MEDiastinal Irradiation and CArdio-Toxic Effects (MEDICATE): Exploring the Relationship between Cardiac Irradiation and High Sensitivity Troponins.

AIMS: Radiation-induced heart disease is a late effect of cardiac irradiation and has been shown in patients with lymphoma and thoracic cancers. There is no established measurement tool to detect acute cardiac damage. However, high sensitivity troponin I and T (HsTnI and HsTnT) and echocardiograms have shown promise in some studies. A pilot trial was conducted to characterise whether these instruments may detect subclinical radiotherapy-induced cardiac damage. MATERIALS AND METHODS: Eligible patients received high cardiac doses defined by either at least 30 Gy to 5% of cardiac volume or a mean dose of 4 Gy. HsTnI and HsTnT were measured before radiotherapy and after 2 and 4 weeks of radiotherapy; three-dimensional echocardiograms were completed before and 1 year after radiotherapy. RESULTS: Of 19 patients, the median 'mean left ventricular dose' was 3.1 Gy and the 'mean cardiac dose' was 8.6 Gy. Significant positive associations between HsTnI and HsTnT were observed at all time points, but there was no significant association with cardiac dose. The mean left ventricular dose and the maximum left ventricular dose were, however, associated with a decrease in ejection fraction (P = 0.054, 0.043) as well as an increase in left ventricular strain (P = 0.058). CONCLUSION: This study suggests that HsTnI and HsTnT are intimately related, but detection of acute cardiac damage was not shown, potentially due to limitations of these markers or low radiotherapy doses using conformal techniques. Our results also suggest subacute damage at 1 year may depend on the dose to the left ventricle. Further studies are needed, as identification of early damage could facilitate the ability to closely monitor and intervene in patients at risk for radiation-induced heart disease.

Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer.

BACKGROUND: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. METHODS: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. CONCLUSIONS: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

Cross-border referral for early breast cancer: an analysis of radiation fractionation patterns.

Because of increasing waiting times for adjuvant radiation in the province of Ontario, patients from one Canadian centre were referred to two centres in the United States. This situation provided an opportunity to compare radiation practices.We performed a retrospective review of radiation prescribed to patients following breast-conserving surgery for invasive breast cancer. Patients with positive margins, 4 or more positive lymph nodes, recurrent disease, or large tumours (>5 cm) were excluded. For comparison, we reviewed a random sample of similar patients treated at the Canadian centre during the same period. A total of 120 referred and 217 non-referred patients were eligible for comparison. The analysis included 98 pairs of patients (N = 196), fully matched on age, nodal status, T stage, grade, and estrogen receptor (er) status.Mean patient age was 60.7 years. The median total dose and number of fractions differed between centres [6040 cGy in 32 fractions (United States) vs. 4250 cGy in 16 fractions (Canadian), both p < 0.001). Boost was used more often in the United States (97% vs. 9%, p < 0.001). Variation in prescribing patterns was seen. In the United States, seven different schedules for whole-breast irradiation were used; at the Canadian centre, two schedules were prescribed. Predicted radiobiologic effects of these schedules were calculated to be similar.Differences in fractionation patterns were observed between and within U.S. and Canadian centres. Such variability is likely to affect patient convenience and resource utilization. Although patient selection, referring surgeon, and change in policies may account for some of the observed differences, further research is necessary to better understand the causes.

Predicting 2-year survival for radiation regimens in advanced non-small cell lung cancer.

AIMS: Total dose, dose per fraction, number of fractions and treatment time are important determinants of the biological effect of a radiation regimen. Several randomised clinical trials (RCTs) have tested a variety of dosing regimens in advanced unresected non-small cell lung cancer, but survival remains poor. This work used past RCT data to develop and validate a predictive model that could help in designing new radiation regimens for successful testing in RCTs. MATERIALS AND METHODS: Eleven RCTs that compared radiation regimens alone were used to define the relationship between radiation regimens and 2-year survival. On the basis of this relationship, predictive models were developed. Predicted values were internally and externally validated against observed values from the same 11 RCTs and 21 other RCTs. Scatter plots and Pearson's correlation coefficient (r) were used for validation. Finally, regimens were explored that could improve survival. RESULTS: Increments in the total dose, dose per day and the number of treatment days were associated with improved survival; increments in dose-squared and treatment weeks were associated with reduced survival. The observed and predicted values were similar on internal (r = 0.96) and external validation (r = 0.76). Regimens that delivered a higher total dose over a shorter time had higher survival rates compared with the standard (60 Gy, 30 fractions, 6 weeks); survival may be improved by delivering the standard treatment in 5 weeks rather than 6 weeks. CONCLUSION: The developed model can predict the effect of thoracic radiation on survival in advanced non-small cell lung cancer patients. It is a useful tool for designing new radiation regimens for clinical trials.

Unresected stage III non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group.

GUIDELINE QUESTIONS: 1) What is the role of different schedules or doses of radiotherapy in patients with unresected, clinical or pathological, stage III non-small-cell lung cancer (NSCLC)? 2) Does chemotherapy combined with radiotherapy provide improved survival compared with radiotherapy alone in patients with unresected NSCLC? OBJECTIVE: To make recommendations about the role of chemotherapy and radiotherapy in the treatment of unresected stage III NSCLC. OUTCOMES: Survival is the primary outcome of interest. Quality of life is a secondary outcome. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 5 members of the Provincial Lung Cancer Disease Site Group (Lung DSG) of the Ontario Cancer Treatment Practice Guidelines Initiative. The Lung DSG comprises medical and radiation oncologists, pathologists, surgeons, epidemiologists, a psychologist and a medical sociologist. No community representative participated in the development of this guideline. QUALITY OF EVIDENCE: Two meta-analyses were available for review. The specific analysis of interest examined the role of combined chemotherapy plus radiotherapy v. radiotherapy alone in locally advanced disease. The first meta-analysis included combined data from 22 randomized controlled (RCTs) involving a total of 3033 patients. The second included combined data from 14 RCTs involving a total of 2589 patients. Also reviewed were 4 RCTs of radiotherapy alone, 1 trial of combined chemotherapy and radiotherapy that was not included in the meta-analysis, 4 abstracts of studies of combined chemotherapy and radiotherapy, and 4 trials examining the role of hyperfractionated radiotherapy. BENEFITS: In the first meta-analysis, an overall benefit was detected at 2 years for the use of combined chemotherapy and radiotherapy. A hazard ratio of 0.90 (p = 0.006), or a 10% reduction in the risk of death, translated into an absolute benefit of 3% at 2 years and 2% at 5 years. A subgroup analysis of cisplatin-based chemotherapy plus radiotherapy versus radiotherapy alone demonstrated a 13% reduction in the risk of death in the combined treatment arm (pooled hazard ratio 0.87, 95% confidence interval [CI] 0.79-0.96), for an absolute benefit of 4% at 2 years. In the second meta-analysis, there was a 13% reduction in the risk of death in the combined therapy arm at 2 years (pooled relative risk [RR] 0.87, 95% CI 0.81-0.94) and a 17% reduction at 3 years (pooled RR 0.83, 95% CI 0.77-0.90). Subgroup analysis of cisplatin-based chemotherapy plus radiotherapy versus radiotherapy alone showed similar results: a 15% reduction in the risk of death in the combined therapy arm at 2 years (pooled RR 0.85, 95% CI 0.79-0.92) and a 19% reduction at 3 years (pooled RR 0.81, 95% CI 0.74-0.88). PRACTICE GUIDELINE: For patients with unresected stage III NSCLC, the combination of cisplatin-based chemotherapy and radical radiotherapy provides a survival benefit compared with radiotherapy alone. This guideline is based on high-quality evidence from 2 meta-analyses of RCTs. Patients with good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1) and minimal weight loss (less than 5% in the preceding 3 months) have been shown to have a survival benefit from treatment with combined chemotherapy and radiotherapy and should be considered for this type of treatment approach (see section V). For these patients, thoracic irradiation of 60 Gy in 30 fractions over 6 weeks, in combination with cisplatin-based chemotherapy, should be recommended as a treatment option. The patient and physician should discuss fully the benefits, limitations and toxic effects of therapy. Patients not meeting these criteria are not candidates for combined therapy; those experiencing symptoms amenable to treatment should receive palliative thoracic irradiation. At this time, hyperfractionated radiotherapy is not recommended outside of the context of a clinical trial. (ABSTRACT TRUNCATED)

A randomised trial of two information packages distributed to new cancer patients before their initial appointment at a regional cancer centre.

The purpose of this study was to evaluate the extent to which a new patient information package (NPIP) or a mini version of the same package (mini-NPIP) reduces emotional distress and meets the informational needs of patients arriving at a tertiary cancer centre for the first time. A comprehensive package, NPIP, consisting of procedural information regarding cancer centre location, description of the health care team, treatment services, research, educational activities, accommodation and community services provided at the centre; and a condensed version of the same package, mini-NPIP, were developed. Consecutive patients with newly diagnosed breast, gynaecological, lung and prostate cancer, referred to the centre for the first time were prerandomised to receive NPIP, mini-NPIP or no information package. Patients randomised to NPIP or mini-NPIP were mailed the information package at least one week before their first appointment. On arrival at the centre, patients were administered the Brief Symptom Inventory (BSI) which measures psychological distress, and interviewed regarding preferences for information and acceptability of the information packages. Of 465 randomised patients, 161 were excluded post-randomisation and 304 completed the entire interview: 100 were randomised to the NPIP, 102 to the mini-NPIP and 102 to the control group. Emotional distress as measured by the BSI was similar for all groups (P = 0.98). Most patients preferred to receive the information (98%), receive it before the first appointment (84%) and by mail (79%). These preferences were more evident for those given the information packages. The majority of patients found the information packages easy to understand (88%) and useful (89%), and no differences were detected between packages. The cost of production and dissemination of NPIP was more than double the cost for mini-NPIP: $ 8.93 vs $ 3.98 (Canadian dollars) per patient. For patients presenting to a cancer centre for the first time, packages of procedural information do not appear to reduce psychological distress, but are preferred by patients. Given the cost of producing NPIP, mini-NPIP is the preferred approach.