Review of current best practice and priorities for research in radiation oncology for elderly patients with cancer: the International Society of Geriatric Oncology (SIOG) task force.

Radiotherapy (RT) is a key component of the management of older cancer patients. Level I evidence in older patients is limited. The International Society of Geriatric Oncology (SIOG) established a task force to make recommendations for curative RT in older patients and to identify future research priorities. Evidence-based guidelines are provided for breast, lung, endometrial, prostate, rectal, pancreatic, oesophageal, head and neck, central nervous system malignancies and lymphomas. Patient selection should include comorbidity and geriatric evaluation. Advances in radiation planning and delivery improve target coverage, reduce toxicity and widen eligibility for treatment. Shorter courses of hypofractionated whole breast RT are safe and effective. Conformal RT and involved-field techniques without elective nodal irradiation have improved outcomes in non-small-cell lung cancer (NSCLC) without increasing toxicity. Where comorbidities preclude surgery, stereotactic body radiotherapy (SBRT) is an option for early-stage NSCLC and pancreatic cancer. Modern involved-field RT for lymphoma based on pre-treatment positron emission tomography data has reduced toxicity. Significant comorbidity is a relative contraindication to aggressive treatment in low-risk prostate cancer (PC). For intermediate-risk disease, 4-6 months of hormones are combined with external beam radiotherapy (EBRT). For high-risk PC, combined modality therapy (CMT) is advised. For high-intermediate risk, endometrial cancer vaginal brachytherapy is recommended. Short-course EBRT is an alternative to CMT in older patients with rectal cancer without significant comorbidities. Endorectal RT may be an option for early disease. For primary brain tumours, shorter courses of postoperative RT following maximal debulking provide equivalent survival to longer schedules. MGMT methylation status may help select older patients for temozolomide alone. Stereotactic RT provides an alternative to whole-brain RT in patients with limited brain metastases. Intensity-modulated radiation therapy provides an excellent technique to reduce dose to the carotids in head and neck cancer and improves locoregional control in oesophageal cancer. Best practice and research priorities are summarised.

RTOG 0518: randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients.

BACKGROUND: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). METHODS: Eligible patients with T-scores of the hip (<-1.0, but >-2.5 vs >-1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. RESULTS: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm 1 and 34.8 months for Arm 2. Only two patients experienced a bone fracture (one in each arm) resulting in no difference in freedom from any bone fracture (P=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs -5%, P<0.0001), left total hip (1% vs -8%, P=0.0002), and left femoral neck (3% vs -8%, P=0.0007). CONCLUSIONS: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.

Flying and midface fractures: the truth is out there.

There are no clear, evidence-based guidelines that dictate when it is safe for a patient to fly after sustaining a midface fracture. From January 2006 to December 2009, the Royal Darwin Hospital Maxillofacial Unit had 48 out of 201 patients with an orbital fracture that involved a paranasal air sinus transported by a variety of aircraft to the unit for definitive management. No orbital complications were recorded for the 24% of patients requiring air travel to our tertiary referral centre. Furthermore, there were no recorded deviations from the standard flight plan. We believe that this demonstrates there are no absolute contraindications to flying on a variety of aircraft with a midface fracture, but clinical assessment remains crucial for an informed decision to transport these patients by air.

Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck.

PURPOSE: To define further the role of concurrent chemoradiotherapy for patients with advanced squamous carcinoma of the head and neck. PATIENTS AND METHODS: The Radiation Therapy Oncology Group developed this three-arm randomized phase II trial. Patients with stage III or IV squamous carcinoma of the oral cavity, oropharynx, or hypopharynx were eligible. Each of three arms proposed a radiation schedule of 70 Gy in 35 fractions. Patients on arm 1 were to receive cisplatin 10 mg/m(2) daily and fluorouracil (FU) 400 mg/m(2) continuous infusion (CI) daily for the final 10 days of treatment. Treatment on arm 2 consisted of hydroxyurea 1 g every 12 hours and FU 800 mg/m(2)/d CI delivered with each fraction of radiation. Arm 3 patients were to receive weekly paclitaxel 30 mg/m(2) and cisplatin 20 mg/m(2). Patients randomly assigned to arms 1 and 3 were to receive their treatments every week; patients on arm 2 were to receive their therapy every other week. RESULTS: Between 1997 and 1999, 241 patients were entered onto study; 231 were analyzable. Ninety-two percent, 79%, and 83% of patients on arms 1, 2, and 3, respectively, were able to complete their radiation as planned or with an acceptable variation. Fewer than 10% of patients had unacceptable deviations or incomplete chemotherapy in the three arms. Estimated 2-year disease-free and overall survival rates were 38.2% and 57.4% for arm 1, 48.6% and 69.4% for arm 2, and 51.3% and 66.6% for arm 3. CONCLUSION: We have demonstrated that three different approaches of concurrent multiagent chemotherapy and radiation were feasible and could be delivered to patients in a multi-institutional setting with high compliance rates.

Relative impact of patient and clinic factors on adherence to primary care preventive service guidelines: an exploratory study.

BACKGROUND: Preventive care service use is commonly compared across health plans, clinics, or individual providers, yet little is known about the influence of the clinic versus patient factors on utilization of these services. OBJECTIVES: To measure the relative influence of the facility (clinic) versus patient factors (demographic, behavioral and functional characteristics) on patients' utilization of mammography, Pap smears, cholesterol screening, and retinal exams for those with diabetes. RESEARCH DESIGN: Retrospective analysis, using administrative and patient survey data. SUBJECTS: Enrollees in 2 University-based clinics and a county hospital-based clinic serving a predominantly low-income population with limited access to health care. Eligibility for cervical cancer screening, screening mammography, cholesterol screening, or annual retinal exam (diabetes) was defined by age, sex, and diagnosis. MEASURES: Multivariate models, one using readily available administrative data, and another using detailed health status and behavior data gathered from a clinics-wide survey. RESULTS: Unadjusted screening rates for three of four procedures were significantly and substantially lower at the county hospital based clinic than the two University-based clinics. After adjusting for patient characteristics, utilization of three screening services at the county hospital remained significantly below the University-based clinics (Odds Ratios [95% CI]: mammogram 0.15 [0.06-0.35]; Pap smear 0.32 [0.21-0.50]; cholesterol 0.19 [0.09-0.38]; diabetes retinal exam10.68 [0.93-3.01]). The models with detailed survey data performed only marginally better than the models using only administrative data. CONCLUSIONS: Patient characteristics were much less important than the clinic for predicting whether patients received primary care preventive services. Our results suggest that case mix adjustment is unlikely to explain away discrepancies in performance between clinics or provider groups.

Immunomodulatory effects of anti-CD4 antibody in host resistance against infections and tumors in human CD4 transgenic mice.

Anti-CD4 antibodies, which cause CD4(+) T-cell depletion, have been shown to increase susceptibility to infections in mice. Thus, development of anti-CD4 antibodies for clinical use raises potential concerns about suppression of host defense mechanisms against pathogens and tumors. The anti-human CD4 antibody keliximab, which binds only human and chimpanzee CD4, has been evaluated in host defense models using murine CD4 knockout-human CD4 transgenic (HuCD4/Tg) mice. In these mice, depletion of CD4(+) T cells by keliximab was associated with inhibition of anti-Pneumocystis carinii and anti-Candida albicans antibody responses and rendered HuCD4/Tg mice susceptible to P. carinii, a CD4-dependent pathogen, but did not compromise host defense against C. albicans infection. Treatment of HuCD4/Tg mice with corticosteroids impaired host immune responses and decreased survival for both infections. Resistance to experimental B16 melanoma metastases was not affected by treatment with keliximab, in contrast to an increase in tumor colonization caused by anti-T cell Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of keliximab. This was further demonstrated by the differential effect of keliximab on type 1 and type 2 cytokine expression in splenocytes stimulated ex vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation of IL-4 and IL-10. Taken together, the effects of keliximab in HuCD4/Tg mice suggest that in addition to depleting circulating CD4(+) T lymphocytes, keliximab has the capability of modulating the function of the remaining cells without causing general immunosuppression. Therefore, keliximab therapy may be beneficial in controlling certain autoimmune diseases.

Preclinical development of keliximab, a Primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies.

The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.

A controlled time-series trial of clinical reminders: using computerized firm systems to make quality improvement research a routine part of mainstream practice.

OBJECTIVE: To explore the feasibility of conducting unobtrusive interventional research in community practice settings by integrating firm-system techniques with time-series analysis of relational-repository data. STUDY SETTING: A satellite teaching clinic divided into two similar, but geographically separated, primary care group practices called firms. One firm was selected by chance to receive the study intervention. Forty-two providers and 2,655 patients participated. STUDY DESIGN: A nonrandomized controlled trial of computer-generated preventive reminders. Net effects were determined by quantitatively combining population-level data from parallel experimental and control interrupted time series extending over two-month baseline and intervention periods. DATA COLLECTION: Mean rates at which mammography, colorectal cancer screening, and cholesterol testing were performed on patients due to receive each maneuver at clinic visits were the trial's outcome measures. PRINCIPAL FINDINGS: Mammography performance increased on the experimental firm by 154 percent (0.24 versus 0.61, p = .03). No effect on fecal occult blood testing was observed. Cholesterol ordering decreased on both the experimental (0.18 versus 0.1 1, p = .02) and control firms (0.13 versus 0.07, p = .03) coincident with national guidelines retreating from recommending screening for young adults. A traditional uncontrolled interrupted time-series design would have incorrectly attributed the experimental-firm decrease to the introduction of reminders. The combined analysis properly indicated that no net prompting effect had occurred, as the difference between firms in cholesterol testing remained stochastically stable over time (0.05 versus 0.04, p = .75). A logistic-regression analysis applied to individual-level data produced equivalent findings. The trial incurred no supplementary data collection costs. CONCLUSIONS: The apparent validity and practicability of our reminder implementation study should encourage others to develop computerized firm systems capable of conducting controlled time-series trials.

Atiprimod (SK&F 106615), a novel macrophage targeting agent, enhances alveolar macrophage candidacidal activity and is not immunosuppressive in Candida-infected mice.

Azaspiranes are novel macrophage-targeting agents with activity in preclinical animal models of autoimmune disease and transplantation. The purpose of this work was to determine the effects of atiprimod (SK&F 106615), an azaspirane being developed for the treatment of rheumatoid arthritis, on rat pulmonary alveolar macrophage (AM) function and immunocompetance in Candida-infected mice. AM from rats treated with 20 mg/kg/day of atiprimod for 15 days demonstrated enhanced killing of Candida albicans ex vivo. Concentration-dependent increases in candidacidal activity were also observed as early as one hour after exposure in vitro in AM from untreated normal rats. Treatment of AM with atiprimod in vitro did not increase particulate-stimulated superoxide production or phagocytosis of Candida but decreased their ability to concentrate acridine orange, indicating an increase in lysosomal pH. Increased candidacidal activity was inhibited by superoxide dismutase and catalase, suggesting a role for reactive oxygen intermediates (ROI). Atiprimod also increased free radical-mediated killing of Candida in the presence of H2O2, iron and iodide in a cell-free system. These findings indicated that treatment with atiprimod increased the candidacidal activity of rat AM in a free radical-dependent manner. The data also suggested that atiprimod did not increase ROI production by AM, but rather increased the efficiency of radical-mediated killing. This increase may be caused by cyclization of atiprimod, facilitating electron transfer and peroxidation of lipid membranes. In vivo studies in Candida-infected CBA mice showed that atiprimod (10 mg/kg/day), did not compromise immune function in the infected mice and could be differentiated from prototypical immunosuppressive compounds used for treatment of autoimmune diseases.

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis.

UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. STUDY DESIGN: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. RESULTS: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. CONCLUSION: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.

Pulmonary function changes in long-term survivors of bone marrow transplantation.

PURPOSE: This study was undertaken to evaluate long-term pulmonary function changes in patients undergoing bone marrow transplantation (BMT), to assess their clinical significance, and to identify factors influencing these changes. METHODS AND MATERIALS: Pulmonary function tests (PFT) were evaluated before and after BMT in 111 adult patients undergoing BMT between 1985 and 1991. Forced expiratory volume at 1 s (FEV1), forced vital capacity (FVC), diffusing capacity (DLCO), and total lung capacity (TLC) were evaluated. One hundred and three patients (92.8%) received total body irradiation (TBI) to a total dose of 14 Gy in nine equal fractions. The lung dose was restricted to < 6.5 Gy in 95% of patients with partial transmission lung shielding. Seventy-eight percent of patients had acute graft-versus-host disease (aGVHD), 69% chronic graft-vs.-host disease (cGVHD), and 63% posttransplant pulmonary infection. Effects of GVHD, TBI, radiation dose to the lungs, dose rate of TBI, posttransplant pulmonary infection, Busulfan use for conditioning, age, and history of smoking were evaluated for their influence on pulmonary function. RESULTS: Posttransplant FEV1, FVC, and TLC were lower than pretransplant values (p < 0.05) at 6 months and 1 year posttransplant with subsequent recovery. DLCO was significantly lower at all posttransplant intervals. FEV1 did not fall significantly in patients without acute or chronic GVHD and recovered earlier than in patients without posttransplant pulmonary infection. Recovery of FVC, TLC, and DLCO was also delayed in patients with acute and chronic GVHD and posttransplant pulmonary infection. Multiple regression analysis revealed an association between a higher radiation dose to the lungs, and decreased FVC at 2 years (p = 0.01). Progressive obstructive pulmonary disease was not observed. CONCLUSION: An initial decline in PFTs with subsequent recovery was observed. Factors associated with delayed recovery and incomplete recovery of PFTs were GVHD, posttransplant pulmonary infection, and higher radiation dose to the lungs. The conditioning regimen used at Medical College of Wisconsin, including relatively high TBI doses with partial transmission pulmonary shielding, appears to be well tolerated by the lungs in long-term survivors. No progressive decline in PFTs or symptomatic decline in pulmonary function was observed during the time interval studied.

Comparison of high dose-rate and low dose-rate dose distributions for vaginal cylinders.

PURPOSE: The identification of appropriate high dose-rate parameters required to produce a "uniform" dose distribution on the surface of a vaginal cylinder. The high dose-rate dose distribution is then compared to the traditional low dose-rate dose distributions obtained with Burnett cylinders. METHODS AND MATERIALS: Dose distributions were calculated for 2, 3, and 3.5 cm diameter Burnett cylinders with and without crossing sources. Three models for the high dose-rate cylinders were developed and compared. High dose-rate dose distributions were calculated for 2, 3, and 3.5 cm diameter cylinders with and without anisotropic corrections for various dose specification points. RESULTS: Low dose-rate distributions are not uniform over the surface of the applicator. The exact distribution depends upon cylinder diameter and upon the exact source loading. High dose rate dose distributions can be configured to provide for a "uniform" dose on the surface, if an apex dose specification point is used together with dose specification points on the surface of the applicator opposite each dwell position. CONCLUSIONS: The conversion of low dose rate techniques to high dose rate techniques for vaginal cylinders involves an appreciation of the details of dose distributions of both approaches. The comparison between traditional low dose-rate distributions and high dose-rate distributions shows that, unlike the low dose-rate distributions, a relatively uniform high dose-rate distribution can be obtained independent of cylinder diameter. The clinical significance of the differences in the low dose-rate and high dose-rate dose distributions remains to be determined by long-term follow up of patients treated with high dose-rate techniques.

The effect of respiratory viral infections on patients with cystic fibrosis.

We examined, in a 2-year prospective study, the frequency of respiratory viral infections in 19 school-age patients with cystic fibrosis and their unaffected siblings. At 2-month intervals throughout the study period, pulmonary function tests, oropharyngeal cultures, and serologic tests for respiratory viruses were performed in all subjects. Quantitative sputum cultures for bacteria were performed in subjects with cystic fibrosis. The same laboratory specimens were also collected at the time of all acute respiratory illnesses. Over the 2-year period, 398 viral cultures and serum samples were collected, 210 from patients with cystic fibrosis and 188 from their siblings. The frequency of culture-documented and seropositive viral infections was not significantly different between patients with cystic fibrosis and their siblings. The patients with the highest frequency of viral infection were younger and had the lowest rate of decline in lung function and severity score. We conclude that school-age patients with cystic fibrosis are no more susceptible to viral infections than their unaffected siblings. We were unable to demonstrate any significant adverse effect of respiratory viral infections on pulmonary function in 19 patients with cystic fibrosis aged 5 to 21 years.

Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis.

To determine the potential toxicity of prolonged aerosol tobramycin administration, 22 patients with cystic fibrosis were monitored while receiving inhaled tobramycin three times a day for 12 weeks. Prior to, four times during administration and approximately 6 weeks after discontinuation of treatment, we assessed pulmonary function, weight, height, body temperature, eighth cranial nerve function, serum creatinine, blood urea nitrogen, urinary creatinine clearance, plasma iothalamate clearance, urinary beta-2 microglobulin concentration, and Pseudomonas aeruginosa density in sputum. There was no detectable laboratory evidence of nephrotoxicity. Neither a decrease in auditory acuity (range 250-20,000 Hz) nor vestibular dysfunction was detected. Pulmonary function tests significantly improved during the first month in all subjects (P less than 0.05) but returned to enrollment values by the end of the 12th week of administration of tobramycin aerosol. Sputum P. aeruginosa density initially decreased from a mean of 10(7) cfu/gm to a mean of 10(4) cfu/gm after 2 weeks of aerosol tobramycin administration and remained significantly below the enrollment value throughout. Coincident with the reduced bacterial density, a reduction in cough frequency and sputum production, as well as a weight gain was observed. Seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrollment yielded resistant organisms during aerosol administration. However, 1 year later all sputum P. aeruginosa isolates obtained from patients were susceptible to tobramycin. We conclude that thrice daily aerosol tobramycin administration for 3 months is not associated with detectable eighth cranial nerve or renal toxicity. Transient emergence of tobramycin resistant P. aeruginosa may occur.

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis.

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.