Mitchell Machtay

Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate

PURPOSE To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. METHODS AND MATERIALS The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2--T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II. RESULTS As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p = 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p = 0.04), disease-free survival (33% vs. 21%, p = 0.004), biochemical disease-free survival = PSA <1.5 (24% vs. 10%, p < 0.0001), and cause-specific mortality (23% vs. 31%, p = 0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2--6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p = 0.015). In patients with Gleason 7--10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival. CONCLUSION In patients with Gleason score 2--6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival.

Sequential vs Concurrent Chemoradiation for Stage III Non–Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410

BACKGROUND The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy. METHODS A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided. RESULTS Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar. CONCLUSION Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials.

BACKGROUND Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate

PURPOSE To determine the potential advantage of androgen ablation following standard external-beam radiation therapy in patients with locally advanced (clinical or pathologic T3; clinical or pathologic node positive) carcinoma of the prostate. METHODS AND MATERIALS In 1987 the RTOG initiated a Phase III trial of long-term adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients were accrued to the study of which 945 remain analyzable: 477 on the adjuvant hormone arm (Arm I); and 468 on the radiation only arm (Arm II) with hormones initiated at relapse. The initial results were reported in the Journal of Clinical Oncology in 1997. RESULTS With a median follow up of 5.6 years for all patients and 6.0 years for living patients local failure at 8 years was 23% for Arm I and 37% for Arm II (p < 0.0001). Distant metastasis was likewise favorably impacted with the immediate use of hormonal manipulation with a distant metastasis rate in Arm I of 27% and 37% in Arm II (p < 0.0001). Disease-free survival (NED survival) and NED survival with PSA of 1.5 ng/mL (bNED) or less were both statistically significant in favor of the immediate hormone arm (both p < 0.0001). Cause-specific failure was not statistically different with a cause-specific failure of 16% for Arm I and 21% in Arm II (p = 0.23). Overall survival was likewise not statistically different between two arms, with a 49% overall survival at 8 years in Arm I and 47% in Arm II (p = 0.36). Subset analysis of centrally reviewed Gleason 8-10 patients who did not undergo prostatectomy showed that for patients receiving radiation therapy plus adjuvant hormones there was a statistically significant improvement in both absolute (p = 0.036) and cause-specific survival (p = 0.019). CONCLUSIONS Use of long-term adjuvant androgen deprivation in addition to definitive radiation therapy results in a highly significant improvement in regards to local control, freedom from distant metastasis, and biochemical free survival in unfavorable prognosis patients with carcinoma of the prostate.

Dual time point fluorine-18 fluorodeoxyglucose positron emission tomography: a potential method to differentiate malignancy from inflammation and normal tissue in the head and neck.

Abstract. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies imaging FDG PET imaging is used to detect and stage head and neck cancers. However, the variable physiologic uptake of FDG in different normal structures as well as at inflammatory sites may either obscure a tumor focus or be falsely interpreted to represent tumor activity. Twenty-one patients (9 men, 12 women, median age 59) were scanned serially at two time points, one at 70 min (range 47–112) and the second at 98 min (77–142) after the intravenous injection of 4.3 MBq/kg of FDG. The mean interval between emission scans was 28 min (13–49). Transmission scans were performed and regions of interest (ROIs) were overlayed on the fully corrected images. Standardiued uptake values (SUVs) were generated for the cerebellum, tongue, larynx, every lesion, and a matched contralateral site. Follow-up and pathologic studies revealed 18 squamous cell carcinomas and nine inflammatory or infectious lesions. Tumor SUVs were 4.0±1.6 (mean ± SD) for the first scan and 4.5±2.2 for the second scan. Contralateral SUVs were 1.2±0.5 and 1.1±0.5 for the two scans. Tumor SUVs increased by 12%±12% as compared with a 5%±17% decrease for contralateral sites (P<0.05). SUVs for inflammatory sites (2.0±0.7 and 2.0±0.9), cerebellum (4.2±1.3 and 4.3±1.4), tongue (1.8±0.4 and 1.9±0.5) and larynx (1.5±0.6 and 1.5±0.6) remained constant over time (+0.6%, +2.8%, +1.4%, and –2.4%; P<0.05 when compared with tumor SUV changes). The ratio tumor/contralateral SUV increased by 23%±29% over time while this ratio for inflamed sites increased by only 5%±15% (P=0.07). The time interval between scans correlated with increase in SUV for tumors (r=0.55, P<0.05) but not for any of the other ROIs. Separation was superior when studies were performed more than 30 min apart (P<0.05). These preliminary data suggest that dual time point imaging compatible with a clinical study protocol is helpful in differentiating malignant lesions from inflammation and normal tissues, especially when separated by a sufficient time interval.

Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer

PURPOSE To identify factors that may predict for severe radiation pneumonitis or pneumonopathy (RP), we reviewed a set of simple, commonly available characteristics. METHODS AND MATERIALS Medical records of 148 lung cancer patients with good performance status (ECOG 0-1) treated definitively with chemoradiation from 6/92-6/98 at the University of Pennsylvania were reviewed. Actuarial survival and the crude rate of severe radiation pneumonitis were determined as a function of several variables. Potential predictive factors examined included age, gender, histology, stage, pulmonary function, performance status (0 vs. 1), weight loss, tumor location, radiation dose, initial radiation field size, chemotherapy regimen, and timing of chemotherapy. Univariate analysis (log-rank test) was performed for each variable. Multivariate analysis was performed using linear regression. RESULTS Median survival for the entire cohort was 14.7 months. Four patients were inevaluable for pneumonitis due to early death from progressive disease. Of the remaining 144 evaluable patients, 12 (8.3%) experienced severe RP. The most significant factor predicting for severe RP was performance status (p < 0.003). The risk of severe RP was 16% for PS-1 patients vs. 2% for PS-0 patients. Women were significantly more likely to develop severe RP than men (p = 0.01). Among 67 patients for whom pre-radiation therapy pulmonary function data were available, forced expiratory volume of the lung in 1 second (FEV(1)) was also significant (p = 0. 03). No patient suffering severe RP had a pretreatment FEV(1) > 2.0 liters. The median radiation dose was 59.2 Gy and median initial radiation field size was 228 cm(2). Neither radiotherapy factor predicted for RP. Other factors studied, including chemotherapy drugs, and schedule, also were not significant predictors of severe RP. CONCLUSIONS Pretreatment performance status, gender, and FEV(1) are significant predictors of severe radiation pneumonopathy, at least when using conventional radiation fields and doses. Complex radiation dose-volume algorithms that attempt to predict lung complication probabilities should probably incorporate these simply obtained clinical parameters.

Organ Preservation Therapy Using Induction Plus Concurrent Chemoradiation for Advanced Resectable Oropharyngeal Carcinoma: A University of Pennsylvania Phase II Trial

PURPOSE To determine the efficacy, feasibility, and toxicity of a new regimen for locally advanced oropharyngeal carcinoma. PATIENTS AND METHODS Patients had technically resectable stage III/IV squamous cell carcinoma of the oropharynx, exclusive of T1-2N1. Induction chemotherapy consisted of carboplatin (area under the curve formula equal to 6) and paclitaxel 200 mg/m(2) for two cycles, followed by re-evaluation. Patients with major response continued to definitive radiotherapy (70 Gy over 7 weeks) plus concurrent once-weekly paclitaxel (30 mg/m(2)/wk). Patients with advanced neck disease also underwent post-radiation therapy neck dissection and two more chemotherapy cycles. RESULTS Fifty-three patients were enrolled. Median follow-up was 31 months (minimum follow-up for survivors was 18 months). The major response rate to induction chemotherapy was 89%; 90% of patients had a complete response after concurrent chemoradiation. Actuarial survival at 3 years was 70%, and 3-year event-free survival was 59%. The 3-year actuarial locoregional control was 82% and the 3-year actuarial rate of distant metastases was 19%. Organ preservation was achieved in 77% of all patients. One patient (2%) died during therapy. Late grade 3 toxicity occurred in 24% of patients, consisting mainly of chronic dysphagia/aspiration and/or radiation soft tissue ulceration. The treatment-related mortality rate was 4% (two patients died from respiratory failure). CONCLUSION Response to induction chemotherapy as studied in this trial was not useful as a predictive marker for ultimate outcome or organ conservation. Overall, however, this regimen offers good disease control and survival for patients with locally advanced oropharyngeal carcinoma, comparable with other concurrent chemoradiation programs. Further study of similar protocols is indicated.

FINAL REPORT OF RTOG 9610, A MULTI-INSTITUTIONAL TRIAL OF REIRRADIATION AND CHEMOTHERAPY FOR UNRESECTABLE RECURRENT SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Our objectives were to determine the incidence of acute and late toxicities and to estimate the 2‐year overall survival for patients treated with reirradiation and chemotherapy for unresectable squamous cell carcinoma of the head and neck (SCCHN).

Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group trial 98-01

PURPOSE To test the ability of the cytoprotectant, amifostine, to reduce chemoradiotherapy-induced esophagitis and evaluate its influence on quality of life (QOL) and swallowing symptoms. PATIENTS AND METHODS A total of 243 patients with stage II to IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m(2) intravenously (IV) days 1 and 22 and carboplatin area under the curve (AUC) days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m(2) IV) and carboplatin (AUC 2), and hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy bid). Patients were randomly assigned at registration to amifostine (AM) 500 mg IV four times per week or no AM during chemoradiotherapy. Beyond standard toxicity end points, physician dysphagia logs (PDLs), daily patient swallowing diaries, and QOL (EORTC QLQ-C30/LC-13) were also collected. Swallowing AUC analyses were calculated from patient diaries and PDLs. RESULTS A total of 120 patients were randomly assigned to receive AM, and 122, to receive no AM (one patient was ineligible); 72% received AM per protocol or with a minor deviation. AM was associated with higher rates of acute nausea (P = .03), vomiting (P = .007), cardiovascular toxicity (P = .0001), and infection or febrile neutropenia (P = .03). The rate of >/= grade 3 esophagitis was 30% with AM versus 34% without AM (P = .9). Patient diaries demonstrated lower swallowing dysfunction AUC with amifostine (z test P = .025). QOL was not significantly different between the two arms, except for pain, which showed more clinically meaningful improvement and less deterioration at 6 weeks follow-up (v pretreatment) in the AM arm (P = .003). The median survival rates for both arms were comparable (AM, 17.3 v no AM, 17.9 months; P = .87). CONCLUSION AM did not significantly reduce esophagitis >/= grade 3 in patients receiving hyperfractionated radiation and chemotherapy. However, patient self-assessments suggested a possible advantage to AM that is being explored with modified dosing route strategies.

Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group.

PURPOSE Patients treated with chemoradiotherapy for locally advanced non-small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity. METHODS AND MATERIALS This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED) using standard formulae. Heterogeneity testing was done with chi-squared statistics, and weighted pooled hazard ratio estimates were used. Cox and Fine and Grays proportional hazard models were used for OS and LRF, respectively, to test the associations between BED and tBED adjusted for other covariates. RESULTS A total of 1,356 patients were analyzed for BED (1,348 for tBED). The 2-year and 5-year OS rates were 38% and 15%, respectively. The 2-year and 5-year LRF rates were 46% and 52%, respectively. The BED (and tBED) were highly significantly associated with both OS and LRF, with or without adjustment for other covariates on multivariate analysis (p < 0.0001). A 1-Gy BED increase in radiotherapy dose intensity was statistically significantly associated with approximately 4% relative improvement in survival; this is another way of expressing the finding that the pool-adjusted hazard ratio for survival as a function of BED was 0.96. Similarly, a 1-Gy tBED increase in radiotherapy dose intensity was statistically significantly associated with approximately 3% relative improvement in local-regional control; this is another way of expressing the finding that the pool-adjusted hazard ratio as a function of tBED was 0.97. CONCLUSIONS Higher radiotherapy dose intensity is associated with improved local-regional control and survival in the setting of chemoradiotherapy.