaxel (TAX) in astrocytoma cell lines. Phase I studies in GBM have demonstrated a maximum tolerated dose for TAX of 225 mg/m(2)/3 h/week x 6, during EBRT, with no exacerbation of typical RT-induced toxicities. The Radiation Therapy Oncology Group (RTOG) therefore mounted a Phase II study to determine the feasibility and efficacy of conventional EBRT and concurrent weekly TAX at its MTD. PATIENTS AND METHODS: Sixty-two patients with histologic diagnosis of GBM were enrolled from 8/16/96 through 3/21/97 in a multi-institutional Phase II trial of EBRT and TAX 225 mg/m(2)/3 h (1-3 h before EBRT), administered the first treatment day of each RT week. Total EBRT dose was 60 Gy (200 cGy/fraction), 5 days per week. A smaller treatment field, to include gross disease plus a margin only, was used after 46 Gy. RESULTS: Sixty-one patients (98%) were evaluable. Median age was 55 years (range, 28-78). Seventy-four percent were > or = 50 years. Recursive partitioning analysis (RPA) Classes III, IV, V, VI included 10 (17%), 21 (34%), 25 (41%), and 5 (8%) patients, respectively. Gross total resection was performed in only 16%. There was no Grade 3 or 4 neutropenia or thrombocytopenia. Hypersensitivity reactions precluding further use of TAX occurred in 4 patients. There were 2 instances of late neurotoxicity (4% Grade 3 or 4). Ninety-one percent of patients received treatment per protocol. Seventy-seven percent completed prescribed treatment (6 weeks). Of 35 patients with measurable disease, CR/PR was observed in 23%, MR in 17%, and SD in 43%. Seventeen percent demonstrated progression at first follow-up. Median potential follow-up time is 20 months. Median survival is 9.7 months, with median survivals for RPA classes III, IV, V, and VI of 16.3, 10.2, 9.5, 2.5 months, respectively. Ten patients remain alive. CONCLUSION: Concurrent full-dose EBRT and weekly high-dose TAX is feasible in the majority of GBM patients. Acute toxicity is acceptable; myelosuppression and peripheral sensory neuropathy are surprisingly modest, despite considerably higher overall dose intensity, compared to that achievable in other disease sites. Median survival by RPA class without prolonged adjuvant therapy is comparable to RTOG controls treated with standard EBRT and BCNU (1 year of BCNU).

Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-04.

PURPOSE: The standard treatment for patients with locally advanced inoperable non-small-cell lung cancer and good prognostic factors has become combined chemotherapy (ChT) and radiotherapy (RT). However, the sequencing of the two modalities, as well as fractionation of RT, has been controversial. The Radiation Therapy Oncology Group (RTOG) Study 92-04 was a randomized Phase II study designed to evaluate further the toxicity and efficacy of 2 different strategies of chemoradiation evaluated in 2 prior RTOG Phase II studies. METHODS: Patients with Stage II or III medically inoperable or unresectable non-small-cell lung cancer, good performance status, and minimal weight loss were enrolled into a prospective randomized Phase II RTOG study. Arm 1 consisted of induction ChT (vinblastine 5 mg/m(2) i.v. bolus weekly for the first 5 weeks, and cisplatin, 100 mg/m(2) i.v. on Days 1 and 29) followed by concurrent ChT/RT (cisplatin 75 mg/m(2) i.v. on Days 50, 71, and 92) during thoracic radiotherapy (63 Gy in 34 fractions during 7 weeks starting on Day 50). Arm 2 was concurrent ChT and hyperfractionated RT starting on Day 1 with a total dose of 69.6 Gy in 58 fractions during 6 weeks, 1.2 Gy/fraction b.i.d. ChT consisted of cisplatin, 50 mg/m(2) i.v. on Days 1 and 8, and oral VP-16, 50 mg b.i.d. for 10 days only on the days of thoracic radiotherapy repeated on Day 29. RESULTS: A total of 168 patients were entered between 1992 and 1994, and 163 patients were eligible for analysis. Eighty-one patients were treated in Arm 1 and 82 patients in Arm 2. Pretreatment characteristics, including age, gender, Karnofsky performance status, histologic features, and stage, were similar. The incidence of acute esophagitis was significantly higher among patients treated in Arm 2 than among those treated in Arm 1 (p <0.0001). The incidence of acute hematologic toxicity was significantly higher among patients treated in Arm 1 (p = 0.01 for anemia and p = 0.03 for other hematologic toxicities) than among those treated in Arm 2. Analysis of late toxicity showed that chronic esophageal toxicity was significantly more frequent in Arm 2 than in Arm 1 (p = 0.003). The time to in-field progression was significantly different (p = 0.009), favoring Arm 2 compared with Arm 1 (26% vs. 45% with failure in 2 years and 30% vs. 49% with failure in 4 years, respectively). The median 2-year and overall 5-year survival rates were similar between the two arms. CONCLUSION: Concurrent ChT and hyperfractionated RT resulted in a significant prolongation of the time to in-field progression, but with higher acute and chronic esophagitis. No other significant differences were observed between the two groups. Investigation with a chemoradio-protector is under way.

Efficacy of a belly board device with CT-simulation in reducing small bowel volume within pelvic irradiation fields.

PURPOSE/OBJECTIVE: Acute and chronic small bowel toxicity associated with pelvic irradiation limits dose escalation for both chemotherapy and radiotherapy for rectal cancer. Various surgical and technical maneuvers including compression and belly board devices (BBD) have been used to reduce small bowel volume in treatment fields. However, quantitative dose volume advantages of such methods have not been reported. In this study, the efficacy of BBD with CT-simulation is presented with dose-volume histogram (DVH) analyses for rectal cancer. METHODS AND MATERIALS: Twelve consecutive patients referred to our department with rectal cancer were included in this study. Patients were given oral contrast 1.5 h prior to scanning and instructed not to empty their bladder during the procedure. The initial CT scan without BBD was taken in the prone position with an immobilization cast. A second CT study was performed with a commercially available BBD consisting of an 18-cm thick hard sponge with an adjustable opening (maximum 42 x 42 cm2). All patients were positioned prone over the BBD so that the opening was above the treatment volume and usually extended from the diaphragm to the bottom of the fourth lumbar spine. Image fusion between both sets of CT scans (with and without BBD) was performed using common bony landmarks to maintain the same target volume. The critical structures including small bowel and bladder were delineated on each slice for DVH analysis. On each study, a three-field optimized plan with conformal blocks in beams-eye-view was generated for volumetric analysis. The DVHs with and without BBD were evaluated for each patient. RESULTS: The median age and body weight of 12 patients (4 females and 8 males) were 57.5 years and 82.7 kg, respectively. The changes in posterior-anterior (PA) and lateral separation with and without BBD at central axis slices were analyzed. The changes in lateral separation were minimal (<0.8 cm); however, the PA separation was reduced by 11.3 +/- 3.3% when BBD was used. The reduction in PA separation was directly related to the reduction in small bowel volume. The small bowel volume was significantly reduced with a median reduction of 70% (range 10-100%) compared to the small bowel volume without BBD. The small bowel volume reduction did not correlate either with body weight, age, gender, or sequence of radiation treatment with surgery (pre-op vs. post-op). The DVH analysis of small bowel with BBD showed significant volume reduction at each dose level. For 50% patients, the DVH analysis demonstrated an increase in bladder volume with BBD. All patients treated with the BBD completed their treatment without any break and without significant acute gastrointestinal or genitourinary toxicity. CONCLUSIONS: For rectal cancers, small bowel is the dose-limiting structure for acute and chronic toxicity. The use of the BBD should improve the tolerance of aggressive combined modality treatment by reducing the small bowel volume within the pelvis compared to the prone position alone. The BBD provides an easy, economical, comfortable, and noninvasive technique to displace small bowel from pelvic treatment fields. The small bowel volume is dramatically reduced at each dose level. The volume reduction does not correlate with gender, age, weight, pelvic separation, and sequence of radiation treatment vs. surgery.

Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales.

PURPOSE: Serious late morbidity (Grade 3/4) from the conformal treatment of prostate cancer has been reported in <1% to 6% of patients based on existing late gastrointestinal (GI) morbidity scales. None of the existing morbidity scales include our most frequently observed late GI complication, which is chronic rectal bleeding requiring multiple fulgerations. This communication documents the frequency of rectal bleeding requiring multiple fulgerations and illustrates the variation in reported late serious GI complication rates by the selection of morbidity scale. METHODS AND MATERIALS: Between May 1989 and December 1993, 352 patients with T1-T3 nonmetastatic prostate cancers were treated with our four-field conformal technique without special rectal blocking. This technique includes a 1-cm margin from the clinical target volume (CTV) to the planning target volume (PTV) in all directions. The median follow-up for these patients was 36 months (range 2-76), and the median center of prostate dose was 74 Gy (range 63-81). Three morbidity scales are assessed: the Radiation Therapy Oncology Group (RTOG), the Late Effects Normal Tissue Task Force (LENT), and our modification of the LENT (FC-LENT). This modification registers chronic rectal bleeding requiring at least one blood transfusion and/or more than two coagulations as a Grade 3 event. Estimates for Grade 3/4 late GI complication rates were determined using Kaplan-Meier methodology. The duration of severe symptoms with chronic rectal bleeding is measured from the first to the last transrectal coagulation. Latency is measured from the end of radiotherapy to surgery, first blood transfusion, or third coagulation procedure. RESULTS: Sixteen patients developed Grade 3/4 complications by one of the three morbidity scales. Two patients required surgery (colostomy or sigmoid resection), three required multiple blood transfusions, two required one or two blood transfusions, and nine required at least three coagulations. The median duration of bleeding for those patients requiring multiple procedures was 7 months (range 3-33) and the median latency was 22 months (range 9-40). The 5-year actuarial rate of Grade 3/4 complications by each scale are: RTOG 0.7%, LENT 2%, and FC-LENT 6%. The rate of chronic rectal bleeding increases with increasing dose and is low in patients treated with conventional techniques owing to lower doses. CONCLUSION: Chronic rectal bleeding requiring any blood transfusion(s) or multiple coagulation procedures is our most frequently observed complication. This complication appears late in follow-up and is present for a long duration. We believe this justifies the inclusion of chronic rectal bleeding requiring multiple coagulation procedures as a Grade 3 event in future morbidity scales. Our data illustrate that published Grade 3/4 morbidity rates are highly dependent on the morbidity scale selected, as our data show 0.7% RTOG, 2% LENT, and 6% FC-LENT. Obviously, a uniform scale is required that includes the newly recognized serious late effects associated with the conformal treatment of prostate cancer.

Conformal technique dose escalation for prostate cancer: biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen > or = 10 NG/ML.

PURPOSE: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer. METHODS AND MATERIALS: We report the biochemical freedom from disease (bNED) rates (bNED failure is Prostate Specific Antigen (PSA) > or = 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (< 10, 10-19.9, and > or = 20 ng/ml). Dose was stated to be at the center of the prostate gland. RESULTS: There was significant improvement in bNED survival for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10-19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA > or = 20 ng/ml (p = 0.003 and 0.02, respectively). CONCLUSIONS: Increasing dose above 71 or 73 Gy did not result in improved bNED survival for patients with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in these patients. A significant improvement in bNED survival was noted for patients with pretreatment PSA > or = 10 ng/ml treated above 71 or 73 Gy; further dose escalation studies are warranted.

To move or not to move: measurements of prostate motion by urethrography using MRI.

PURPOSE: Urethrography is commonly used to aid in definition of the prostate apex during CT simulation for prostate cancer. If the position of the prostate were altered by the urethrogram itself, then systematic error could be introduced into the patient's treatment. Sagittal MRI scans were acquired immediately before and after a localization urethrogram to determine the extent of displacement. METHODS AND MATERIALS: Thirteen patients underwent sagittal T2-weighted fast spin echo MRI scans. Patients were scanned supine in an alpha cradle cast in the treatment position. The prostate was contoured by 3 different observers to determine the apex location on the central sagittal MRI section and the center of mass relative to an immobile bony landmark. Statistical multivariate analysis was performed to establish if there was a net displacement of the prostate (systematic error), and to determine the margin required to cover the random prostate position within a 95% confidence interval. RESULTS: There was no significant systematic motion of either the prostate nor its apex in either the anterior-posterior or superior-inferior directions. The average motion of the prostate center of mass was 0.04 +/- 0.40 cm (1 SD) and 0.01 +/- 0.33 cm in the anterior-posterior and superior-inferior direction, respectively. The corresponding figures for location of the apex were 0.05 +/- 0.30 cm and 0.01 +/- 0.33 cm, respectively. The statistical analysis revealed that a margin of 2 mm is sufficient to cover any random motion of the prostate that could occur as a result of the urethrogram 95% of the time. CONCLUSION: Urethrography during CT simulation for prostate cancer does not cause significant prostate displacement or systematic error in planning and delivering external-beam radiation.

Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06.

PURPOSE: The recursive partitioning analysis (RPA) classes for malignant glioma patients were previously established using data on over 1500 patients entered on Radiation Therapy Oncology Group (RTOG) clinical trials. The purpose of the current analysis was to validate the RPA classes with a new dataset (RTOG 90-06), determine the predictive power of the RPA classes, and establish the usefulness of the database norms for the RPA classes. PATIENTS AND METHODS: There are six RPA classes for malignant glioma patients that comprise distinct groups of patients with significantly different survival outcome. RTOG 90-06 is a randomized Phase III study of 712 patients accrued from 1990 to 1994. The minimum potential follow-up is 18 months. The treatment arms were combined for the purpose of this analysis. There were 84, 13, 105, 240, 150, and 23 patients in the RPA Classes I-VI from RTOG 90-06, respectively. RESULTS: The median survival times (MST) and 2-year survival rates for the six RPA classes in RTOG 90-06 are compared to those previously published. The MST and 2-year survival rates for the RTOG RPA classes were within 95% confidence intervals of the 90-06 estimates for Classes I, III, IV, and V. The RPA classes explained 43% of the variation (squared error loss). By comparison, a Cox model explains 30% of the variation. The RPA classes within RTOG 90-06 are statistically distinct with all comparisons exceeding 0.0001, except those involving Class II. A survival analysis from a prior RTOG study indicated that 72.0 Gy had superior outcome to literature controls; analysis of this data by RPA classes indicates the survival results were not superior to the RTOG database norms. CONCLUSION: The validity of the model is verified by the reliability of the RPA classes to define distinct groups with respect to survival. Further evidence is given by prediction of MST and 2-year survival for all classes except Class II. The RPA classes explained a good portion of the variation in survival outcome in the data. Lack of correlation in RPA Class II between datasets may be an artifact of the small sample size or an indication that this class is not distinct. The validation of the RPA classes attests to their usefulness as historical controls for the comparison of future Phase II results.

A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104.

PURPOSE: To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis. METHODS AND MATERIALS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin. RESULTS: The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm. CONCLUSION: Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.

Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions.

PURPOSE: To report the 5-year outcomes of dose escalation with 3D conformal treatment (3DCRT) of prostate cancer. METHODS AND MATERIALS: Two hundred thirty-two consecutive patients were treated with 3DCRT alone between 6/89 and 10/92 with ICRU reporting point dose that increased from 63 to 79 Gy. The median follow-up was 60 months, and any patient free of clinical or biochemical evidence of disease was termed bNED. Biochemical failure was defined as prostate-specific antigen (PSA) rising on two consecutive recordings and exceeding 1.5 ng/ml. Morbidity was reported by the Radiation Therapy Oncology Group (RTOG) scale, the Late Effects Normal Tissue (LENT) scale, and a Fox Chase modification of the latter (FC-LENT). All patients were treated with a four-field technique with a 1 cm clinical target volume (CTV) to planning target volume (PTV) margin to the prostate or prostate boost; the CTV and gross tumor volume (GTV) were the same. Actuarial rates of outcome were calculated by Kaplan-Meier and cumulative incidence methods and compared using the log rank and Gray's test statistic, respectively. Cox regression models were used to establish prognostic factors predictive of the various measures of outcome. Five-year Kaplan-Meier bNED rates were utilized by dose group to estimate logit response models for bNED and late morbidity. RESULTS: PSA <10 ng/ml: No dose response was demonstrated using estimated bNED rates or by analysis of PSA nadir vs. dose. PSA 10-19.9 ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model showed 5-year bNED rates of 35% at 70 Gy and 75% at 76 Gy (p = 0.0049) and illustrated the relative ineffectiveness of conventional dose treatment. PSA 20+ ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model indicated a 5-year bNED rate of 10% at 70 Gy and 32% at 76 Gy (p = 0.10). Morbidity: Dose response was demonstrated for FC-LENT grade 2 and grade 3,4 GI morbidity and for LENT grade 2 GU sequelae. RTOG grade 3,4 GI morbidity at 5 years was <1%. Factors associated with bNED, cause-specific survival, and metastasis were studied using Cox multivariate analysis. Pretreatment PSA (p = 0.0001), Gleason score 7-10 (p = 0.0001), and dose (p = 0.017) were significantly predictive of bNED. For each 1 Gy increase in dose, the hazard of bNED failure decreased by 8%. Palpation stage was associated with cause-specific survival (p = 0.002) and distant metastasis (p = 0.0004). Gleason score was also predictive of distant metastasis (p = 0.02). CONCLUSIONS: A dose response was observed for patients with pretreatment PSA >10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA < 10 ng/ml. Dose response was observed for FC-LENT grade 2 and grade 3,4 GI sequelae and for LENT grade 2 GU sequelae. Optimization of treatment was made possible by the results in this report. The improvement in 5-year bNED rates for patients with PSA levels > 10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76-80 Gy.

Importance of the mini-mental status examination in the treatment of patients with brain metastases: a report from the Radiation Therapy Oncology Group protocol 91-04.

PURPOSE: Little information is available on the importance of pretreatment Mini-Mental Status Exam (MMSE) on long-term survival and neurologic function following treatment for unresectable brain metastases. This study examines the importance of the MMSE in predicting outcome in a group of patients treated with an accelerated fractionation regimen of 30 Gy in 10 daily fractions in 2 weeks. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastases were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. Two hundred twenty-four patients were entered on the accelerated fractionated arm, and 182 were eligible for analysis (7 patients were judged ineligible, no MMSE information in 29, no survival data in 1, no forms submitted in 1). RESULTS: Average age was 60 years; 58% were male and 25% had a single intracranial lesion on their pretherapy evaluation. KPS was 70 in 32%, 80 in 31%, 90 in 29%, and 100 in 14%. The average MMSE was 26.5, which is the lower quartile for normal in the U.S. population. The range of the MMSE scores was 11-30 with 30 being the maximum. A score of less than 23 indicates possible dementia, which occurred in 16% of the patients prior to treatment. The median time from diagnosis to treatment was 5 days (range, 0-158 days). The median survival was 4.2 months with a 95% confidence interval of 3.7-5.1 months. Thirty-seven percent of the patients were alive at 6 months, and 17% were alive at 1 year. The following variables were examined in a Cox proportional-hazards model to determine their prognostic value for overall survival: age, gender, KPS, baseline MMSE, time until MMSE below 23, time since diagnosis, number of brain metastases, and radiosurgery eligibility. In all Cox model analyses, age, KPS, baseline MMSE, time until MMSE below 23, and time since diagnosis were treated as continuous variables. Statistically significant factors for survival were pretreatment MMSE (p = 0.0002), and KPS (p = 0.02). Age was of borderline significance (p = 0.065) as well as gender (p = 0.074). A poorer outcome is associated with an increasing age, male gender, lower MMSE, and shorter time until MMSE below 23. Improvement in MMSE over time was assessed; 62 patients died prior to obtaining follow-up MMSE, and 30 patients had a baseline MMSE of 30 (the maximum), and, therefore, no improvement could be expected. Of the remaining 88, 48 (54.5%) demonstrated an improvement in their MMSE at any follow-up visit. Lack of decline of MMSE below 23 was seen in long-term survivors, with 81% at 6 months and 66% at 1 year of patients maintaining a MMSE above 23. Analysis of time until death from brain metastases demonstrated that decreasing baseline MMSE (p = 0.003) and primary site (breast vs. lung vs. other p = 0.032) were highly associated with a terminal event. CONCLUSION: While gender and perhaps age remain significant predictors for survival, MMSE is also an important way of assessing a patient's outcome. Accelerated fractionation used in the treatment of brain metastases (30 Gy in 10 fractions) appears to also be associated with an improvement in MMSE and a lack of decline of MMSE below 23 in long-term survivors.

Can costs be measured and predicted by modeling within a cooperative clinical trials group? Economic methodologic pilot studies of the radiation therapy oncology group (RTOG) studies 90-03 and 91-04.

PURPOSE: To (1) measure radiation therapy costs for patients in randomized controlled clinical trials, (2) compare measured costs to modeling predictions, (3) examine cost distributions, and (4) assess feasibility of collecting economic data within a cooperative group. METHODS: The Radiation Therapy Oncology Group conducted economic pilot studies for two Phase III studies that compared fractionation patterns. Expected quantities of Current Procedural Terminology (CPT) codes and relative value units (RVU) were modeled. Institutions retrospectively provided procedure codes, quantities, and components, which were converted to RVUs used for Medicare payments. Cases were included if the radiation therapy quality control review judged them to have been treated per protocol or with minor variation. Cases were excluded if economic quality review found incomplete economic data. RESULTS: The median and mean RVUs were within the range predicted by the model for all arms of one study and above the predicted range for the other study. CONCLUSION: The model predicted resource use well for patients who completed treatment per protocol. Actual economic data can be collected for critical cost items. Some institutions experienced difficulty collecting retrospective data, and prospective collection of data is likely to allow wider participation in future Radiation Therapy Oncology Group economic studies.