The purpose of clinical research is to add to medical knowledge using hypothesis-driven scientific methods for the betterment of clinical care and for ultimate improvement in patient outcomes. Over the millennia, development and dissemination of medical knowledge have moved in a nonsequential fashion from observation of individual patients to retrospective and prospective evaluation of institutional, national, and international groups of patients. Randomized controlled clinical trials, whose onset has often been dated to 1948, have usually been based on general drug, device, type of intervention, and patient characteristics. More recently, clinical trials are based on the unique molecular and genetic tumor characteristics in an individual patient. Previously, the discipline of surgery has been severely criticized for the lack of such published studies. But in the last decade, there has been a marked increase in surgery-only randomized trials (laparoscopy vs open interventions for colon and rectal cancer) as well as surgeons both leading and participating in multidisciplinary randomized oncology clinical trials. Of course, while it is generally recognized that properly conducted, randomized clinical trials are the “gold standard,” there are many individual and group (institution and large database) observations such as the introduction and evaluation of laparoscopic cholecystectomy that have led to controlled trials and major improvements in clinical outcomes for patients.

Prospective randomized clinical trials do not discover or create new drugs or therapies, but their purpose is to identify true advances in drug therapy, device usage, and technological surgical advances that lead to changes in clinical practice and make outcome improvements for our patients with cancer. Statistical methods such as meta-analysis of randomized trials performed in a uniform way can provide an overall perspective. However, even using strict methodology, meta-analysis techniques and results from them are only as good as the individual trials that are compiled, and complicated statistical techniques cannot make up for improper research methods, lack of blinding of investigators, bias, and too few patient numbers, leading to a lack of observation power and incorrect conclusions.

Major issues impeding progress in the development of new medical knowledge in our current environment are the costs of clinical trials research, the ability to incorporate all segments of our population into randomized trials, the plethora of new drugs and devices that are coming from research laboratories, and the difficulties with patient accrual to such trials. More recently, statistical methods have been used to shorten the time to completion of randomized clinical trials using adaptive randomization within individual studies. These techniques have resulted in more rapid determination of outcome results within phase 2 trials by eliminating therapeutic arms unlikely to demonstrate meaningful results and concentrating on those drug interventions that have a high likelihood of success. For example, the I-SPY 2 trial compares up to 12 experimental therapies with a common control in subgroups of patients with breast cancer. The randomization is stratified by tumor HER2 and hormone receptor status and 70 gene signatures. Adaptive randomization increases the likelihood of assignment to a given therapy as evidence accrues that the treatment improves results. Importantly, this trial design is a model for future clinical research as it offers molecular fingerprinting of the tumor for truly personalized experimental intervention and adaptive randomization that reduces the number of subjects required and decreases the time to identify potential candidate drugs for subsequent phase 3 trials.

The development of strict guidelines for the conduct of randomized clinical trials and statistical methods to improve time to trial completion has been an important milestone in clinical research. The ethical advances in human protection have also included several milestones, such as the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, and the International Conference on Harmonization and Good Clinical Practice guidance in 1996. More recently, the National Institutes of Health (NIH) has issued guidance on the required use of a central Institutional Review Board to help speed the initiation of randomized clinical trials among multiple institutions. In addition, in September 2016, the NIH issued a final policy to promote broad and responsible dissemination of information from NIH-funded clinical trials through ClinicalTrials.gov . Under this policy, every clinical trial funded in whole or in part by NIH is expected to be registered on ClinicalTrials.gov and have summary results information submitted and posted in a timely manner. Taken together, all of these actions have decreased the time from drug and device discovery to proper clinical testing through prospective, randomized clinical trials to dissemination of results, both good and bad, leading to new, updated governmental and specialized society guidelines for patients receiving antineoplastic therapy.

This issue of Surgical Oncology Clinics of North America brings together the results of recent randomized clinical trials within disease sites, providing new guidelines for clinical care. Several important results are noted herein, but full reading of all the articles should be done.

In their article, Tseng and Posner summarized results of 24 randomized trials in the management of patients with gastric cancer and noted that a D2 lymph node dissection has not been consistently shown to improve overall survival over D1 lymph node dissection and is associated with an increase in perioperative complications and mortality. Neoadjuvant therapy has become a standard approach in many centers for patients with locally advanced gastric cancer (T3, N any) who are fit to tolerate treatment. Over 1000 patients after curative D2 gastrectomy were randomly assigned (Classic Trial) to receive adjuvant chemotherapy or surgery alone. Three-year disease-free survival was 74% in the chemotherapy and surgery group and 59% in the surgery-only group ( P <.0001), indicating the short-term value of adjuvant chemotherapy. Iqbal and George described more recent trials for patients with colon and rectal cancer, noting that 14 additional randomized controlled trials and meta-analysis on laparoscopic surgery for colon cancer have confirmed the short-term benefits and oncologic noninferiority of the open approach. Sim, Knox, and Dawson in their article noted that use of lamivudine for chronic hepatitis B significantly reduced the rate of hepatocellular carcinoma development from 7% to 4% in a recent randomized trial. McAuliffe and Wolin reported the largest and most important randomized controlled trial evaluating the antiproliferative effects of a somatostatin analogue. Eligible patients were those with somatostatin receptor–positive, locally advanced or metastatic sporadic, nonfunctioning neuroendocrine tumors of well or moderate differentiation with a Ki-67 less than 10% and mitotic index of less than 2 mitoses per 10 high-power fields. At 24 months, the estimated progression-free survival was 65% in the Lanreotide group and 33% in the placebo group. Finally, in another trial, patients with well-differentiated, somatostatin receptor–positive, metastatic midgut neuroendocrine tumors were treated with ¹⁷⁷ Lu-Dotatate plus octreotide LAR or octreotide LAR alone. The 20-month progression-free survival was 65.2% for those treated with ¹⁷⁷ Lu-Dotatate as compared with 10.8% in the control group.

These reports are but a few examples of the major progress to date in patients with a variety of solid tumors treated in a multidisciplinary approach with greater understanding of the biology of cancer. Adaptation of the results of these trials and other trials described in this issue into standards of care for our patients with cancer offers great promise for significant improvement in patient outcomes. Our patients can’t wait; we can’t wait.