Statistical controversies in clinical research: Value of adverse events relatedness to study treatment: analyses of data from randomized double-blind placebo-controlled clinical trials.

BACKGROUND: Collection and reporting of adverse events (AEs) and their relatedness to study treatment, known commonly as attribution, in clinical trials is mandated by regulatory agencies (the National Cancer Institute and the Food and Drug Administration). Attribution is assigned by the treating physician using judgment based on various factors including patient's baseline status, disease history, and comorbidity as well as knowledge about the safety profile of the study treatments. We evaluate the patterns of AE attribution (unrelated, unlikely, possibly, probably, and definitely related to the treatment) in treatment, symptom intervention (cancer patients) and cancer prevention (participants at high risk for cancer) setting. MATERIALS AND METHODS: Nine multicenter placebo-controlled trials (two treatment, two symptom intervention, and five cancer prevention) were analysed separately (2155 patients). Frequency and severity of AEs were summarized by arm. Attribution and percentage of repeated AEs whose attribution changed overtime were summarized for the placebo arms. Percentage of physician over- or under-reporting of AE relatedness was calculated for the treatment arms using the placebo arm as the reference. RESULTS: Across all trials and settings, a very high proportion of AEs reported as related to treatment were classified as possibly related, a significant proportion of AEs in the placebo arm were incorrectly reported as related to treatment, and clinician-reported attribution over-estimated the rate of AEs related to treatment. Fatigue, nausea, vomiting, diarrhea, constipation, and neurosensory were the common AEs that were over reported by clinician as related to treatment. CONCLUSIONS: These analyses demonstrate that assigning causality to AE is a complex and difficult process that produces unreliable and subjective data. In randomized double-blind placebo-controlled trials where data are available to objectively assess relatedness of AE to treatment, attribution assignment should be eliminated.

Survival following early-stage colon cancer: an ACCENT-based comparison of patients versus a matched international general population†.

BACKGROUND: Post-treatment survival experience of early colon cancer (CC) patients is well described in the literature, which states that cure is probable for some patients. However, comparisons of treated patients' survival versus that expected from a matched general population (MGP) are limited. PATIENTS AND METHODS: A total of 32 745 patients from 25 randomized adjuvant trials conducted from 1977 to 2012 in 41 countries were pooled. Observed long-term survival of these patients was compared with expected survival matched on sex, age, country, and year, both overall and by stage (II and III), sex, treatment [surgery, 5-fluorouracil (5-FU), 5-FU + oxaliplatin], age (<70 and 70+), enrollment year (pre/post 2000), and recurrence (yes/no). Comparisons were made at randomization and repeated conditional on survival to 1, 2, 3, and 5 years. CC and MGP equivalence was tested, and observed Kaplan-Meier survival rates compared with expected MGP rates 3 years out from each landmark. Analyses were also repeated in patients without recurrence. RESULTS: Within most cohorts, long-term survival of CC patients remained statistically worse than the MGP, though conditional survival generally improved over time. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free patients achieved subsequent 3-year survival rates within 5% of the MGP, with recurrence-free patients achieving equivalence. CONCLUSIONS: Conditional on survival to 5 years, long-term survival of most CC patients on clinical trials remains modestly poorer than an MGP, but achieves MGP levels in some subgroups. These findings emphasize the need for access to quality care and improved treatment and follow-up strategies.

Endpoint comparison for bone mineral density measurements in North Central Cancer Treatment Group cancer clinical trials N02C1 and N03CC (Alliance).

UNLABELLED: Bone mineral density (BMD) measurement can vary depending upon anatomical site, machine, and normative values used. This analysis compared different BMD endpoints in two clinical trials. Trial results differed across endpoints. Future clinical trials should consider inclusion of multiple endpoints in sensitivity analysis to ensure sound overall study conclusions. INTRODUCTION: Methodological issues hamper efficacy assessment of osteoporosis prevention agents in cancer survivors. Osteoporosis diagnosis can vary depending upon which bone mineral density (BMD) anatomical site and machine is used and which set of normative values are applied. This analysis compared different endpoints for osteoporosis treatment efficacy assessment in two clinical studies. METHODS: Data from North Central Cancer Treatment Group phase III clinical trials N02C1 and N03CC (Alliance) were employed involving 774 patients each comparing two treatments for osteoporosis prevention. Endpoints for three anatomical sites included raw BMD score (RawBMD); raw machine-based, sample-standardized, and reference population-standardized T scores (RawT, TSamp, TRef); and standard normal percentile corresponding to the reference population-standardized T score (TPerc). For each, treatment arm comparison was carried out using three statistical tests using change and percentage change from baseline (CB, %CB) at 1 year. RESULTS: Baseline correlations among endpoints ranged from 0.79 to 1.00. RawBMD and TPerc produced more statistically significant results (14 and 19 each out of 36 tests) compared to RawT (11/36), TSamp (8/36), and TRef (7/36). Spine produced the most statistically significant results (26/60) relative to femoral neck (20/60) and total hip (13/60). Lastly, CB resulted in 44 statistically significant results out of 90 tests, whereas %CB resulted in only 15 significant results. CONCLUSIONS: Treatment comparisons and interpretations were different across endpoints and anatomical sites. Transforming via sample statistics provided similar results as transforming via reference or machine-based norms. However, RawBMD and TPerc may be more sensitive to change as clinical trial endpoints.

Palliative communications: addressing chemotherapy in patients with advanced cancer.

Patients with advanced cancers often endure chemotherapy late in their disease course leading to unnecessary adverse effects, loss of quality of life, and delay in hospice referral. Compassionate and honest communication about the use of chemotherapy can facilitate better patient care. This manuscript will explore communication issues regarding palliative-intent chemotherapy.

A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB).

INTRODUCTION: Hot flashes represent a significant problem in men undergoing androgen deprivation therapy. MATERIALS AND METHODS: Via a prospective, double-blind, placebo-controlled clinical trial, men with hot flashes, on a stable androgen deprivation therapy program for prostate cancer, received a placebo or gabapentin at target doses of 300, 600, or 900 mg/day. Hot flash frequencies and severities were recorded daily during a baseline week and for 4 weeks while the patients took the study medication. RESULTS: In the 214 eligible patients who began the study drug on this trial, comparing the fourth treatment week to the baseline week, mean hot flash scores decreased in the placebo group by 4.1 units and in the three increasing dose gabapentin groups by, 3.2, 4.6, and 7.0 units. Comparing the three combined gabapentin arms to the placebo arm did not result in significant hot flash differences. Wilcoxon rank-sum P values for change in hot flash scores and frequencies after 4 weeks of treatment were 0.10 and 0.02, comparing the highest dose gabapentin arm to the placebo arm, respectively. The gabapentin was well tolerated in this trial. CONCLUSION: These results support that gabapentin decreases hot flashes, to a moderate degree, in men with androgen ablation-related vasomotor dysfunction.

In vitro induction of human skin ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

A method was developed for the in vitro induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) activity in human skin punch biopsy samples. Addition of TPA to 1 ml serum-free minimum essential medium containing a single 3-mm human skin punch biopsy sample obtained from a surgical specimen resulted in an induction of ODC activity with a peak activity at 5 hours after TPA addition. In vitro induction of human epidermal ODC activity was dependent on the TPA concentration in the medium; about a twofold increase in ODC activity was observed 6 hours after the addition of 0.1 microM TPA, and about a fivefold increase in ODC activity was observed with 1 microM TPA. TPA also caused about a fivefold to sixfold increase in ODC activity in 3-mm skin punch biopsy samples from healthy volunteers. Human skin punch biopsy samples remained responsive to TPA induction of ODC activity even when stored in serum-free medium at 4 degrees C for 24 hours. A similar degree of induction of ODC activity by TPA was observed whether whole unfractionated human epidermis or a soluble epidermal extract was used for ODC assays. Increased ODC activity was the result of the increase in enzymatically active ODC protein, quantitated by a [3H]difluoromethylornithine-binding assay. Thus human skin, like mouse skin, is responsive to TPA for ODC induction.

Phase II study of ifosfamide-etoposide-mesna in adults with advanced nonosseous sarcomas.

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.

Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia.

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.