Mitochondrial Toxicity Associated with Imatinib and Sorafenib in Isolated Rat Heart Fibers and the Cardiomyoblast H9c2 Cell Line.

Tyrosine kinase inhibitors (TKIs) are associated with cardiac toxicity, which may be caused by mitochondrial toxicity. The underlying mechanisms are currently unclear and require further investigation. In the present study, we aimed to investigate in more detail the role of the enzyme complexes of the electron transfer system (ETS), mitochondrial oxidative stress, and mechanisms of cell death in cardiac toxicity associated with imatinib and sorafenib. Cardiac myoblast H9c2 cells were exposed to imatinib and sorafenib (1 to 100 µM) for 24 h. Permeabilized rat cardiac fibers were treated with both drugs for 15 min. H9c2 cells exposed to sorafenib for 24 h showed a higher membrane toxicity and ATP depletion in the presence of galactose (favoring mitochondrial metabolism) compared to glucose (favoring glycolysis) but not when exposed to imatinib. Both TKIs resulted in a higher dissipation of the mitochondrial membrane potential in galactose compared to glucose media. Imatinib inhibited Complex I (CI)- and CIII- linked respiration under both conditions. Sorafenib impaired CI-, CII-, and CIII-linked respiration in H9c2 cells cultured with glucose, whereas it inhibited all ETS complexes with galactose. In permeabilized rat cardiac myofibers, acute exposure to imatinib and sorafenib decreased CI- and CIV-linked respiration in the presence of the drugs. Electron microscopy showed enlarged mitochondria with disorganized cristae. In addition, both TKIs caused mitochondrial superoxide accumulation and decreased the cellular GSH pool. Both TKIs induced caspase 3/7 activation, suggesting apoptosis as a mechanism of cell death. Imatinib and sorafenib impaired the function of cardiac mitochondria in isolated rat cardiac fibers and in H9c2 cells at plasma concentrations reached in humans. Both imatinib and sorafenib impaired the function of enzyme complexes of the ETS, which was associated with mitochondrial ROS accumulation and cell death by apoptosis.

Effects of Simvastatin on Lipid Metabolism in Wild-Type Mice and Mice with Muscle PGC-1α Overexpression.

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b.

Mechanisms of statin-associated skeletal muscle-associated symptoms.

Statins lower the serum low-density lipoprotein cholesterol and prevent cardiovascular events by inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase. Although the safety of statins is documented, many patients ingesting statins may suffer from skeletal muscle-associated symptoms (SAMS). Importantly, SAMS are a common reason for stopping the treatment with statins. Statin-associated muscular symptoms include fatigue, weakness and pain, possibly accompanied by elevated serum creatine kinase activity. The most severe muscular adverse reaction is the potentially fatal rhabdomyolysis. The frequency of SAMS is variable but in up to 30% of the patients ingesting statins, depending on the population treated and the statin used. The mechanisms leading to SAMS are currently not completely clarified. Over the last 15 years, several research articles focused on statin-induced mitochondrial dysfunction as a reason for SAMS. Statins can impair the function of the mitochondrial respiratory chain, thereby reducing ATP and increasing ROS production. This can induce mitochondrial membrane permeability transition, release of cytochrome c into the cytosol and induce apoptosis. In parallel, statins inhibit activation of Akt, mainly due to reduced function of mTORC2, which may be related to mitochondrial dysfunction. Mitochondrial dysfunction by statins is also responsible for activation of AMPK, which is associated with impaired activation of mTORC1. Reduced activation of mTORC1 leads to increased skeletal muscle protein degradation, impaired protein synthesis and stimulation of apoptosis. In this paper, we discuss some of the different hypotheses how statins affect skeletal muscle in more detail, focusing particularly on those related to mitochondrial dysfunction and the impairment of the Akt/mTOR pathway.

Mitochondrial oxidative stress plays a critical role in the cardiotoxicity of sunitinib: Running title: Sunitinib and oxidative stress in hearts.

Sunitinib is cardiotoxic, but the mechanisms are not entirely clear. We aimed to enlarge our knowledge about the role of mitochondria in cardiac toxicity of sunitinib in vitro and in vivo. For this reason, we studied the toxicity of sunitinib on cardiac H9c2 cells exposed for 24 h, permeabilized rat cardiac fibers exposed for 15 min and in mice treated orally with sunitinib for 2 weeks (7.5 mg/kg/day). In H9c2 cells exposed for 24 h, sunitinib was more cytotoxic under galactose (favoring mitochondrial metabolism) compared to glucose conditions (favoring glycolysis). Sunitinib dissipated the mitochondrial membrane potential starting at 10 µM under glucose and at 5 µM under galactose conditions. Sunitinib reduced activities of mitochondrial enzyme complexes of the electron transport chain (ETC), increased mitochondrial ROS accumulation and decreased the cellular GSH pool. Electron microscopy revealed swollen mitochondria with loss of cristae. Accordingly, sunitinib caused caspase 3 activation and DNA fragmentation in H9c2 cells. Co-exposure with mito-TEMPO (mitochondrial-specific ROS scavenger) for 24 h prevented ATP and GSH depletion, as well as the increases in H2O2 and caspase 3/7 activity observed with sunitinib. In mice, treatment with sunitinib for two weeks increased plasma concentrations of troponin I and creatine kinase MB, indicating cardiomyocyte damage. The activity of enzyme complexes of the ETCwas decreased, mitochondrial ROS were increased and cleavage of caspase 3 was increased, suggesting cardiomyocyte apoptosis. In conclusion, mitochondrial damage with ROS accumulation appears to be an important mechanism of cardiotoxicity associated with sunitinib, eventually leading to apoptotic cell death.

Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle.

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. They are generally well tolerated, but can cause insulin resistance in patients. Therefore, we investigated the mechanisms underlying the statin-induced insulin resistance. We used mice and C2C12 myotubes (murine cell line): mice (n = 10) were treated with oral simvastatin (5 mg/kg/day) or water (control) for 21 days and C2C12 cells were exposed to 10 µM simvastatin for 24 h. After intraperitoneal glucose application (2 g/kg), simvastatin-treated mice had higher glucose but equal insulin plasma concentrations than controls and lower glucose transport into skeletal muscle. Similarly, glucose uptake by C2C12 myotubes exposed to 10 µM simvastatin for 24 h was impaired compared to control cells. In simvastatin-treated C2C12 myotubes, mRNA and protein expression of the insulin receptor (IR) ß-chain was increased, but the phosphorylation (Tyr1361) was impaired. Simvastatin decreased numerically Akt/PKB Thr308 phosphorylation (via insulin signaling pathway) and significantly Akt/PKB Ser473 phosphorylation (via mTORC2), which was explained by impaired phosphorylation of mTOR Ser2448. Reduced phosphorylation of Akt/PKB impaired downstream phosphorylation of GSK3ß, leading to impaired translocation of GLUT4 into plasma membranes of C2C12 myotubes. In contrast, reduced phosphorylation of AS160 could be excluded as a reason for impaired GLUT4 translocation. In conclusion, simvastatin caused insulin resistance in mice and impaired glucose uptake in C2C12 myotubes. The findings in myotubes can be explained by diminished activation of Akt/PKB by mTORC2 and downstream effects on GSK3ß, impairing the translocation of GLUT4 and the uptake of glucose.

PGC-1ß modulates statin-associated myotoxicity in mice.

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1ß expression in human and rat skeletal muscle, suggesting that PGC-1ß may play a role in statin-induced myopathy. PGC-1ß is a transcriptional co-regulator controlling the expression of important genes in mitochondrial biogenesis, antioxidative capacity and energy metabolism. The principle aim of the current study was to investigate the interaction between atorvastatin and PGC-1ß in more detail. We therefore treated wild-type mice and mice with selective skeletal muscle knockout of PGC-1ß (PGC-1ß(i)skm-/- mice) with oral atorvastatin (5 mg/kg/day) for 2 weeks. At the end of treatment, we determined body parameters, muscle function, structure, and composition as well as the function of muscle mitochondria, mitochondrial biogenesis and activation of apoptotic pathways. In wild-type mice, atorvastatin selectively impaired mitochondrial function in glycolytic muscle and caused a conversion of oxidative type IIA to glycolytic type IIB myofibers. Conversely, in oxidative muscle of wild-type mice, atorvastatin enhanced mitochondrial function via activation of mitochondrial biogenesis pathways and decreased apoptosis. In PGC-1ß(i)skm-/- mice, atorvastatin induced a switch towards glycolytic fibers, caused mitochondrial dysfunction, increased mitochondrial ROS production, impaired mitochondrial proliferation and induced apoptosis in both glycolytic and oxidative skeletal muscle. Our work reveals that atorvastatin mainly affects glycolytic muscle in wild-type mice and demonstrates the importance of PGC-1ß for oxidative muscle integrity during long-term exposure to a myotoxic agent.

Older age predicts decreased metastasis and prostate cancer-specific death for men treated with radiation therapy: meta-analysis of radiation therapy oncology group trials.

PURPOSE: The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death (PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa. METHODS AND MATERIALS: Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD. RESULTS: Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age (≤70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p<0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p<0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p<0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p<0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio [HR], 1.56 [95% confidence interval [CI], 1.43-1.70] p<0.0001) but with decreased metastasis (HR, 0.72 [95% CI, 0.63-0.83] p<0.0001) and PCSD (HR, 0.78 [95% CI, 0.66-0.92] p<0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated. CONCLUSIONS: These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.

Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31.

PURPOSE: Gonadotropin-releasing hormone (GnRH) agonists are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about potential impact on cardiovascular mortality. We assessed the relationship between GnRH agonists and cardiovascular mortality in a large randomized phase III trial of men treated with or without adjuvant goserelin after radiation therapy (RT) for locally advanced prostate cancer. PATIENTS AND METHODS: Between 1987 and 1992, 945 men with locally advanced prostate cancer were randomly assigned to RT and adjuvant goserelin or RT alone. Fine and Gray's regression was used to evaluate treatment effect on cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus (DM), body mass index, race, Gleason score, stage, acid phosphatase level, prostatectomy history, and nodal involvement. RESULTS: After a median follow-up of 8.1 years, there were 117 cardiovascular-related deaths but no treatment-related increase in cardiovascular mortality. At 9 years, cardiovascular mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray's P = .17). In multiple regression analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 0.73; 95% CI, 0.47 to 1.15; P = .16; when censoring at time of salvage goserelin therapy, HR = 0.99; 95% CI, 0.58 to 1.69; P = .97). Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality. CONCLUSION: GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer. Further studies are warranted to evaluate adverse effects of GnRH agonists in men with lower cancer-specific mortality.

Diabetes and mortality in men with locally advanced prostate cancer: RTOG 92-02.

PURPOSE: Diabetes is associated with lower risk of prostate cancer. Most men with diabetes are obese, and obesity is associated with greater prostate cancer mortality. Whether diabetes influences outcomes after prostate cancer diagnosis is unknown. PATIENTS AND METHODS: We assessed the relationship between prevalent diabetes and mortality using data from Radiation Therapy Oncology Group Protocol 92-02, a large randomized trial of men (N = 1,554) treated with radiation therapy and short-term versus long-term adjuvant goserelin for locally advanced prostate cancer. Regression and proportional hazard models were performed to evaluate relationships between prevalent diabetes and all-cause mortality, prostate cancer mortality, and non-prostate cancer mortality. Covariates included age, race, tumor stage, Gleason score, prostate-specific antigen, weight, and treatment arm. RESULTS: There were a total of 765 deaths; 210 (27%) were attributed to prostate cancer. In univariate analyses, prevalent diabetes was associated with greater all-cause mortality and non-prostate cancer mortality but not prostate cancer mortality. After controlling for other covariates, prevalent diabetes remained significantly associated with greater all-cause mortality and non-prostate cancer mortality (hazard ratio [HR] = 2.12; 95% CI, 1.69 to 2.66; P < .0001) but not prostate cancer mortality (HR = 0.80; 95% CI, 0.51 to 1.25; P = .34). In contrast, weight was associated with greater prostate cancer mortality (HR = 1.77; 95% CI, 1.22 to 2.55; P = .002) but not all-cause or non-prostate cancer mortality. CONCLUSION: Weight but not prevalent diabetes is associated with greater prostate cancer mortality in men receiving combined modality treatment for locally advanced disease. These observations suggest that the association between obesity and greater prostate cancer mortality is mediated by mechanism(s) other than the characteristic metabolic alterations of diabetes.

Protein kinase A RI-alpha predicts for prostate cancer outcome: analysis of radiation therapy oncology group trial 86-10.

PURPOSE: The RI-alpha regulatory subunit of protein kinase A type 1 (PKA) is constitutively overexpressed in human cancer cell lines and is associated with active cell growth and neoplastic transformation. This report examined the association between PKA expression and the endpoints of biochemical failure (BF), local failure (LF), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality in men treated with radiotherapy, with or without short-term androgen deprivation in Radiation Therapy Oncology Group trial 86-10. METHODS AND MATERIALS: Pretreatment archival diagnostic tissue samples from 80 patients were stained for PKA by immunohistochemical methods from a parent cohort of 456 cases. PKA intensity was scored manually and by image analysis. The Cox proportional hazards model for overall mortality and Fine and Gray's regression models for CSM, DM, LF and BF were then applied to determine the relationship of PKA expression to the endpoints. RESULTS: The pretreatment characteristics of the missing and determined PKA groups were not significantly different. On univariate analyses, a high PKA staining intensity was associated with BF (image analysis, continuous variable, p = 0.022), LF (image analysis, dichotomized variable, p = 0.011), CSM (manual analysis, p = 0.037; image analysis, continuous, p = 0.014), and DM (manual analysis, p = 0.029). On multivariate analyses, the relationships to BF (image analysis, continuous, p = 0.03), LF (image analysis, dichotomized, p = 0.002), and DM remained significant (manual analysis, p = 0.018). In terms of CSM, a trend toward an association was seen (manual analysis, p = 0.08; image analysis, continuous, p = 0.09). CONCLUSION: PKA overexpression was significantly related to patient outcome and is a potentially useful biomarker for identifying high-risk prostate cancer patients who might benefit from a PKA knockdown strategy.

Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02.

OBJECTIVES: Gonadotropin-releasing hormone agonists (GnRHa) are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about their potential effects on cardiovascular mortality. We assessed the relationship between duration of GnRHa therapy and cardiovascular mortality in a large randomized trial of men treated with short-term versus longer-term adjuvant goserelin and radiation therapy (RT) for locally advanced prostate cancer. METHODS: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-4, prostate-specific antigen [PSA] <150 ng/ml) received RT and 4 mo of goserelin and then were randomized to no additional therapy (arm 1) or 24 mo adjuvant goserelin (arm 2) in a phase 3 trial (Radiation Therapy Oncology Group [RTOG] 92-02). Cox regression analyses were performed to evaluate the relationship between treatment arm and cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes (DM), race, PSA, Gleason score, and stage. RESULTS: After median follow-up of 8.1 yr, 185 cardiovascular-related deaths had occurred. No increase in cardiovascular mortality occurred for men receiving a longer duration of goserelin. At 5 yr, cardiovascular mortality for men receiving longer-term adjuvant goserelin was 5.9% versus 4.8% with short-term goserelin (Gray's p=0.16). In multivariate analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR]=1.09; 95% confidence interval [CI], 0.81-1.47; p=0.58; when censoring at time of salvage goserelin, HR=1.02, 95%CI, 0.73-1.43; p=0.9). Traditional cardiac risk factors, including age, prevalent CVD, and DM, were significantly associated with greater cardiovascular mortality. CONCLUSIONS: Longer duration of adjuvant GnRHa therapy does not appear to increase cardiovascular mortality in men with locally advanced prostate cancer.

Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term follow-up results. MATERIALS AND METHODS: Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF). RESULTS: Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. CONCLUSION: The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.

Obesity and mortality in men with locally advanced prostate cancer: analysis of RTOG 85-31.

BACKGROUND: Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy and radiation therapy (RT). Whether BMI is associated with prostate cancer-specific mortality (PCSM) was investigated in a large randomized trial of men treated with RT and androgen deprivation therapy (ADT) for locally advanced prostate cancer. METHODS: Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled in a phase 3 trial (RTOG 85-31) and randomized to RT and immediate goserelin or RT alone followed by goserelin at recurrence. Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relations between BMI and all-cause mortality, PCSM, and nonprostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI. RESULTS: The 5-year PCSM rate for men with BMI <25 kg/m(2) was 6.5%, compared with 13.1% and 12.2% in men with BMI > or =25 to <30 and BMI > or =30, respectively (Gray's P = .005). In multivariate analyses, greater BMI was significantly associated with higher PCSM (for BMI > or =25 to <30, hazard ratio [HR] 1.52, 95% confidence interval [CI], 1.02-2.27, P = .04; for BMI > or =30, HR 1.64, 95% CI, 1.01-2.66, P = .04). BMI was not associated with nonprostate cancer or all-cause mortality. CONCLUSIONS: Greater baseline BMI is independently associated with higher PCSM in men with locally advanced prostate cancer. Further studies are warranted to evaluate the mechanism(s) for increased cancer-specific mortality and to assess whether weight loss after prostate cancer diagnosis alters disease course.

Bcl-2 and bax expression and prostate cancer outcome in men treated with radiotherapy in Radiation Therapy Oncology Group protocol 86-10.

PURPOSE: Bcl-2 and bax are proteins with opposing roles in apoptosis regulation; yet abnormal expression of either has been associated with failure after radiotherapy (RT). In this study we examined bcl-2 and bax expression as predictive markers in men treated with radiotherapy +/- androgen deprivation on Radiation Therapy Oncology Group (RTOG) protocol 86-10. EXPERIMENTAL DESIGN: Suitable archival diagnostic tissue was obtained from 119 (26%) patients for bcl-2 analysis and 104 (23%) patients for bax analysis. Cox proportional hazards multivariate analysis was used to determine the relationship of abnormal bcl-2 and bax expression to the end points of local failure, distant metastasis, cause-specific mortality, and overall mortality. Bcl-2 overexpression was classified as any tumor cell cytoplasmic staining and altered bax expression was classified as greater or lesser cytoplasmic staining intensity of tumor cells as compared with adjacent normal prostate epithelium. RESULTS: The study cohort exhibited bcl-2 overexpression in 26% (n = 30) of cases and abnormal bax expression in 47% (n = 49) of cases. A borderline significant relationship was observed between abnormal bax expression and higher Gleason score (p = 0.08). In univariate and multivariate analyses, there was no statistically significant relationship seen between abnormal bcl-2 or bax expression and outcome. CONCLUSIONS: Abnormal bcl-2 and bax expression were not related to any of the end points tested. The cohort examined was comprised of patients with locally advanced disease and it is possible that these markers may be of greater value in men with earlier-stage prostate cancer.

Phase III study of pentosanpolysulfate (PPS) in treatment of gastrointestinal tract sequelae of radiotherapy.

OBJECTIVES: To evaluate the effectiveness of pentosanpolysulfate (PPS) in the treatment of gastrointestinal tract sequelae of radiotherapy. METHODS: Eligible patients were those with grade 1 to 3 radiation related proctitis, diarrhea and/or melena. At least 4 weeks had to elapse since the completion of the radiotherapy course. Patients with bleeding diathesis or ulcers, and patients receiving anticoagulants or chemotherapy were excluded. Stratification criteria included the type of sequelae (proctitis, diarrhea, melena), the severity grade and the onset (<3 months post-RT, >3 months post-RT). Patients were randomized to one of the following arms: 100 mg PPS 3 times per day (300 mg/day), 200 mg PPS 3 times per day (600 mg/day), or placebo 3 times per day. If there was no improvement in symptoms after 2 months, the protocol treatment was discontinued. If the symptoms improved or resolved, the protocol treatment was continued for additional 4 months. Patients under treatment were evaluated monthly, than every 2 to 3 months for the next 18 months. A symptom assessment questionnaire was used to measure quality of life endpoints. RESULTS: From June 1999 to March 2001 180 patients were accessioned from 34 institutions. A total of 168 were analyzable. Neither the best observed response within 3 months for the entire population, nor the response rate within sequelae category or the quality of life measures differed significantly between the 3 arms of the study. CONCLUSION: Administration of PPS has not been associated with an improvement in the clinical course of radiation related morbidity of the gastrointestinal tract.

Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group--RTOG 9705.

PURPOSE: To determine the overall survival, progression-free survival, and toxicity associated with concurrent paclitaxel/carboplatin and thoracic radiotherapy for completely resected patients with stage II and IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eighty-eight eligible patients had surgical resection for pathologic stage II or IIIA disease and received postoperative paclitaxel and carboplatin. Concurrent thoracic radiotherapy at 50.4 Gy in 28 fractions for 6 weeks (1.8 Gy/d, 5 days/wk) was given during cycles 1 and 2. A boost of 10.8 Gy in six fractions was given for extracapsular nodal extension or T3 lesions. RESULTS: Treatment compliance was acceptable, with 93% compliance for radiation therapy and 86% for chemotherapy completion. The median duration of follow-up was 56.7 months (range, 17 to 61 months). The median overall survival time was 56.3 months, with 1-, 2-, and 3-year survival rates of 86%, 70%, and 61%, respectively. The 1-, 2-, and 3- year progression-free survival rates were 70%, 57%, and 50%, respectively. Brain metastasis occurred as the sole site of first failure in 11%, and 9% failed in other metastatic sites as first failure. Of the 43 patients who died, the cause of death was the treated cancer in 31 (35%). Local failure was a component of first failure in 15% of patients. Toxicities were acceptable. An overall survival comparison to Eastern Cooperative Oncology Group 3590 is favorable. CONCLUSION: The mature results of this trial suggest an improved overall and progression-free survival in this group of resected NSCLC patients, compared with previously reported trials. A phase III trial comparing this treatment regimen with standard therapy seems warranted.

Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31.

PURPOSE: Radiation Therapy Oncology Group protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT). METHODS AND MATERIALS: Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression. RESULTS: Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p <0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p <0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm. CONCLUSION: In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7-10.

Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31.

PURPOSE: To update the effect of immediate androgen suppression in conjunction with standard external-beam irradiation versus radiation alone on a group of histologically lymph node-positive patients with adenocarcinoma of the prostate. MATERIALS AND METHODS: A national prospective randomized trial (Radiation Therapy Oncology Group 85-31) of standard external-beam irradiation plus immediate androgen suppression versus external-beam irradiation alone was initiated in 1985 for patients with locally advanced adenocarcinoma of the prostate. One hundred seventy-three patients in this trial had histologically involved lymph nodes. Ninety-eight patients received radiation plus immediate androgen suppression (luteinizing hormone-releasing hormone [LHRH] agonist), whereas 75 patients received radiation alone with hormonal manipulation instituted at the time of relapse. RESULTS: With a median follow-up of 6.5 years for all patients and 9.5 years for living patients, estimated progression-free survival with prostate-specific antigen (PSA) level less than 1.5 ng/mL at 5 and 9 years was 54% and 33%, respectively, for patients who received immediate LHRH agonist versus 10% [corrected] and 4% for patients who received radiation alone with hormonal manipulation instituted at time of relapse (P < .0001). Multivariate analysis revealed radiation therapy and immediate hormonal manipulation as having a statistically significant impact on all end points analyzed: absolute survival, disease-specific failure, metastatic failure, and biochemical control with PSA less than 4 ng/mL and less than 1.5 ng/mL. CONCLUSION: Pending the results of randomized trials, patients with adenocarcinoma of the prostate who have pathologically involved pelvic lymph nodes (pathologic node-positive or clinical stage D1) should be considered for external-beam irradiation plus immediate hormonal manipulation rather than radiation alone with hormone manipulation at the time of relapse.

Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy.

PURPOSE: A phase III, randomized, double-blind study was conducted by the North Central Cancer Treatment Group to determine the efficacy and toxicity of oral glutamine for the prevention of acute diarrhea in patients receiving pelvic radiation therapy (RT). PATIENTS AND METHODS: All 129 patients enrolled from 14 institutions between February 1998 and October 1999 were eligible. Patients received 4 g of glutamine or placebo orally, twice a day, beginning with the first or second day of RT and continuing for 2 weeks after RT. During treatment, patients were assessed weekly for toxicity, and a bowel function questionnaire was administered. The primary measures of treatment efficacy were diarrhea levels measured by maximum grade of diarrhea, incidence of diarrhea, and average diarrhea score. After completion of RT, the bowel function questionnaire was administered weekly for 4 weeks and at 12 and 24 months. Toxicity was measured by National Cancer Institute common toxicity criteria. RESULTS: The median age of patients was 69 years (range, 34 to 86 years). The two treatment arms were balanced with respect to all baseline factors. There were no significant differences in toxicity by treatment. Quality-of-life scores and the mean number of problems reported on the bowel function questionnaire were virtually identical for both treatment groups. The incidence of grade 3 or higher diarrhea was 20% for the glutamine arm and 19% for the placebo arm (P =.99). The maximum number of stools per day was 5.1 for the glutamine arm and 5.2 for the placebo arm (P =.99). CONCLUSION: There is no evidence of a beneficial effect of glutamine during pelvic RT.

Overview of bladder cancer trials in the Radiation Therapy Oncology Group.

In the United States, radical cystectomy is viewed as the gold standard and, with few exceptions, is the only treatment recommended for patients with invasive bladder cancer. In many areas of cancer treatment, however, the trend in the 1990s has been toward organ conservation using combined chemotherapy and radiation with or without conservative local surgery. For patients with breast, esophageal, anal, and laryngeal cancers as well as limb sarcomas, conservative therapy often is recommended. However, invasive bladder cancer has not been viewed generally as a condition that allows for conservative management. In the past 15 years, the Radiation Therapy Oncology Group (RTOG) has completed six prospective protocols of combined-modality therapy for patients with muscle-invasive cancer who were candidates for cystectomy. Bladder preservation with intravesical surgery, chemotherapy, and radiation therapy were combined as initial treatment, with radical cystectomy recommended for incomplete responders. Five of the RTOG protocols were Phase I-II trials of concurrent chemotherapy and radiation therapy, and one protocol was a Phase III trial that tested the efficacy of adjuvant chemotherapy with methotrexate, cisplatin, and vinblastine. A total of 415 patients were entered on these trials. The 5-year overall survival rate was approximately 50%, with three-quarters of those patients achieving a cure for their bladder cancer while maintaining a functioning bladder. The current RTOG protocol and its successor are directed toward better tolerated and potentially more effective chemotherapy regimens that may result in a high protocol compliance rate and, possibly, a higher overall survival rate. The trimodality therapeutic approach used in all of these RTOG protocols was more effective compared with the radiation monotherapy offered in the 1970s and with protocols that used only chemotherapy. Trimodality therapy with selective bladder preservation is not designed to take the place of radical cystectomy; however, it may be offered as a reasonable alternative to patients with invasive bladder cancer who are not willing to undergo radical cystectomy and urinary diversion. A bladder-sparing strategy may be offered appropriately to highly selected patients with the understanding that radical cystectomy is an available option in those who fail combined radiation and chemotherapy with no diminution in survival related to the delay in cystectomy.