The future of surgical research: the role of the American College of Surgeons Oncology Group

EJSO (2005) 31, 695–701

www.ejso.com

The future of surgical research: the role of the American College of Surgeons Oncology Group K.E. Posther, S.A. Wells Jr* Department of Surgery, Duke University School of Medicine, American College of Surgeons Oncology Group, Durham, NC, USA Accepted for publication 10 February 2005 Available online 26 April 2005

KEYWORDS Surgery; Oncology; Clinical trials; Multicenter studies; Biomedical research

Abstract The American College of Surgeons Oncology Group (ACOSOG) was established in 1997; it is funded by the National Cancer Institute (NCI) and American College of Surgeons (ACS) for the purpose of conducting multicenter phases II and III clinical trials in the field of surgical oncology. After eight years, ACOSOG has successfully completed seven trials and has five studies currently open to accrual for patients with brain, breast, gastrointestinal, head and neck, and lung cancers. The history of randomized controlled trials in surgery and the structure and function of ACOSOG are discussed. ACOSOG is establishing an extensive specimen bank for current and future correlative science studies, providing unique educational opportunities for surgeons in clinical research, and pursuing collaborative relationships in order to conduct trials with private industries. Also, ACOSOG has expanded its membership to include international sites, which contribute to the success of ACOSOG studies and enhance the portfolio of future protocols. The participation of general surgeons and surgical oncologists in clinical trials is essential to the improvement of treatment options for cancer patients. Q 2005 Elsevier Ltd. All rights reserved.

Introduction Before the advent of the randomized controlled trial (RCT), most physicians compared new and standard treatments and evaluated outcomes based on individual clinical experience and the results of retrospective case reviews. The concept of randomization was first introduced in the 1920s by * Corresponding author. Address: ACOSOG, 2434 Erwin Road, Suite 606, Durham, NC 27705, USA. Tel.: C1 919 668 8435; fax: C1 919 668 7123. E-mail address: [email protected] (S.A. Wells).

R. A. Fisher as a critical component of experimental design and statistical analysis in agricultural field studies.1 In 1937, statistician A. B. Hill published a series of articles in the Lancet, establishing standards for the experimental design of clinical trials with human subjects.2 Later under Hill’s direction, the British Medical Research Council conducted the first randomized, double-blind, placebo-controlled trial, ‘Streptomycin treatment of pulmonary tuberculosis.’ Published in the British Medical Journal in 1948, this landmark study

0748-7983/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2005.02.018

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Table 1 USA Cooperative Clinical Trials Groups and dates of establishment American College of Surgeons Oncology Group (ACOSOG) Cancer and Leukemia Group B (CALGB) Children’s Oncology Group (COG) Eastern Cooperative Oncology Group (ECOG) Gynaecologic Oncology Group (GOG) National Surgical Adjuvant Breast and Bowel Project (NSABP) North Central Cancer Treatment Group (NCCTG) Radiation Therapy Oncology Group (RTOG) Southwest Oncology Group (SWOG)

1997 1955 Merged 2000 1955 1970 1958 1977 1968 1958

established randomization as the superior design for investigations with patients, minimizing potential sources of bias.3,4 The modern era of clinical trials practice began with this study, and the stage was set for expanding the broad field of clinical research to include the science of quantitative medicine, clinical epidemiology, and outcomes research. The federal government established the National Institutes of Health in 1887 in order to support research about disease detection, treatment, and prevention. In 1937, the 75th USA Congress passed the National Cancer Act, creating the National Cancer Institute (NCI) ‘for the purposes of conducting researches, investigations, experiments, and studies relating to the cause, diagnosis, and treatment of cancer’.5 Congress subsequently approved the NCI cooperative group program in 1955 and founded the Chemotherapy National Service Center specifically for the study of chemotherapy in cancer. In 1954, the Cancer and Leukemia Group B (CALGB) and the Children’s Cancer and Leukemia Group were the first cooperative groups to be founded. Clinical oncologists from academic medical centers and private practice groups across the country joined these groups and collaborated to evaluate promising therapeutic regimens in patients with leukemia. By 1958, 17 cooperative groups had been established, and the emphasis on chemotherapy gradually shifted towards the multimodal treatment and management of cancer. Today, there are nine such cooperative clinical trials groups in the USA (Table 1). These groups are structured as cooperative agreements within the NCI, with all activities being

monitored and governed by the cancer therapy evaluation program (CTEP).6 Since, the inception of the NCI cooperative group program, over 10,000 physicians and 200,000 patients have participated in NCI-sponsored clinical trials; however, less than 4% of eligible adult cancer patients are enrolled in studies each year. Yet cancer continues to grow as a major public health problem in the USA, responsible for over 1,200,000 new cases and 500,000 deaths each year. Furthermore, the diagnosis and treatment of cancer cost over $100 billion annually, and even greater costs are attributed to lost time from work or early death.5 Clearly, there is significant room for improved patient and physician participation in NCI-sponsored clinical trials. Despite the advent of the randomized controlled trial, the birth of NCI cooperative groups, and the growing application of evidence-based medicine to the clinical practice of oncology, there has been a relative dearth of clinical trials in the field of surgical oncology. The first RCT in surgery was not conducted until 1964, when J. C. Goligher and colleagues compared three techniques (vagotomy with gastroenterostomy, vagotomy with antrectomy, and subtotal gastrectomy) for the elective surgical management of duodenal ulcers.7 Although the RCT has become the gold standard for comparing treatment options in the setting of true clinical equipoise, only 3–9% of surgical studies employ a randomized controlled clinical study design, and less than 20% of surgical RCTs are designed to compare surgical, rather than medical, techniques.8,9 Randomization is particularly difficult to conduct in the surgical research arena, for several reasons. The modern patient, or ‘consumer’ of healthcare services, will express preferences and request newer, less invasive procedures despite the lack of supportive, randomized phase III data. Surgeons may unwittingly introduce bias to a study due to discrepant experience in performing two different surgical interventions, or technical variations between surgeons. Surgeons by necessity cannot be blinded to the randomized intervention assigned to their patients, and surgical placebos (‘sham operations’) are no longer appropriate controls.10 In the process of obtaining informed consent, surgeons are reluctant to express clinical uncertainty and possibly jeopardize their relationships with patients.11 Despite these obstacles, surgeons have increasingly recognized the need for randomized clinical trials in all specialties, especially in the field of surgical oncology. In the 1970s, academic and community surgeons participated in the National Surgical Adjuvant Breast and Bowel

ACOSOG/clinical trials in surgical oncology Project (NSABP) studies B-04 and B-06, which led to major changes in the management of invasive breast cancer and demonstrated the potential impact and contribution of clinical trials to the surgical management of cancer.

The development of ACOSOG In 1995 a small number of surgical oncologists met to discuss the possibility of organizing a cooperative group to conduct clinical trials designed to evaluate the surgical management of patients with malignant solid tumours. These surgeons were driven by the knowledge that over 50% of patients with early stage malignant solid tumours are cured by surgical resection alone. Surgeons are thus uniquely poised as both the operating surgeon and primary care physician to encourage many of their patients to participate in clinical trials. The decision was made to develop a surgical trial program from within the American College of Surgeons (ACS), primarily because there are over 70,000 international surgeon members in the college, and the cancer department of the college offers unique resources, such as the National Cancer Database, which could support cooperative group activities. The NCI awarded the investigators a planning grant to define the structure and function of the trial group, and in 1997 the American College of Surgeons Oncology Group (ACOSOG) was established at the ACS headquarters, the first new cooperative group to be funded by the NCI in 17 years. In 2001, the ACOSOG relocated its Administrative Coordinating Center (ACC) and Statistics and Data Coordinating Center (SDCC) to Duke University Medical Center, where proximity to the Duke Clinical Research Institute (DCRI) and the CALGB statistical headquarters would provide the additional infrastructure and experience needed to support a young and rapidly growing cooperative trials group. The ACOSOG membership spans all medical and surgical specialties, across academic medical centers, community hospitals, and private practices. Any board-certified, practicing oncologist in the field of surgery, medicine, pathology, laboratory medicine or radiology, is eligible to become a member of ACOSOG. Registered nurse oncologists, Clinical Research Associates (CRAs) and basic science investigators are also encouraged to become members. From this broad-based leadership, ACOSOG merges expertize in oncology with clinical trials experience, creating a strong

697 Table 2 ACOSOG Organ Site Committees and Working Groups (OSC/WG) Breast Central Nervous System Colorectal/Upper Gastrointestinal Genitourinary Head and Neck Melanoma Sarcoma Thoracic

foundation for the development and direction of surgical protocols. ACOSOG members may belong to one or more Organ Site Committees or Working Groups (OSC/WG), depending on their professional interests. There are eight OSC/WGs, and an Organ Site Chair and one or two Vice Chairs moderate their committee’s activities (Table 2). Twenty members are selected from each OSC/WG to form a multidisciplinary Core Group, which oversees protocol development and active trial management for each OSC/WG. In addition to the OSC/WGs, there are additional Modality Committees (Table 3), whose members are critical to study development, support and performance. The ACOSOG is in its ninth year of operation, has five trials open for patient accrual, and has completed seven studies to date (Table 4). The ACOSOG has two semi-annual meetings, during which time patient accrual to active clinical studies is evaluated and progress with new study development is reviewed. In addition to meetings of the Organ Site Committees and the Modality Committees, there are plenary sessions and educational programs for ACOSOG members. In the interim between the semi-annual meetings the OSC’s Working Groups and the Modality Committees continue their progress through conference phone calls, workshops at the ACOSOG headquarters, or Table 3

ACOSOG Modality Committees

Administrative Committees

Scientific Direction Committees

Auditing Constitution and Bylaws Corporate Relations Education Ethics International Relations Membership Quality of Life Patient Advocacy Special Populations

Basic Science and Correlative studies Diagnostic Imaging Medical Oncology Nursing/CRA Radiation Oncology Tumour Registrars Pathology

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Table 4

ACOSOG Clinical Trials

Study

Title

First patient registration

Accrual goal

Accrual as of 2/14/2005

Study status

Z0010

A prognostic study of sentinel node and bone marrow micrometastases in women with clinical T1 or T2 N0 M0 breast cancer A randomized trial of axillary node dissection in women with clinical T1–T2 N0 M0 breast cancer who have a positive sentinel node Randomized phase III trial of hyperthermic isolated limb perfusion and melphalan with or without tumour necrosis factor in the patient with localized, advanced, extremity melanoma Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma A prospective study of the prognostic significance of occult metastases in the patient with resectable non-small cell lung carcinoma The utility of positron emission tomography (PET) in staging of patients with potentially operable non-small cell lung carcinonoma The utility of positron emission tomography (PET) in staging of patients with potentially operable carcinoma of the thoracic esophagus A randomized trial of radical prostatectomy versus brachytherapy for patients with T1c or T2a N0 M0 prostate cancer Health-related quality of life in patients with low risk, localized prostate cancer randomized to radical prostatectomy or brachytherapy A prospective study of the prognostic significance of microsatellite instability in patients with early age-of-onset colorectal cancer A phase III randomized trial of the role of whole brain radiation therapy in addition to radiosurgery in the management of patients with one to three cerebral metastases A trial of lymphatic mapping and sentinel node lymphadenectomy for patients with T1 or T2 clinically N0 oral cavity squamous cell carcinoma A phase II study of adjuvant STI571 (Gleevece) therapy in patients following completely resected high-risk primary gastrointestinal stromal tumour (GIST)

5/10/1999

5300

5539

Completed May 2003

5/17/1999

1900

891

Closed December 2004

5/29/1999

216

133

Completed January 2004

6/8/1999

1000

1111

Completed February 2004

1/24/2000

1200

1309

Completed April 2004

1/18/2000

375

445

Completed April 2004

2/15/2000

235

262

Completed July 2004

8/16/2002

1980

56

Closed April 2004

7/16/2003

500

5

Closed April 2004

3/4/2003

3000

306

Closed December 2004

12/10/2002

480

70

Closed December 2004

12/27/2002

161

121

Open

11/2/2001

89

110

Completed 9/30/2003

Z0011

Z0020

Z0030

Z0040

Z0050

Z0060

Z0070

Z0071

Z0190

Z0300

Z0360

Z9000

ACOSOG/clinical trials in surgical oncology Table 4

699

(continued)

Study

Title

First patient registration

Z9001

A phase III randomized double-blind study of adjuvant STI571 (Gleevece) versus placebo in patients following the resection of primary gastrointestinal stromal tumour (GIST) Use of proteomic analysis of serum samples for detection of non-small cell lung cancer A phase II study of interferon-based adjuvant chemoradiation in patients with resected pancreatic adenocarcinoma A phase II trial of toxicity assessment in two cohorts of patients (resection alone or ablation with or without resection of hepatic metastases from colorectal cancer) treated with adjuvant hepatic arterial infusion (HAI) FUDR plus systemic CPT-11

7/31/2002

Z04031

Z05031

Z05032

Accrual goal

Accrual as of 2/14/2005

Study status

380

363

Open

1000

332

Open

7/11/2003

93

52

Open

3/16/2004

94

11

Closed December 2004

4/2/04

during meetings of the surgical societies or associations. The banking of biological specimens is a critical component of ACOSOG protocols, as surgeons are uniquely positioned to acquire tissue and serum for the purpose of correlative scientific study. The ACOSOG Tissue Bank is located at Washington University in St Louis, and is the repository of all biological samples that are collected under protocol by the group. Several active ACOSOG protocols include companion biomolecular studies aimed at identifying new molecular markers and potential therapeutic targets of malignant disease.

The conduct of clinical trials Study Development is the center of activity in ACOSOG, as it evaluates the scientific merit of study ideas, the development of clinical protocols and the subsequent accrual of large number of patients that make a cooperative group successful. Any member of ACOSOG may present a study idea to the appropriate OSC/WG for consideration. If approved for further development, the idea is submitted to the ACOSOG Study Development team, which works directly with the Principal Investigator, Study Committee, and Core Group to write the complete protocol. In planning phase of the trial, it is necessary to identify potential sites and to recruit large numbers of clinical oncologists to participate. Once a study protocol has been

submitted to CTEP and approved, it is opened to members for patient registration and accrual. As a new cooperative group, ACOSOG has provided many surgeons with their first opportunity to participate in clinical trials. Consequently, it has been necessary to develop educational programs to teach participating physicians about the critical aspects of clinical trials. With ACOSOG instruction, participating sites have improved their process of informed consent, source documentation, and CRA preparation, and this in turn has improved sites’ regulatory compliance and quality of data collected during the conduct of trials. A very important part of ACOSOG clinical trial performance is the process of surgeon skills verification. The performance of surgical procedures must be standardized in order to minimize bias, and there must be assurance that the principal interventions, the basis of the clinical questions, are performed correctly and consistently. At each participating site, the CRA and Data Manager are critical to the successful conduct of a clinical trial. These personnel oversee the process of informed consent, review eligibility criteria, assure adequate source documentation, and guarantee the submission of accurate and complete data. Participating sites receive financial support for their material and personnel expenses for the clinical trial through a capitation system, which provides a stipend for each patient, accrued to study. Data reports are received at ACOSOG headquarters by an electronic fax system, permitting the efficient receipt and management of vast

700 quantities of data and storage in a paperless format. Each clinical site participating in an ACOSOG study must be audited within eighteen months of entering the first patient on a trial, and then every three years thereafter. The site audit is conducted by ACOSOG staff and involves professional auditors and surgeons who are familiar with the clinical trials.

The future of ACOSOG ACOSOG has extended it membership to international sites, and physician groups in Australia and Ireland have recently opened studies and registered patients to active trials. International contributions to protocol development, patient recruitment, and group leadership have broadened the perspective and potential of ACOSOG. In the past, disagreements and differences in practice patterns have resulted in regional and national variations in costs, utilization, and techniques of medical procedures.12,13 With its international cooperative group structure, ACOSOG strives to establish the most effective interventions and to standardize operative techniques for the surgical management of solid tumour malignancies. Correlative science studies are a critical component of clinical trials. The importance of normal and malignant tissue acquisition cannot be underestimated in the era of increasingly individualized treatment regimens and targeted biologic therapies.14 A number of investigators have been awarded grants through ACOSOG or directly from the NIH to pursue basic science studies such as gene array, protein microarray, serum proteomic profiling, and DNA methylation patterns using specimens acquired through ACOSOG studies. Using these advanced techniques, researchers will attempt to elucidate novel diagnostic and prognostic markers for different tumour types. In addition, the growing ACOSOG biological resource, collected with each patient’s corresponding demographic data, will be of unlimited value to future cancer research. In the recent past, surgeons have lacked the necessary training, expertize, and opportunity to design and participate in surgical RCTs.15–17 ACOSOG’s educational goals extend beyond the instruction of surgeons in the practical aspects of clinical trials, to creative strategies for educating the next generation of academic surgeons. The current emphasis on quality assurance and clinical outcomes makes it critically important that surgical residents be encouraged to pursue training in clinical research, participate in clinical trials, and

K.E. Posther, S.A. Wells practice evidence-based surgery. We have initiated an innovative and multidimensional educational model for training surgical housestaff in clinical trials, translational research, and the practice of evidence-based medicine. ACOSOG Clinical Research Fellows gain experience in the cooperative group setting across the spectrum of clinical trial responsibilities, including protocol development, regulatory oversight, trials management, and auditing. The trainees also complete didactic coursework and obtain a master’s degree through the Clinical Research Training Program (CRTP) at the Duke University School of Medicine. Trainee salary and tuition are fully funded by an NIH T-32 training grant, which supports four surgical housestaff for the 2-year program. In addition to supporting phase II and randomized phase III trials and correlative basic science studies in oncology, ACOSOG aims to expand its activity into the arenas of private industry-sponsored projects, outcomes research, and additional surgical fields. Quality of life, cost-effectiveness, and decision analyses are critical research endpoints in the overall efforts to improve the quality and effectiveness of medical and surgical interventions. There is a critical need for studies to answer important questions regarding the optimal surgical and medical treatment of patients with solid tumour malignancies. Hippocrates defined the physician’s objectives as, ‘Declare the past, diagnose the present, foretell the future; practice these acts.’ The purpose of cooperative groups such as ACOSOG is to facilitate and advance prospective research studies that will determine the best diagnostic, prognostic and therapeutic interventions for cancer patients. As ACOSOG expands its scope of studies and educational opportunities for its members, it is critical that surgeons increase their participation and leadership in NCI-sponsored protocols and expand their understanding, support, and prioritization of clinical research.

Acknowledgement Supported by a grant from the National Cancer Institute: U10 CA 76001-09, and by the American College of Surgeons.

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