process. Rather, it is an integral part of the medical research cycle (see Figure 4, p. 27) because observations made during the routine use of new medical products can be used to accelerate the pace at which similar products are developed and to stimulate the development of new, more effective products. New FDA-approved medical products are traditionally utilized alongside treatments already in use, including surgery, radiotherapy, and cytotoxic chemotherapy, which continue to be the mainstays of clinical cancer care (see Figure 15, p. 76). Researchers are also evaluating new ways to refine the use of surgery, radiotherapy, and existing cytotoxic chemotherapeutics to improve survival and quality of life for patients. As one example, a recent clinical trial showed that for patients with early-stage prostate cancer, active monitoring of their disease is a safe alternative to receiving immediate surgery or radiotherapy (346). In most cases, prostate cancer grows slowly. Therefore, the study directly compared the long-term outcomes of the three approaches, prostate removal surgery, radiotherapy, or active monitoring and found that there was no difference in prostate cancer mortality at the 15-year follow-up between the three groups. These data provide hope for patients with prostate cancer who opt for active monitoring to avoid treatment-related adverse effects, such as sexual and incontinence problems. The following sections focus on the recent advances across the five pillars of cancer treatment including the 14 new anticancer therapeutics approved by the FDA in the 12 months spanning this report, August 1, 2022, to July 31, 2023 (see Table 3, p. 77, and Supplemental Table 2, p. 192). Also highlighted are the 12 previously approved anticancer therapeutics that received FDA approval for treating additional types of cancer in that period. Phases of Clinical Trials Clinical trials evaluating potential new therapeutics for treating patients with cancer have traditionally been done in three successive phases, each with an increasing number of patients. Phase I studies are designed to determine the optimal dose of an investigational anticancer therapeutic, how humans process it, and potential toxicities. Phase I trials are not designed to evaluate efficacy of a therapeutic. Thanks to progress in trial design and conduct, patient response rates in phase I studies have nearly doubled over the past two decades (328). Phase II studies are designed to determine the initial efficacy of an investigational therapy, in addition to continually monitoring for potential toxicities. Phase III studies are large trials designed to determine therapeutic efficacy as compared to standard of care; when successful, the results of these trials can be used by the U.S. Food and Drug Administration (FDA) to approve new therapeutics or new indications for existing therapeutics. Phase IV studies are conducted after a therapy is provisionally approved by the FDA and provide additional effectiveness or “real-world” data on the therapy. In some cases, researchers combine different phases into one clinical trial (labeling depends on the phases combined, e.g., phase I/II or phase III/IV clinical trials), which allows research questions to be answered more quickly or with fewer patients. Sometimes Phase 0 clinical studies are performed prior to traditional clinical trials where low doses of potential therapeutics are administered to small number of patients to determine whether such treatments may have the desired effect. Adapted from (163). FIGURE 13 PHASE IV PHASE III Therapeutic e cacy compared to standard of care Thousands of patients Postmarketing studies providing e ectiveness or “real-world” data Thousands of patients Safety and e cacy Hundreds of patients PHASE II Safety and dosage Tens of patients PHASE I AACR Cancer Progress Report 2023 Advancing the Frontiers of Cancer Science and Medicine 72
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