An additional 5 years of adjuvant aromatase-inhibitor therapy in women with early hormone-receptor–positive breast cancer resulted in longer disease-free survival and a lower incidence of ...contralateral breast cancer than placebo, but not in longer overall survival.
The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely.
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Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety of adjuvant regimens, including tamoxifen for 10 years, tamoxifen for up to 5 years followed by an aromatase inhibitor for 5 years, or an initial aromatase inhibitor for 5 years.
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Extrapolating from these results, many patients have chosen to continue taking an aromatase inhibitor for more than 5 years (if they do not have unacceptable side effects), despite . . .
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and ...quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
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.
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.
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.
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.
Conventional external beam radiotherapy is the standard palliative treatment for spinal metastases; however, complete response rates for pain are as low as 10–20%. Stereotactic body radiotherapy ...delivers high-dose, ablative radiotherapy. We aimed to compare complete response rates for pain after stereotactic body radiotherapy or conventional external beam radiotherapy in patients with painful spinal metastasis.
This open-label, multicentre, randomised, controlled, phase 2/3 trial was done at 13 hospitals in Canada and five hospitals in Australia. Patients were eligible if they were aged 18 years and older, and had painful (defined as ≥2 points with the Brief Pain Inventory) MRI-confirmed spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0–2, a Spinal Instability Neoplasia Score of less than 12, and no neurologically symptomatic spinal cord or cauda equina compression. Patients were randomly assigned (1:1) with a web-based, computer-generated allocation sequence to receive either stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions or conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions using standard techniques. Treatment assignment was done centrally by use of a minimisation method to achieve balance for the stratification factors of radiosensitivity, the presence or absence of mass-type tumour (extraosseous or epidural disease extension, or both) on imaging, and centre. The primary endpoint was the proportion of patients with a complete response for pain at 3 months after radiotherapy. The primary endpoint was analysed in the intention-to-treat population and all safety and quality assurance analyses were done in the as-treated population (ie, all patients who received at least one fraction of radiotherapy). The trial is registered with ClinicalTrials.gov, NCT02512965.
Between Jan 4, 2016, and Sept 27, 2019, 229 patients were enrolled and randomly assigned to receive conventional external beam radiotherapy (n=115) or stereotactic body radiotherapy (n=114). All 229 patients were included in the intention-to-treat analysis. The median follow-up was 6·7 months (IQR 6·3–6·9). At 3 months, 40 (35%) of 114 patients in the stereotactic body radiotherapy group, and 16 (14%) of 115 patients in the conventional external beam radiotherapy group had a complete response for pain (risk ratio 1·33, 95% CI 1·14–1·55; p=0·0002). This significant difference was maintained in multivariable-adjusted analyses (odds ratio 3·47, 95% CI 1·77–6·80; p=0·0003). The most common grade 3–4 adverse event was grade 3 pain (five 4% of 115 patients in the conventional external beam radiotherapy group vs five (5%) of 110 patients in the stereotactic body radiotherapy group). No treatment-related deaths were observed.
Stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions was superior to conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions in improving the complete response rate for pain. These results suggest that use of conformal, image-guided, stereotactically dose-escalated radiotherapy is appropriate in the palliative setting for symptom control for selected patients with painful spinal metastases, and an increased awareness of the need for specialised and multidisciplinary involvement in the delivery of end-of-life care is needed.
Canadian Cancer Society and the Australian National Health and Medical Research Council.
Women with breast cancer who are undergoing breast-conserving surgery were assigned to receive whole-breast irradiation with or without regional nodal irradiation. At 10 years, disease-free survival ...in the nodal-irradiation group was improved but overall survival was not.
Many women with early-stage breast cancer undergo breast-conserving surgery followed by whole-breast irradiation, which reduces the rate of local recurrence.
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Radiotherapy to the chest wall and regional lymph nodes, termed regional nodal irradiation, which is commonly used after mastectomy in women with node-positive breast cancer who are treated with adjuvant systemic therapy, reduces locoregional and distant recurrence and improves overall survival.
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An unanswered question is whether the addition of regional nodal irradiation to whole-breast irradiation after breast-conserving surgery has the same effect. Whole-breast irradiation may involve irradiation of the lower axillary and internal mammary lymph nodes.
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However, regional . . .
The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and ...quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.
IMPORTANCE: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical ...studies. OBJECTIVE: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. DESIGN, SETTING, AND PARTICIPANTS: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. INTERVENTIONS: Patients were randomized (stratified for hormone receptor estrogen receptor and/or progesterone receptor {ER/PgR} status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 ERBB2, formerly HER2 or HER2/neu, positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. MAIN OUTCOMES AND MEASURES: The primary outcome was invasive disease–free survival in hormone receptor–positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse–free survival, and breast cancer–free interval were analyzed. RESULTS: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women 99.8%), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR−, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease–free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease–free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio HR, 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR−, followed up for a median of 94.1 months, incidence of invasive disease–free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). CONCLUSIONS AND RELEVANCE: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease–free survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01101438
Stereotactic body radiation therapy (SBRT) improves complete pain response for painful spinal metastases compared with conventional external beam radiation therapy (cEBRT). We report mature local ...control and reirradiation rates in a large cohort of patients treated with SBRT versus cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control 24 phase 2/3 trial.
One hundred thirty-seven of 229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT and 71 patients (169 segments) treated with cEBRT. The primary outcomes were magnetic resonance–based local control and reirradiation rates for each treated spine segment.
The median follow-up was 11.3 months (interquartile range, 5.3-27.7 months), and median overall survival in the SBRT and cEBRT cohorts were 21.6 (95% confidence interval CI, 11.3, upper bound not reached) and 18.9 (95% CI, 12.2-29.1) months (P = .428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of mass (paraspinal and/or epidural disease extension). Risk of local failure after SBRT versus cEBRT at 6, 12, and 24 months were 2.8% (95% CI, 0.8%-7.4%) versus 11.2% (95% CI, 6.9%-16.6%), 6.1% (95% CI, 2.5%-12.1%) versus 28.4% (95% CI, 21.3%-35.9%), and 14.8% (95% CI, 8.2-23.1%) versus 35.6% (95% CI, 27.8%-43.6%), respectively (P < .001). cEBRT (hazard ratio HR, 3.48; 95% CI, 1.94-6.25; P < .001) and presence of mass (HR, 2.07; 95% CI, 1.29-3.31; P = .002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT versus cEBRT were 2.2% (95% CI, 0.4-7.0%) versus 15.8% (95% CI, 10.4%-22.3%) (P = .002) and 22.9 months versus 9.5 months, respectively. cEBRT (HR, 2.60; 95% CI, 1.27-5.30; P = .009) and radioresistant histology (HR, 2.00; 95% CI, 1.12-3.60; P = .020) independently predicted for reirradiation. Eight of 12 iatrogenic vertebral compression fractures were after SBRT and 4 of 12 after cEBRT; grade 3 adverse fracture effects were isolated to the SBRT cohort (5 of 12).
Risk of local failure and reirradiation is lower with SBRT compared with cEBRT for spinal metastases. Although the iatrogenic vertebral compression fracture rates were within expectations, grade 3 vertebral compression fractures were isolated to the SBRT cohort.
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