scholarly journals Serious Adverse Events Reporting in Phase III Randomized Clinical Trials of Colorectal Cancer Treatments: A Systematic Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanhong Yao ◽  
Zhentao Liu ◽  
Hua Zhang ◽  
Jian Li ◽  
Zhi Peng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Logistic Regression ◽  
England Journal ◽  
New England ◽  
Randomized Clinical Trials ◽  
Binary Logistic Regression ◽  
Phase Iii ◽  
Cancer Treatments ◽  
Serious Adverse Events

Objective: The occurrence, development, and prognosis of serious adverse events (SAEs) associated with anticancer drugs in clinical trials have important guiding significance for real-world clinical applications. However, to date, there have been no studies investigating SAEs reporting in randomized clinical trials of colorectal cancer treatments. This article systematically reviewed the SAEs reporting of phase III randomized clinical trials of colorectal cancer treatments and analyzed the influencing factors.Methods: We reviewed all articles about phase III randomized clinical trials of colorectal cancer treatments published in the PubMed, Embase, Medline, and New England Journal of Medicine databases from January 1, 1993, to December 31, 2018, and searched the registration information of clinical trials via the internet sites such as “clinicaltrials.gov”. We analyzed the correlation between the reported proportion (RP) of SAEs in the literature and nine elements, including the clinical trial sponsor and the publication time. Chi-square tests and binary logistic regression were used to identify the factors associated with improved SAEs reports. This study was registered on PROSPERO.Results: Of 1560 articles identified, 160 were eligible, with an RP of SAEs of 25.5% (41/160). In forty-one publications reporting SAEs, only 14.6% (6/41) described the pattern of SAEs in detail. In clinical trials sponsored by pharmaceutical companies, the RP of SAEs was significantly higher than that in those sponsored by investigators (57.6 versus 20.7%, p < 0.001). From 1993 to 2018, the RP of SAEs gradually increased (none (0/6) before 2000, 17.1% (12/70) from 2000 to 2009, and 34.5% (29/84) after 2009). The average RP of SAEs published in the New England Journal of Medicine (N Engl J Med), the Lancet, the Journal of the American Medical Association (JAMA), the Lancet Oncology (Lancet Oncol), and the Journal of Clinical Oncology (J Clin Oncol) was significantly higher than that published in other journals (31.9 versus 16.7%, p = 0.030). In the clinical trials referenced by clinical guidelines, the RP of SAEs was higher than that in non-referenced clinical trials (32.0 versus 15.9%, p = 0.023). Binary logistic regression analysis showed that pharmaceutical company sponsorship, new drug research, and sample size greater than 1000 were positive influencing factors for SAEs reporting.Conclusion: Although the RP of SAEs increased over time, SAEs reporting in clinical trials needs to be further improved. The performance, outcomes and prognosis of SAEs should be reported in detail to guide clinical practice in the real world.

Survival among metastatic colorectal patients in clinical trials compared to the real world.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 673-673
Author(s):  
Ziwei Wang ◽  
Lindsay Hwang ◽  
James Don Murphy
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Median Survival ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
The Real ◽  
Clinical Trial Results

673 Background: Randomized clinical trials play a central role in clinical research though only a small fraction of patients partake in clinical studies. Questions thus arise regarding the generalizability of clinical trial results to the remainder of the population. This study evaluated whether patient survival from randomized clinical trials in metastatic colorectal cancer reflects real world outcomes. Methods: A Pubmed search was used to identify randomized phase III clinical trials of first-line treatment for metastatic colorectal cancer published between 2005 and 2010. We excluded secondary or pooled analyses, second-line treatments, non-metastatic patients, non-English language, and non-randomized studies. Thirty-one clinical trials met these criteria, comprised of 79 distinct clinical trial arms. Overall survival among clinical trial patients was compared to metastatic colorectal cancer patients within the Surveillance, Epidemiology, and End Results (SEER) program. Within SEER, we restricted the analysis time-period and age of patients to match the enrollment period and age of patients within each individual clinical trial. Results: The clinical trials enrolled a total of 16,614 patients. Among all clinical trial arms the median survival ranged from 6.7-62 months, 1-year survival ranged from 30-97%, and 2-year survival ranged from 6-88%. Compared to SEER, the median survival was higher in 95% of the individual clinical trial arms by an average of 5.4 months (p<0.0001). The 1-year survival was higher in 94% of the clinical trial arms by an average of 16.7% (p<0.0001). The 2-year survival was higher in 71% of the clinical trial arms by an average of 7.2% (p<0.0001). Conclusions: This study found substantially improved survival among clinical trial participants compared to patients in the SEER database suggesting that survival estimates from clinical trials may not generalize to the “real world.” Potential patient factors such as differences in underlying comorbidity, performance status, disease burden, as well as variation in treatment could not be addressed in this study, though these factors likely explain some of the observed survival differences.

Trends in the design and interpretation of metastatic colorectal cancer phase III clinical trials.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 692-692
Author(s):  
Sunil Parimi ◽  
Soundouss Raissouni ◽  
Yongtao Lin ◽  
Jose Gerard Monzon ◽  
Patricia A. Tang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Primary Endpoint ◽  
Trial Design ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
Steady Increase ◽  
Study Results ◽  
Over Time

692 Background: Increasing use of subsequent lines of therapy and crossover in phase III randomized clinical trials (P3 RCTs) has shifted how we perceive the effectiveness of treatments for metastatic colorectal cancer (mCRC). This study aims to characterize the evolution of P3 RCTs in mCRC with respect to clinical trial design and result interpretation. Methods: Abstracts of P3 RCTs of systemic therapy for mCRC conducted between 1980 and 2014 were identified by searching PubMed, Medline, and ASCO abstracts. Data regarding trial design, agent(s) investigated, primary endpoint, secondary endpoint(s), primary endpoint significance and interpretation of the study results (conclusions) were extracted. Results: A total of 422 trials were identified by the search strategy, and 132 eligible trials were included. Over time the sample size of P3 RCTs in mCRC has been increasing and there has been a steady increase in trials studying targeted therapy (see table below for detailed results by decade). A trend towards a smaller percentage of P3 RCTs sponsored by co-operative groups has been observed in recent decades. The most common primary endpoint was overall survival (OS) which was used in 35% of the trials. A decreasing trend in the use of OS was observed since the 1990s. Other common primary endpoints include: progression-free survival (PFS) in 28% and response rate (RR) in 20% of the P3 RCTs. The primary endpoint was met in 45% of the trials. There was discordance between the primary endpoint significance and the authors’ conclusions in 14% of the trials. Conclusions: The design and interpretation of P3 RCTs for mCRC has changed over time from 1980 to present. The use of OS as the primary endpoint is decreasing, while the use of PFS is increasing. [Table: see text]

Effect of subsequent chemotherapy on overall survival in first-line chemotherapy with targeted agents for patients with metastatic colorectal cancer: Systematic review and meta-analysis of randomized control trials.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 782-782
Author(s):  
Daisuke Sakai ◽  
Toshihiro Kudo ◽  
Aya Kato ◽  
Toshinori Sueda ◽  
Hidekazu Takahashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
First Line ◽  
Line Chemotherapy

782 Background: One of recent standard first line chemotherapies for metastatic colorectal cancer is doublet of cytotoxic agents, fluorouracil and oxaliplatin or irinotecan, in combination with target agent, bevacizumab, or anti-EGFR antibody as cetuximab or panitumumab for KRAS or RAS wild type (WT). In this decade, nevertheless progression free survival (PFS) of clinical trials was little improved, overall survival (OS) had been increased. Methods: We analyzed data from 14 recently published phase III randomized clinical trials in mCRC to correlate the percentage of patients receiving subsequent chemotherapy with the reported OS. Results: Median PFS and OS were 10.3 and 25.0 months, respectively. In all comer trials, median OS is significantly correlated with the percentage of patients who received subsequent chemotherapy after first line chemotherapy of their disease [regression coefficient (R2) = 0.85 p = 0.0018]. In trials with KRAS WT, a correlation between OS and the rate of subsequent therapy was modest [r2 = 0.605, p = 0.0637]. Median PFS and RR were not correlated with median OS. Conclusions: Our results support the strategy of making salvage chemotherapy available to all patients with advanced CRC to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, PFS might no longer be regarded as the appropriate surrogate end point of OS by which to assess the efficacy of a palliative first-line treatment in CRC.

scholarly journals First-Line Maintenance Treatment in Metastatic Colorectal Cancer (mCRC): Quality and Clinical Benefit Overview

2021 ◽  
Vol 10 (3) ◽  
pp. 470
Author(s):  
Marta Martín-Richard ◽  
Maria Tobeña
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Clinical Benefit ◽  
Maintenance Treatment ◽  
Randomized Clinical Trials ◽  
Line Treatment ◽  
First Line ◽  
Design Quality ◽  
Primary Endpoints ◽  
First Line Treatment

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.

What are the reciprocal influences of randomized clinical trials and the patient–psychiatrist relationship?

1999 ◽  
Vol 14 (2) ◽  
pp. 93-100
Author(s):  
J. Catteau ◽  
C. Cyran ◽  
R. Bordet ◽  
C.E. Thomas ◽  
B.A. Dupuis
Keyword(s):  
Clinical Trials ◽  
Depressive Disorders ◽  
Randomized Clinical Trials ◽  
Antidepressant Drugs ◽  
Antidepressant Medication ◽  
Study Data ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Clinical Trials ◽  
Reciprocal Influences

SummaryThe goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

scholarly journals Is Bayesian Analysis Ready for Use in Phase III Randomized Clinical Trials?

Stroke ◽  
2005 ◽  
Vol 36 (7) ◽  
pp. 1622-1623 ◽  
Author(s):  
George Howard ◽  
Christopher S. Coffey ◽  
Gary R. Cutter
Keyword(s):  
Clinical Trials ◽  
Bayesian Analysis ◽  
Randomized Clinical Trials ◽  
Phase Iii

scholarly journals Systemic therapy for colorectal cancer

2003 ◽  
Vol 11 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Borut Stabuc
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Adjuvant Chemotherapy ◽  
Metastatic Colorectal Cancer ◽  
Adjuvant Treatment ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
Phase Iii ◽  
Oral Fluoropyrimidines ◽  
Significant Difference

Colorectal cancer alone accounts for around 200,000 deaths in Europe and represents a significant health problem. Although about fifty percent of patients are cured by surgery alone, the other half will eventually die due to metastatic disease, which includes approximately 25% of patients who have evidence of metastases at the time of diagnosis. Surgical resection of the primary tumor and regional lymph nodes is the only curative therapy for colorectal cancer. However, adjuvant chemotherapy in stage III for colon cancer following curative resection has been shown to reduce the risk of recurrence by 19-40% and of death by 16-33%. Today, 5-fluoroUracil and Leucovorin given for six months may represent the best adjuvant treatment available The contribution of levamisole to adjuvant treatment seems to be marginal, if any. The benefit of adjuvant chemotherapy for the patients with Dukes B colon cancer is less clear. A meta-analysis of 1,381 patients with advanced colorectal cancer showed a significant increase in response rate with the bolus 5-fluoroUracil and Leucovorin versus 5-fluoroUracil alone but no significant difference in median survival. Continuous infusion allows higher doses of 5-FU than rapid bolus infusion and improves response rate survival and time to progression. Oral fluoropyrimidines (capecitabine and Uracil/Tegafur [UFT]) are as active as intravenous fluoropyrimidines. Compared to intravenous 5FU, oral fluoropyrimidines have safety advantages clinical benefits, and are more convenient for patients. Phase III randomized clinical trials in patients with metastatic colorectal cancer demonstrate the significant superiority of combining irinotecan with 5-fluoroUracil and Leucovorin or oxaliplatin with 5-fluoroUracil and Leucovorin over the same 5-fluoroUracil and Leucovorin alone. Several phase II studies have shown that the combination of the oral fluoropyrimidines plus irinotecan or oxaliplatin is very active in metastatic colorectal cancer. Trials with agents acting on novel targets in colorectal cancer are progressing rapidly, including doxifluridine, new inhibitors of thymidylate synthase (ZD9331), oral camptothecins (Rubitecan), multitarget antifolate antimetabolite (Premetrexet), inhibitors of epidermal growth factor receptor (Cetuximab), COX-2 inhibitors (celecoxib) and farnesyltransferaze inhibitors (Zarnestra). However, a few randomized trials failed to show a survival advantage compared with placebo in patients with advanced refractory colorectal cancer.

scholarly journals Evaluation of the Value of Attribution in the Interpretation of Adverse Event Data: A North Central Cancer Treatment Group and American College of Surgeons Oncology Group Investigation

2010 ◽  
Vol 28 (18) ◽  
pp. 3002-3007 ◽  
Author(s):  
Shauna L. Hillman ◽  
Sumithra J. Mandrekar ◽  
Brian Bot ◽  
Ronald P. DeMatteo ◽  
Edith A. Perez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Group ◽  
Cancer Treatment ◽  
Randomized Clinical Trials ◽  
Study Drug ◽  
Phase Iii ◽  
Oncology Group ◽  
North Central ◽  
American College Of Surgeons ◽  
Group Trial

Purpose In March 1998, Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AEs) to study drug. We investigate whether attribution adds value to the interpretation of AE data. Patients and Methods Patients in the placebo arm of two phase III trials—North Central Cancer Treatment Group Trial 97-24-51 (carboxyamino-triazole v placebo in advanced non–small-cell lung cancer) and American College of Surgeons Oncology Group Trial Z9001 (imatinib mesylate v placebo after resection of primary gastrointestinal stromal tumors)—were studied. Attribution was categorized as unrelated (not related or unlikely) and related (possible, probable, or definite). Results In total, 398 patients (84 from Trial 97-24-51 and 314 from Trial Z9001) and 7,736 AEs were included; 47% and 50% of the placebo-arm AEs, respectively, were reported as related. When the same AE was reported in the same patient on multiple visits, the attribution category changed at least once 36% and 31% of the time. AE type and sex (Trial Z9001) and AE type and performance status (Trial 97-24-51) were associated with a higher likelihood of AEs being deemed related. Conclusion Nearly 50% of AEs were reported as attributed to study drug on the placebo arm of two randomized clinical trials. These data provide strong evidence that AE attribution is difficult to determine, unreliable, and of questionable value in interpreting AE data in randomized clinical trials.

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