NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients.

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

A Phase I Study of Tomotherapy in Patients With Primary Benign and Low-grade Brain Tumors: Late Toxicity and Quality of Life.

OBJECTIVES: To evaluate longitudinal quality of life and late neurotoxicity (>12 mo) of tomotherapy in patients with primary benign and low-grade brain tumors. METHODS: Between January 2006 and October 2009, 49 patients with brain tumors were treated with tomotherapy at 2 radiotherapy centers in Canada. The median age of the patients was 51.0 years (range, 21 to 74 y); there were 21 men (42.86%) and 28 women (57.14%). All 49 patients had an initial Karnofsky performance score ≥70. One patient (2.04%) received 45 Gy in 25 fractions, 27 patients (55.10%) received 50.4 Gy in 28 fractions, 15 patients (30.6%) received 54 Gy in 30 fractions, and 5 patients (10.2%) received 60 Gy in 30 fractions. A total of 47 patients were analyzed for late toxicity and outcomes. RESULTS: Changes in the Karnofsky Performance Status of the patients did not reach statistical significance (P>0.05). The majority of the quality of life parameters that reached a statistically significant level (P<0.05) of change at 2 years were changes toward improvement (drowsiness, itchy skin, emotional functioning, fatigue, nausea, and appetite). Statistically significant (P<0.05) interval deterioration in physical, role, and social functioning was observed. Actuarial overall survival at 5 years was 91.6%; disease-free survival at 5 years was 86.6%. CONCLUSIONS: IMRT helical tomotherapy is well tolerated, without statistically significant constitutional and late neurotoxicity up to the 2-year mark.

Changes in serial magnetic resonance spectroscopy predict outcome in high-grade glioma during and after postoperative radiotherapy.

AIM: To determine any correlation between magnetic resonance spectroscopy (MRS) pattern of high-grade glioma before, during, and after radiotherapy (RT) with overall survival (OS) and progression-free survival (PFS). PATIENTS AND METHODS: Twenty-six patients prospectively underwent surgery and RT to 60 Gy. MRS was performed before RT, at week 4 of RT, and 2 months post-RT. Normalized and relative metabolite ratios were evaluated. Patients were grouped according to similar evolving MRS patterns and analyzed for differences in OS and PFS. RESULTS: Significant decreases in tumor choline/N-acetyl-aspartate and normalized choline were observed from baseline to post-RT. After a median follow-up of 22.9 months, patients with >40% decrease in normalized choline from week 4 during RT to 2 months post-RT had a significantly worse median OS (9.1 months vs. not reached, p<0.00001) and PFS (5.8 vs. 19.8 months, p=0.0018). CONCLUSION: The change in normalized choline at 2 months post-RT was highly prognostic for PFS and OS. This may allow more individualized response-based treatment.

Assessment of extended-field radiotherapy for stage IIIC endometrial cancer using three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy.

PURPOSE: To perform a dosimetric comparison of three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (HT) plans for pelvic and para-aortic RT in postoperative endometrial cancer patients; and to evaluate the integral dose (ID) received by critical structures within the radiation fields. METHODS AND MATERIALS: We selected 10 patients with Stage IIIC endometrial cancer. For each patient, three plans were created with 3D-CRT, IMRT, and HT. The IMRT and HT plans were both optimized to keep the mean dose to the planning target volume (PTV) the same as that with 3D-CRT. The dosimetry and ID for the critical structures were compared. A paired two-tailed Student t test was used for data analysis. RESULTS: Compared with the 3D-CRT plans, the IMRT plans resulted in lower IDs in the organs at risk (OARs), ranging from -3.49% to -17.59%. The HT plans showed a similar result except that the ID for the bowel increased 0.27%. The IMRT and HT plans both increased the IDs to normal tissue (see Table 1 and text for definition), pelvic bone, and spine (range, 3.31-19.7%). The IMRT and HT dosimetry showed superior PTV coverage and better OAR sparing than the 3D-CRT dosimetry. Compared directly with IMRT, HT showed similar PTV coverage, lower Ids, and a decreased dose to most OARs. CONCLUSION: Intensity-modulated RT and HT appear to achieve excellent PTV coverage and better sparing of OARs, but at the expense of increased IDs to normal tissue and skeleton. HT allows for additional improvement in dosimetry and sparing of most OARs.

Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404.

PURPOSE: This study was an open-label, randomized Phase III trial in newly diagnosed patients with anaplastic glioma other than glioblastoma multiforme comparing external beam radiotherapy (EBRT) plus adjuvant procarbazine, cyclohexylchloroethylnitrosurea (lomustine), and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-h infusion each week of RT. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible. A central pathology review was accomplished for most patients, but was not mandated before registration. The study had initially opened as a Northern California Oncology Group trial in 1991, becoming an Intergroup Radiation Therapy Oncology Group (RTOG), Southwestern Oncology Group and the North Central Cancer Treatment Group study in July 1994. A total accrual of 293 patients was planned for the sample size, using survival as the primary end point. The experimental arm (RT/BUdR + PCV) was to be compared with the control arm (RT + PCV) using a one-sided alpha = 0.05, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after enrollment completion. RESULTS: Between July 1994 and August 1996, 134 patients were randomized to EBRT + PCV (non-BUdR patients) and 134 to EBRT/BUdR + PCV (BUdR patients). The study was closed before the full-anticipated accrual on the basis of an interim analysis that predicted no survival benefit for the BUdR arm. Of the 268 patients, 41 and 37, respectively, were ineligible or canceled primarily on the basis of the central pathology review findings. Thus, 93 patients and 97 patients were eligible/analyzable in the non-BUdR and BUdR arms, respectively. Patient characteristics were well balanced in both arms, with most <50 years old and in the RTOG recursive partitioning analysis (RPA) Class I category. The minimal potential follow-up was 4.6 years. The median survival for non-BUdR patients was 4.1 years compared with 4.6 years for the BUdR patients (p = 0.61). The 4-year overall survival rate was 51% in both arms. For RPA Class I patients (the best prognostic class), the median survival had not been reached for non-BUdR patients (4-year survival rate 61%) and was 5.6 years for BUdR patients (4-year survival rate 64%; p = 0.91). Each arm was also compared with the RTOG historical database for RPA Class I patients with no statistically significant difference found in overall survival (BUdR vs. historical, p = 0.31 and non-BUdR vs. historical, p = 0.48). Grade 4 toxicity occurred in 15 and 17 patients in the non-BUdR and BUdR arms, respectively, with one treatment-related death in the BUdR group. CONCLUSION: No survival advantage was noted by adding BUdR to EBRT and PCV in this patient population

The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: an analysis of RTOG data.

PURPOSE: To evaluate in-field progression and survival of patients with unresectable non-small cell lung cancer (NSCLC) in relation to adequacy of coverage of thoracic regional nodal areas in the radiotherapy volume. MATERIALS AND METHODS: A total of 1705 patients from four large RTOG trials (78-11, 79-17, 83-11 and 84-07) were analyzed for this purpose. For each of these trials, the dose delivered to nodal regions was recorded and an assessment of adequacy of field borders was made. Each nodal site was assessed for progression, defined as in-field or out-of-field. In patients who had adequate borders on nodal regions, the results were analyzed according to the dose delivered. RESULTS: The majority (74%) of patients were between the age of 55-75. Forty-six percent of the patients had KPS of 60-80 and 52% had KPS of 90-100. Sixty percent of patients had a weight loss of less than 5% in the 6 months prior to diagnosis. Deviations from the protocol in field borders (borders not per protocol) were most frequent for the contralateral hilum (25.2%) and least frequent in the ipsilateral hilum (6.3%). The adequacy of ipsilateral hilar coverage was important for preventing the in-field progression (11.6 vs. 22% for adequately vs. inadequately covered ipsilateral hilum, respectively, P=0.01), however, did not influence the 2-year-survival (35 vs. 37%) or median survival (1.3 vs. 1.1 year). Neither the in-field progression nor the 2-year-survival were affected by adequacy of nodal coverage in the mediastinum, ipsilateral supraclavicular area and contralateral hilum, even when different doses were analyzed. CONCLUSION: These data suggest that elective irradiation of mediastinal, contralateral hilar and supraclavicular lymph nodes may not be necessary in the treatment of unresectable NSCLC.