Michael Brundage

Sleep disturbance in cancer patients

Sleep difficulty is a prominent concern of cancer patients, yet there has been no large study of the prevalence and nature of sleep disturbance in cancer patients. This cross-sectional survey study examined: (a) the prevalence of reported sleep problems in patients attending six clinics at a regional cancer centre; (b) sleep problem prevalence in relation to cancer treatment; and (c) the nature of reported insomnia (type, duration, and associated factors). For three months, all patients attending clinics for breast, gastrointestinal, genitourinary, gynecologic, lung, and non-melanoma skin cancers were offered a brief sleep questionnaire. Response rate was 87%; the final sample size was 982. Mean age of respondents was 64.9 years (SD 12.5). The most prevalent problems were excessive fatigue (44% of patients), leg restlessness (41%). insomnia (31%), and excessive sleepiness (28%). Chi square tests showed significant variation among clinics in the prevalence of most sleep problems. The lung clinic had the highest or second-highest prevalence of problems. The breast clinic had a high prevalence of insomnia and fatigue. Recent cancer treatment was associated with excessive fatigue and hypersomnolence. Insomnia commonly involved multiple awakenings (76% of cases) and duration > or = 6 months (75% of cases). In 48% of cases, insomnia onset was reported to occur around the time of cancer diagnosis (falling within the period 6 months pre-diagnosis to 18 months post-diagnosis). The most frequently identified contributors to insomnia were thoughts, concerns, and pain/discomfort. In a multivariate logistic regression analysis, variables associated with increased odds of insomnia were fatigue, age (inverse relationship), leg restlessness, sedative/hypnotic use, low or variable mood, dreams, concerns, and recent cancer surgery. This study provides new information about sleep-related phenomena in cancer patients, information which will be useful in planning supportive care services for cancer patients.

Reporting of Patient-Reported Outcomes in Randomized Trials: The CONSORT PRO Extension

The CONSORT (Consolidated Standards of Reporting Trials) Statement aims to improve the reporting of randomized controlled trials (RCTs); however, it lacks guidance on the reporting of patient-reported outcomes (PROs), which are often inadequately reported in trials, thus limiting the value of these data. In this article, we describe the development of the CONSORT PRO extension based on the methodological framework for guideline development proposed by the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network. Five CONSORT PRO checklist items are recommended for RCTs in which PROs are primary or important secondary end points. These recommendations urge that the PROs be identified as a primary or secondary outcome in the abstract, that a description of the hypothesis of the PROs and relevant domains be provided (ie, if a multidimensional PRO tool has been used), that evidence of the PRO instruments validity and reliability be provided or cited, that the statistical approaches for dealing with missing data be explicitly stated, and that PRO-specific limitations of study findings and generalizability of results to other populations and clinical practice be discussed. Examples and an updated CONSORT flow diagram with PRO items are provided. It is recommended that the CONSORT PRO guidance supplement the standard CONSORT guidelines for reporting RCTs with PROs as primary or secondary outcomes. Improved reporting of PRO data should facilitate robust interpretation of the results from RCTs and inform patient care.

Phase III Trial Comparing Radical Radiotherapy With and Without Cisplatin Chemotherapy in Patients With Advanced Squamous Cell Cancer of the Cervix

PURPOSE To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.

Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial

Summary Background Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. Methods Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65–69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. Results Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4–8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0·77, 95% CI 0·61–0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). Interpretation The benefits of combined modality treatment—ADT and RT—should be discussed with all patients with locally advanced prostate cancer. Funding Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.

Randomized Trial Comparing Two Fractionation Schedules for Patients With Localized Prostate Cancer

Purpose The optimal radiation dose fractionation schedule for localized prostate cancer is unclear. This study was designed to compare two dose fractionation schemes (a shorter 4-week radiation schedule v a longer 6.5-week schedule). Patients and Methods Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The study was designed as a noninferiority investigation with a predefined tolerance of −7.5%. The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity. Results From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470 were assigned to the long arm, and 466 were assigned to the short arm. The median follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and 59.95% in the short arm (difference = −7.0%; 90...

Waiting for radiotherapy in Ontario

PURPOSE Waiting lists for radiotherapy are a fact of life at many Canadian cancer centers. The purpose of this study was to provide a detailed description of the magnitude of the problem in Ontario. METHODS AND MATERIALS The interval between diagnosis and initiation of radiation treatment was calculated for all patients receiving primary radiotherapy for carcinoma of the larynx, cervix, lung, and prostate at seven Ontario cancer centers between 1982 and 1991. The interval between surgery and initiation of postoperative radiotherapy for breast cancer was also calculated over the same period. The intervals between diagnosis and referral (t1), between referral and consultation (t2), and between consultation and initiation of radiotherapy (t3), were analyzed separately to determine where delay occurred. RESULTS Median waiting times between diagnosis and initiation of radical treatment for carcinoma of the larynx, carcinoma of the cervix, nonsmall cell lung cancer, and carcinoma of the prostate were 30.3 days, 27.2 days, 27.3 days, and 93.3 days, respectively. The exceptional interval between diagnosis and treatment of prostate cancer was due to much longer delays between diagnosis and referral. The median waiting time between diagnosis and initiation of postoperative radiotherapy for breast cancer was 61.4 days and the median time between the completion of surgery and initiation of postoperative radiotherapy was 57.8 days. There were significant intercenter variations in median waiting times, but in every situation the median waiting time in Ontario as a whole increased steadily between 1982 and 1991. Median waiting times from diagnosis to the start of curative treatment for laryngeal cancer, cervical cancer, nonsmall cell lung cancer, and prostate cancer increased by 178.7%, 105.6%, 158.3%, and 62.9%, respectively. Waiting time from completion of surgery to initiation of postoperative radiotherapy for breast cancer increased by 102.7%. Most of the increase in treatment delay was found in the interval between consultation and initiation of radiotherapy. CONCLUSIONS The Committee on Standards of the Canadian Association of Radiation Oncologists recommends that the interval between referral and consultation should not exceed 2 weeks and that the interval between consultation and initiation of radiotherapy should also not exceed 2 weeks. The majority of patients treated in Ontario met both those standards in 1982, but by 1991 few patients received care within the prescribed intervals.

Perception of Quantitative Information for Treatment Decisions

The study was designed to determine which formats for displaying quantities, such as probabilities of treatment risks and benefits, are perceived most accurately and easily by patients. Accuracy and speed of processing were compared for six different presentation formats: pie charts, vertical bars, horizontal bars, numbers, systematic ovals, and random ovals. Quantities were used in two tasks: a choice task that required larger/smaller judgments and an estimate task that required more precise evaluation. The impacts of blue-yellow color and of a treatment-decision context on performance in the two tasks were also investigated. The study included four experiments. Taken together the results suggest that the formats best for making a choice differ from those best for estimating the size of an amount. For making a choice, vertical bars, horizontal bars, numbers, and systematic ovals were equally well perceived; pie charts and random ovals caused slower and less accurate performances. For estimating, numbers led to the most accurate estimates, followed by systematic ovals. The other four formats led to the least accurate estimates. Color and context did not alter which formats were best. Key words: decision making; quantitative information presentation; questionnaire format. (Med Decis Making 2000;20:228-238)

Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial

BACKGROUND Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. METHODS We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. FINDINGS Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094). INTERPRETATION In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. FUNDING Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.

Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15)

PURPOSE This multi-institutional Phase III randomized study compared 10 Gy single-fraction radiotherapy (RT) with 20 Gy in five fractions in the palliation of thoracic symptoms from lung cancer. METHODS AND MATERIALS The primary end point was palliation of thoracic symptoms at 1 month after RT, evaluated by a patient-completed daily diary card. Secondary end points included quality of life, toxicity, and survival. RESULTS Most (69%) of 230 patients randomized had locally advanced disease unsuitable for curative treatment. The treatment arms were well balanced with respect to the known prognostic factors. At 1 month after RT, no difference was found in symptom control between the two arms, as judged by the daily diary scores. The changes in the scores on the Lung Cancer Symptom Scale indicated that the fractionated RT (five fractions) group had greater improvement in symptoms related to lung cancer (p = 0.009), pain (p = 0.0008), ability to carry out normal activities (p = 0.037), and better global quality of life (p = 0.039). The European Organization for Research and Treatment of Cancer QLQ-C30 scores showed that patients receiving five fractions had a greater improvement in scores with respect to pain (p = 0.04). No significant difference was found in treatment-related toxicity. Patients who received five fractions survived on average 2 months longer (p = 0.0305) than patients who received one fraction. CONCLUSION Although the two treatment strategies provided a similar degree of palliation of thoracic symptoms, the difference in survival between the two study arms was of a clinically relevant magnitude.

Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer

Purpose We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. Patients and Methods NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. Results One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. Conclusion This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.