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In recent years, the landscape in clinical trial development has changed to involve many molecularly targeted agents, immunotherapies, or radiotherapy, as a single agent or in combination. Given their different mechanisms of action and lengths of administration, these agents have different toxicity profiles, which has resulted in numerous challenges when applying traditional designs such as the 3 + 3 design in dose-finding clinical trials. Novel methods have been proposed to address these design challenges such as combinations of therapies or late-onset toxicities. However, their design and implementation require close collaboration between clinicians and statisticians to ensure that the appropriate design is selected to address the aims of the study and that the design assumptions are pertinent to the study drug. The goal of this paper is to provide guidelines for appropriate questions that should be considered early in the design stage to facilitate the interactions between clinical and statistical teams and to improve the design of dose-finding clinical trials for novel anticancer agents. [ABSTRACT FROM AUTHOR]

REFERENCES 1 Ratain MJ: Designing dose-finding phase I clinical trials: Top questions that should be discussed with your clinical pharmacologist. Dr Ratain attributes inappropriate dosing of approved drugs to a reliance on toxicity end points to determine the dose. Incorporating pharmacokinetic (PK) information in the dose-finding process can better estimate the dose-toxicity curve while maintaining MTD selection performance. [Extracted from the article]

Background: Adjuvant therapy plays a major role in treating colorectal cancer, and physicians' views of its effectiveness influence treatment decisions. We assessed physicians' views of the relative benefits and risks of adjuvant chemotherapy and radiotherapy for stages II and III colon and rectal cancers. Methods: The Cancer Care Outcomes Research and Surveillance Consortium surveyed a geographically dispersed population of medical oncologists, radiation oncologists, and surgeons in the United States about the benefits and risks of adjuvant therapies for colorectal cancer. We used logistic regression to assess the association of physician and practice characteristics with beliefs about adjuvant therapies. Results: Among 1,296 respondents, 90% believed the benefits of adjuvant therapies for stage III colorectal cancer outweigh the risks. Only 21.9%, 50%, and 50.4% believed in the net benefit of chemotherapy for stage II colon cancer, chemotherapy for stage II rectal cancer, and radiation for stage II rectal cancer, respectively. Younger physicians were less likely than others to perceive adjuvant therapy for stage II colorectal cancer as beneficial. Medical oncologists were more likely than surgeons and radiation oncologists to endorse the benefits of adjuvant chemotherapy and radiation for stage II rectal cancer, but less likely for stage II colon cancer. Conclusions: Physicians largely agreed that the benefits of adjuvant chemotherapy for stage III colon cancer, as well as chemotherapy, and radiation for stage III rectal cancer, outweigh the risks, consistent with strong evidence, but were divided over the net benefit of adjuvant therapies for stage II colorectal cancer, where evidence is inconsistent. [ABSTRACT FROM AUTHOR]

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively ( P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group ( P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Inclusion of advocates as partners in research is now required by numerous international funding agencies. The role of advocates has expanded in recent years to include all areas of research, including basic cancer research, translational research, and clinical trial design and development. The involvement of advocates as partners in cancer research can be challenging for the advocate and for the researchers, but this collaboration is beneficial to all involved. Herein, we will define patient advocacy, explore advocate engagement, and share information on programs that train advocates and researchers to work together as partners.

Purpose: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited., Methods: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival., Results: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates., Conclusion: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

In the past 40 years, the treatment of locally advanced rectal cancer has evolved with the addition of radiotherapy or chemoradiotherapy and providing (neo)adjuvant systemic chemotherapy to major surgery. However, recent trends have focused on improving our ability to risk-stratify patients and tailoring treatment to achieve the best oncologic outcome while limiting the impact on long-term quality of life. Therefore, there has been increasing interest in pursuing a watch-and-wait approach to achieve organ preservation. Several retro- and prospective studies suggest safety of the watch-and-wait approach, though it is still considered controversial due to limited clinical evidence, concerns about tumor regrowth, and subsequent distant progression. To further reduce treatment, MRI risk stratification, together with patient characteristics and patient preferences, can guide personalized treatment and reserve radiation and chemotherapy for a select patient population. Ultimately, improved options for reassessment during neoadjuvant treatment may allow for more adaptive therapy options based on treatment response. This article provides an overview of some major developments in the multimodal treatment of locally advanced rectal cancer. It reviews some relevant, controversial issues of the watch-and-wait approach and opportunities to personally tailor and reduce treatment. It also reviews the overall neoadjuvant treatment, including total neoadjuvant therapy trials, and how to best optimize for a potential complete response. Finally, it provides an algorithm as an example of how such a personalized, tailored, adaptive, and reduced treatment could look like in the future.

The incidence of gastroesophageal junction (GEJ) adenocarcinomas has been rising over the past few decades, creating a need for effective therapeutic strategies. Treatment of locally advanced GEJ tumors, in particular, present a unique challenge because these tumors have generally been approached as either esophageal or gastric cancers, and thus optimal preoperative management remains uncertain. Both neoadjuvant chemoradiation and perioperative chemotherapy have been widely adopted in standard practice; however, it is unclear which approach offers the optimal outcome for the fit patient capable of receiving any planned strategy. In this review, we debate the management of locally advanced GEJ adenocarcinoma, and discuss areas of ongoing investigation which may provide more effective and individualized treatment of patients with GEJ cancers.

Biliary tract cancer, or cholangiocarcinoma, arises from the biliary epithelium of the small ducts in the periphery of the liver (intrahepatic) and the main ducts of the hilum (extrahepatic), extending into the gallbladder. The incidence and epidemiology of biliary tract cancer are fluid and complex. It is shown that intrahepatic cholangiocarcinoma is on the rise in the Western world, and gallbladder cancer is on the decline. Radiation therapy has emerged as an important component of adjuvant therapy for resected disease and definitive therapy for locally advanced disease. The emerging sophisticated techniques of imaging tumors and conformal dose delivery are expanding the indications for radiotherapy in the management of bile duct tumors. As we understand more about the molecular pathways driving biliary tract cancers, targeted therapies are at the forefront of new therapeutic combinations. Understanding the gene expression profile and mutational burden in biliary tract cancer allows us to better discern the pathogenesis and identify promising new developmental therapeutic targets.

Treatment of rectal cancer has improved greatly over recent decades. This review looks at the pivotal trials in the development of the current standard of therapy as well as new directions for more individualized therapy for rectal cancer. Rates of local recurrence and overall survival (OS) for surgery alone have improved with the use of (neo)adjuvant 5-fluorouracil (5-FU)-based chemoradiation. New surgical techniques have improved outcomes, but preoperative radiotherapy still confers an additional benefit. Despite benefits in the metastatic setting, the addition of oxaliplatin to 5-FU and radiotherapy has not shown improved outcomes, although it increased toxicity. Preoperative therapy also allows for the identification of predictive and prognostic markers for response to treatment, which has great potential to individualize treatment. Currently, the search for validated biomarkers and the refinement of risk stratification are the focus of ongoing study. Tailored therapy may include modification of the pelvic radiotherapy field, nonoperative therapy, or avoidance of radiotherapy.

Purpose: To evaluate the risk of late morbidity and mortality, and to assess long-term health-related quality of life (QOL) among patients with relapsed/refractory Hodgkin's lymphoma (HL) after high-dose chemoradiotherapy (HDT) and autologous stem-cell rescue (ASCR)., Patients and Methods: From 1985 to 1998, 218 patients with HL were treated on HDT with ASCR salvage protocols. Of these 218, 153 (70%) who survived > or = 2 years after ASCR were evaluated for late morbidity and mortality from causes other than HL. QOL information was obtained through self-administered questionnaires. Risk ratios (RR) were calculated to compare observed second malignancy (SM) rates in this cohort with expected SM rates from the Surveillance Epidemiology and End Results (SEER) registry., Results: Median follow-up after ASCR was 11.5 years. Among 153 patients, there were 53 deaths; 33 from HL and 20 from other causes. Thirteen deaths were caused by SM, with median time from ASCR to SM diagnosis of 9 years (range, 3 to 18 years). The RR of SM was 6.5 (95% CI, 3.6 to 10.7) when compared with the general population, but 2.4 (95% CI, 1.4 to 4.05) when compared with patients with HL. Global QOL of ASCR survivors was comparable with the general population, but for specific domains, respondents' scores indicated reduced functioning and worse symptoms., Conclusion: HL accounts for most deaths among patients surviving HDT and ASCR. Survivors of ASCR had an elevated risk of SM compared with the cancer risk in the general population, but when compared with patients with HL in SEER, the risk was less pronounced.