Surgical Oncology Trials Research Articles

The Representation of Surgery in Oncology Clinical Trials: 2001 to 2022.

Surgery is a mainstay of cancer care. Since the advancement of cancer treatment occurs through clinical trials, it is critical to investigate the degree and nature of representation of surgery in oncological clinical trials. This observational analysis used publicly available data from clinicaltrials.gov to investigate non-industry-funded oncological clinical trials in the United States between 2012 and 2022. From 2012 to 2022, 1,861 (15.7%) of the 11,843 registered oncologic clinical trials were surgical. There was a 43.2% increase in proportional surgical trials and an 18.9% increase in oncology trials over the last two decades. Surgery+diagnostic-technique trials increased from 5.14 to 12.6% (P < 0.001, 95%CI [-0.097, -0.052]), surgery+radiation trials increased from 5.24 to 8.1% (P = 0.004, 95%CI [-0.047, -0.0088]), surgery+systemic-therapy trials decreased from 34.5 to 29.2% (P = 0.003, 95%CI [0.018, 0.088]), surgery+supportive-therapy trials increased from 8.0 to 11.3% (P = 0.004, 95%CI [-0.056, -0.01]) and 'surgery-as-the-variable' trials decreased from 12.0 to 3.5% (P < 0.001, 95%CI[0.065, 0.1]). Systemic therapy with biologics increased from 38.1 to 53.9% (P < 0.001, 95%CI [-0.22, -0.091]). Surgery-vs.-no-surgery trials increased from 16.8 to 37.3% (P = 0.001, 95%CI [-0.32, -0.078]). Surgical oncology trials increased by 43.2% over the last 10 years. The focus of clinical trials is changing to the encouragement of innovation in more diagnostic and less invasive techniques, and targeted therapies.

Analysis of Female Participant Representation in Registered Oncology Clinical Trials in the United States from 2008 to 2020.

Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding. Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation. Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials. Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

Meeting the ongoing challenges of outcome selection in surgical oncology trials.

Meeting the ongoing challenges of outcome selection in surgical oncology trials.

Analysis of Registered Clinical Trials in Surgical Oncology, 2008-2020

This quality improvement study characterizes surgical oncology trials, analyzes growth, identifies associations with early discontinuation or results reporting, and evaluates proportions of trials involving each neoplasm site.

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

The surgical oncology clinical trial landscape: A cross-sectional analysis of ClinicalTrials.gov from 2008-2020.

1561 Background: Surgical interventions are studied less often than medical or radiation interventions in oncology clinical trials. We characterized surgical oncology trials registered on ClinicalTrials.gov, analyzed funding sources and identified features associated with early discontinuation and results reporting. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded all 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020. After excluding non-interventional trials, applying cancer/oncology specific Medical Subject Heading terms to the remaining trials and excluding phase 1 trials, 27,915 trials were identified for manual review. Primary exposure variables were trial focus: neoplasia site and treatment modality (surgical interventions included investigations of outcomes from surgical resection or intra-operative/peri-operative changes), and funding: industry, U.S. government, academic. Results: 26,815 trials were found to have true oncology content; 1,661 (6.2%) involved surgical oncology, representing 311,789 patients. Funding sources were: 82.7% by academic institutions, 10.9% by industry, and 6.2% by U.S. government. The most studied neoplasia sites were colorectal (17.4% of trials), breast (10.7%), gastric (10.5%), hepatic (8.6%), lung (7.5%), brain/CNS (6.7%) and cervical (6.6%). U.S. government funded surgical oncology trials had the lowest risk of early discontinuation (adjusted HR 0.50, 95% CI: 0.26-0.99, p&lt;0.047) and the highest odds of results reporting (adjusted OR 1.08, 95% CI: 0.55-2.11, p=0.83) (Table 1). Conclusions: There is a paucity of surgical oncology clinical trials compared to other treatment modalities, especially in context of surgery’s role in overall cancer care. From 2008-2020 only 6.2% of trials focused on surgical oncology, and U.S. government funded trials displayed the lowest hazard of early discontinuation and highest odds of results reporting. Stakeholders should look to government funded trials as models of improvement, but must increase representation and results dissemination of surgical oncology trials to guide treatment recommendations. Surgical oncology trial features and associated early discontinuation/results reporting. [Table: see text]

Randomized controlled trials in surgical resection of colorectal peritoneal metastases: Disentangling negativity in PRODIGE 7 and PROPHYLOCHIP.

Surgeons have been castigated for lack of enthusiasm and delivery of trials in surgical oncology (1). Trials are few and mis-interpretation common. Jonathon Swift, best known for "Gulliver's Travels", warned us years ago about misinterpretation and "fake news". In this context, few oncological trials have created as much debate, controversy, and mis-information as PRODIGE 7.

A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311.

Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA. E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections. 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients. We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.

Building a collaboration to improve surgical research through EORTC/ESSO 1409-CLIMB study: A prospective liver metastasis database with an integrated quality assurance program

The challenges of conducting surgical oncology trials have resulted to low quantity and poor quality research [1,2]. Considering the definitive role of surgery to offer cure, immediate response to improve surgical research is needed [3]. The European Organization for Research and Treatment of Cancer (EORTC) and the European Society of Surgical Oncology (ESSO) share the vision to achieve excellent surgical research and care for cancer patients. Building on their complimentary expertise, they embarked on a pilot project to map out challenges and initiate a sustainable collaboration to advance cancer surgery research in Europe. This pilot project is EORTC-ESSO 1409 GITCG/ ESSO-01: A Prospective Colorectal Liver Metastasis Database with an Integrated Quality Assurance Program (CLIMB). This article will describe the challenges, milestones and vision of both organizations in setting up this collaboration.

Progress in surgical oncology trials

What developments have been made in collaborative research and clinical trials?

Recommendations for Randomised Trials in Surgical Oncology

Trials of surgical procedures in the treatment of malignant disease face a unique set of challenges. This review aimed to describe recommendations for the design, delivery and reporting of randomised trials in surgical oncology. A literature search was carried out without date limits to identify articles related to trial methodology research in surgery and surgical oncology. A narrative review was framed around two open National Institute of Health Research portfolio trials in colon and rectal cancer: the STAR-TREC trial (ISRCTN14240288) and the ROCCS trial (ISRCTN46330337). Twelve specific challenges were highlighted: standardisation of technique; pilot and feasibility studies; balancing treatments; the recruitment pathway; outcome measures; patient and public representation; trainee-led networks; randomisation; novel techniques and training; learning curves; blinding; follow-up. Evidence-based recommendations were made for the future design and conduct of surgical oncology trials. Better understanding of the challenges facing trials in the surgical treatment of cancer will accelerate high-quality evaluation and rapid adoption of innovation for the benefit of patient care.

Commentary to “Barriers to participation in surgical randomized controlled trials in pediatric urology: A qualitative study of key stakeholder perspectives”

As pediatric urologists and active clinical investigators, it is with great interest that we read the recently published paper “Barriers to participation in surgical randomized controlled trials in pediatric urology: a qualitative study of key stakeholder perspectives” by Vemoulakonda and Jones [1] in the Journal. This is a unique, single-center study providing qualitative perspectives in the typically quantitatively dominated field of pediatric urology research. The authors provide an important basis to understand potential parental and healthcare provider barriers to enroll children in randomized controlled trials (RCTs). With these perceived obstacles in mind, investigators may be able to modify recruitment strategies in such a way that it may facilitate enrollment and increase participation. While this is undoubtedly a significant contribution to the literature, the authors base their study [1] on the assumption that pediatric urology surgical trials suffer from similarly low recruitment rates as those seen in adult surgical oncology trials [2]. Although reasonable, this simply may not always be the case. A clear example of high recruitment within pediatric urology surgical trials can be seen in the currently ongoing “Expertise-Based Randomized Controlled Trial of Scrotal Versus Inguinal Orchidopexy on Post-operative Pain” (NCT02158780), where, to date, 41 of 50 (82%) eligible patients have been recruited to participate [3]. Another example of reasonably high recruitment rate is seen in the challenging setting of a placebo control versus antibiotic prophylaxis for infants with highgrade prenatal hydronephrosis [4]. A 57% recruitment rate has been achieved thus far, providing further proof that RCTs are a feasible (and needed) study design in pediatric

Surgery: Limitations of prospective surgical oncology trials - a US view.

Surgeons should promote the best standard of surgical care through evidence-based results from prospective trials. European surgical investigators, in this issue of the journal, highlight the difficulties in patient accrual to surgical trials, patient and physician biases, and referral and quality assurance hurdles. We expand on these points and suggest some solutions.

What can we learn from oncology surgical trials?

Conducting high-quality prospective clinical trials in surgical oncology remains a challenge, and many seemingly well-designed trials lack this high quality because of inadequate recruitment accrual, lack of clinician interest, or evolution of treatment strategy during the many years over which such trials are conducted. In this Perspectives we examine some of the failures in published surgical oncology trials and discuss why they failed, and we make a critical assessment of the established prospective trial methodology in oncological practice (that is, phase 0, I, II, III and IV trials, and large prospective comparative audits) and how these methods might be used more effectively in future evaluation of cancer-surgery practice.

The future of trials in surgical oncology.

Patients with cancer generally have better outcomes when treated as part of a clinical trial compared with patients not enrolled in a clinical trial. Unfortunately, surgical participation in, and leadership of such studies, is limited. This lack of clinical investigation is adversely affecting progress in cancer surgery research and, ultimately, hinders the treatment of patients. Some of the reasons for poor surgical participation in clinical research include: limitations on funding provision; inadequate training of junior surgeons in clinical trials methodology; and inadequate support of surgical faculty members as clinical investigators. Despite these shortcomings, numerous successful surgical studies have helped to change concepts, and improve patient care in certain clinical areas. Finally, a number of possible solutions are proposed, which might improve surgical involvement in clinical trials and result in more, and better-designed and executed clinical trials in this important area of research.

Clinical Research in Surgical Oncology: An Analysis of ClinicalTrials.gov

The objective of this study was to provide a descriptive analysis of registered clinical trials in surgical oncology at ClinicalTrials.gov. Data was extracted from ClinicalTrials.gov using the following search engine criteria: "Cancer" as Condition, "Surgery OR Operation OR Resection" as Intervention, and Non-Industry sponsored. The search was limited to Canada and the United States and included trials registered from January 1, 2001 to January 1, 2011. Of 9,961 oncology trials, 1,049 (10.5%) included any type of surgical intervention. Of these trials, 125 (11.9%, 1.3% of all oncology trials) assessed a surgical variable, 773 (73.7%) assessed adjuvant/neoadjuvant therapies, and 151 (14.4%) were observational studies. Of the trials assessing adjuvant therapies, systemic treatment (362 trials, 46.8%) and multimodal therapy (129 trials, 16.7%) comprised a large focus. Of the 125 trials where surgery was the intervention, 59 trials (47.2%) focused on surgical techniques or devices, 45 trials (36.0%) studied invasive diagnostic methods, and 21 trials (16.8%) evaluated surgery versus no surgery. The majority of the 125 trials were nonrandomized (72, 57.6%). The number of registered surgical oncology trials is small in comparison to oncology trials as a whole. Clinical trials specifically designed to assess surgical interventions are vastly outnumbered by trials focusing on adjuvant therapies. Randomized surgical oncology trials account for <1% of all registered cancer trials. Barriers to the design and implementation of randomized trials in surgical oncology need to be clarified in order to facilitate higher-level evidence in surgical decision-making.

Integration of clinical and patient-reported outcomes in surgical oncology

Patient-reported outcomes (PROs) provide information about the patient perspective and experience of undergoing surgery for cancer, but evidence suggests that they are not used widely to influence practice. This review considers key challenges and opportunities for using PROs effectively in gastrointestinal surgical oncology, drawing on principles learnt from surgical oncology in general. Systematic reviews of randomized controlled trials (RCTs) in surgical oncology reporting PROs as primary or secondary outcomes, and studies examining methods to communicate PRO information, were identified. Common themes are summarized and the future of PRO studies considered. Reviews highlighted the need for improved design, conduct and reporting of PROs in RCTs in surgical oncology. Main issues related to the multiplicity of PRO measures hindering data synthesis and clinical understanding, problems with missing data risking bias, and limited integration of clinical and PRO data undermining the role of PRO data in practice. Reviews indicated that patients want PRO data to meet information needs and early work shows that graphically displayed PROs are understood by patients. PROs have a role in the evaluation of surgical oncology, but increased consensus and collaboration between surgeons and methodologists is needed to improve the design, conduct and reporting of PROs with clinical outcomes in trials. Possible solutions include investing more effort and systematic thought into the PRO rationale in RCTs, the development and use of 'core outcome sets' with PROs, and implementation of the extension to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting PROs in RCTs.

Standards of Outcome Reporting in Surgical Oncology: A Case Study in Esophageal Cancer

Multimodal strategies before surgery are often used to improve outcomes, but disease progression (precluding surgical resection) and inoperability at planned surgery still occur following neoadjuvant treatment. The standards of reporting of these outcomes have not previously been considered. This study examined reporting of rates of progression to surgical resection and inoperability at planned surgery following neoadjuvant treatment in surgical oncology, using esophageal cancer as a case study. A systematic review identified randomized trials and prospective nonrandomized studies reporting short-term outcomes of neoadjuvant treatment and surgery for esophageal cancer. Of 4,763 abstracts, 224 papers were retrieved and 76 studies included (8 randomized trials and 68 cohort studies of 19,441 esophagectomies). Articles reported outcomes of preoperative chemotherapy (n = 33, 43.4 %), chemoradiotherapy (n = 13, 17.1 %), or both within one paper (n = 18, 23.7 %) and 12 (15.8 %) did not specify the type of neoadjuvant treatment. Also, 20 papers (26.3 %) reported numbers of patients not progressing to surgery after neoadjuvant treatment (with rates of nonprogression ranging between 2.0 and 35.3 %). In addition, 24 papers (31.6 %) reported rates of inoperability at planned surgery (with inoperability rates ranging between 0 and 26.2 %). More randomized controlled trials (RCTs) than observational studies reported nonprogression (4 randomized and 16 nonrandomized studies, 95 % CI -9.6 to 62.6 %, p = 0.108) and inoperability (6 randomized trials and 18 observational studies, 95 % CI 16.8-80.3 %, p = 0.005). Some 17 and 10 articles provided reasons for the observed rates of nonprogression and inoperability, respectively. Reporting rates of progression to surgery after neoadjuvant treatment and inoperability at planned surgery for esophageal cancer were poor, limiting data synthesis and comparisons. It is suggested that core outcome sets for trials in surgical oncology are developed with inclusion of these important endpoints. Collaboration between medical and surgical oncologists is necessary to achieve this.

Geographic and socioeconomic determinants of participation by elderly patients in surgical oncology trials.

6127 Background: A recent report by our group demonstrated that &lt;0.5% of elderly patients with breast, prostate and lung cancer participate in surgical oncology trials. However, little work to date has evaluated the roles of regional healthcare infrastructure and socioeconomic factors on clinical trial participation in this cohort. Methods: The NCI Cooperative Group Surgical Oncology Trial (CGSOT) database was queried for patients treated for breast, prostate and lung cancer cancer between 2000 and 2008 (n=13,541). Geographical Information Systems data were used to evaluate proximity to healthcare facilities while regional socioeconomic characteristics were obtained from the 2000 US Census and Area Resource file. Counts were used to create a proportion of respondents with the corresponding 95% confidence interval calculated using the central limit theorem. Independent t-tests were used to assess differences in outcome measures between the two age groups. Results: We found that 4136 participants in the NCI CGSOT database were 65 years of age or older. Interestingly, 92.7% of this cohort was white and 85.7% was female. Socioeconomic determinants of participation are shown in the table. Conclusions: The work presented herein suggests that elderly minority patients are less likely to participate in surgical oncology trials than their white counterparts. Furthermore, elderly participants tend to reside in less affluent areas. Future work will utilize interventions that improve the recruitment of elderly patients to these trials. [Table: see text]

Clinical research in surgical oncology: An analysis of clinicaltrials.gov.

591 Background: The conduction of randomized clinical trials has expanded in medical specialties, but to a far lesser degree in surgery. This is due to design challenges with standardization of treatment, blinding and lack of surgeon equipoise. The objective of this study was to assess the current landscape of clinical trials in surgical oncology registered at clinicaltrials.gov. Methods: Data was extracted from clinicaltrials.gov using the following search engine criteria: ‘Cancer’ as Condition, ‘Surgery OR Operation OR Resection’ as Intervention, and Non-Industry sponsored. The search was limited to Canada and the United States and included trials registered from January 1, 2001 to January 1, 2011. The search was performed on March 23, 2011 by three investigators in parallel. The total number of oncology trials was also obtained. Results: Of 9990 oncology trials, 1049 (10.5%) included any type of surgical intervention. Of these trials, 125 (11.9%; 1.3% of all oncology trials) manipulated a surgical variable, 773 (73.7%) assessed adjuvant/neoadjuvant therapies, and 151 (14.4%) were observational studies. Trials assessing adjuvant therapies focused on systemic treatment (362 trials, 46.8%) and multimodal therapy (129 trials, 16.7%). Of the 125 trials where surgery was the manipulated variable, 59 trials (47.2%) focused on surgical techniques (including minimally invasive) or devices, 45 trials (36.0%) studied invasive diagnostic methods, and 21 trials (16.8%) evaluated surgery vs. no surgery. The majority of the 125 trials were non- randomized (72, 57.6%), and Phase III trials accounted for less than one-quarter (29, 23.2%). Conclusions: The number of registered surgical oncology trials is small in comparison to oncology trials as a whole. Clinical trials specifically designed to assess surgical interventions are vastly outnumbered by trials focusing on adjuvant therapies, and are frequently non-randomized. Randomized surgical oncology trials account for &lt;1% of all registered cancer trials. Barriers to the design and implementation of randomized trials in surgical oncology need to be clarified to facilitate higher-level evidence in surgical decision making.