https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61121-X.pdf

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial

A B S T R AC T BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy–surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy– surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy–surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P = 0.003). CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.)

/pdf/preoperative-chemoradiotherapy-for-esophageal-or-junctional-3hmqg1vd6m.pdf

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

Pathology and genetics of tumours of the urinary system and male genital organs

Background Advanced gastric cancer can respond to S-1, an oral fluoropyrimidine. We tested S-1 as adjuvant chemotherapy in patients with curatively resected gastric cancer. Methods Patients in Japan with stage II or III gastric cancer who underwent gastrectomy with extended (D2) lymph-node dissection were randomly assigned to undergo surgery followed by adjuvant therapy with S-1 or to undergo surgery only. In the S-1 group, administration of S-1 was started within 6 weeks after surgery and continued for 1 year. The treatment regimen consisted of 6-week cycles in which, in principle, 80 mg of oral S-1 per square meter of body-surface area per day was given for 4 weeks and no chemotherapy was given for the following 2 weeks. The primary end point was overall survival. Results We randomly assigned 529 patients to the S-1 group and 530 patients to the surgery-only group between October 2001 and December 2004. The trial was stopped on the recommendation of the independent data and safety monitoring committee, ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa072252

Adjuvant Chemotherapy for Gastric Cancer with S-1, an Oral Fluoropyrimidine

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

/pdf/strategies-to-reduce-attrition-in-randomised-trials-a-4dz3ciqiax.pdf

Strategies to reduce attrition in randomised trials: a Cochrane systematic review and meta-analysis

Background/Aims 
Clinical trials should be designed and managed to minimise important errors with potential to compromise patient safety or data integrity, employ monitoring practices that detect and correct important errors quickly, and take robust action to prevent repetition. Regulators highlight the use of risk-based monitoring, making greater use of centralised monitoring and reducing reliance on centre visits. The TEMPER study was a prospective evaluation of triggered monitoring (a risk-based monitoring method), whereby centres are prioritised for visits based on central monitoring results. Conducted in three UK-based randomised cancer treatment trials of investigational medicine products with time-to-event outcomes, it found high levels of serious findings at triggered centre visits but also at visits to matched control centres that, based on central monitoring, were not of concern. Here, we report a detailed review of the serious findings from TEMPER centre visits. We sought to identify feasible, centralised processes which might detect or prevent these findings without a centre visit. 
Methods
We considered a representative example of each finding type through a three-staged consensus exercise. 1: Three trialists independently reviewed the issues and graded their potential for detection by central monitoring or prevention by some described process, each on a five-point scale. 2. Results of round 1 were shared anonymously and each trialist re-reviewed the list choosing whether or not to change their grading. 3. The three trialists discussed and agreed grades for any issues without consensus, and proposed a feasibility score for each proposed process. In a consultation exercise, the proposed processes were reviewed and rated for feasibility by an invited external trialist group. The primary outcome was the proportion of all major and critical findings theoretically detectable or preventable through a feasible, centralised process.
Results
In TEMPER, 312 major or critical findings were identified at 94 visits. These findings comprised 120 distinct issues, for which we proposed 56 different centralised processes. Following independent review of the feasibility of the proposed processes by 87 consultation respondents across different stakeholder groups, we conclude that 306/312 (98%) findings could theoretically be prevented or identified centrally. 
Conclusions
This work presents a best-case scenario, where a large majority of monitoring findings were deemed theoretically preventable or detectable by central processes. Caveats include the cost of applying all necessary methods, and the resource implications of enhanced central monitoring for both centre and trials unit staff. Of processes not currently deemed feasible, use of electronic health records has the largest potential benefit. 
Our results will inform future monitoring plans and emphasise the importance of continued critical review of monitoring processes and outcomes to ensure they remain appropriate. 
Key words: monitoring, central monitoring, on-site monitoring, risk-based monitoring, efficient trial conduct

https://medrxiv.org/content/10.1101/2020.04.01.20033647v1.full.pdf

Assessing the potential for prevention or earlier detection of on-site monitoring findings from randomised controlled trials: further analyses of findings from the prospective TEMPER triggered monitoring study

Sally P. Stenning

Papers

Strategies to reduce attrition in randomised trials: a Cochrane systematic review and meta-analysis

Assessing the potential for prevention or earlier detection of on-site monitoring findings from randomised controlled trials: further analyses of findings from the prospective TEMPER triggered monitoring study

Strategies to improve retention in randomised trials (Review)

Prognostic indices in malignant glioma-matching form to function

Medical Research Council (MRC) randomised trial of adjuvant chemotherapy in primary CNS lymphoma (PCL)- BR06.