•PRISMA systematic review including 10 HPV-associated de-intensification trials.•Chemoradiotherapy de-escalation strategies show promising outcomes, few toxicities.•Two trials showed superior ...outcomes with cisplatin versus cetuximab.•Although de-escalations strategies differ, many feasible options exist.•Long-term follow-up is required for firm treatment recommendations.
Numerous trials have been launched over the prior decade examining the safety and efficacy of therapy de-escalation in human papillomavirus (HPV)-associated oropharyngeal cancer (OPC). Because no summative assessment of these prospective trials exists to date, we systematically reviewed the outcomes and toxicities associated with therapy de-intensification for this population. PRISMA-guided systematic PubMed searches (along with articles known to the authors and references thereof) were performed for prospective studies reporting clinical outcomes and/or toxicities of de-intensified RT and/or systemic therapy (with or without surgery), exclusively for HPV-associated OPC. Ten prospective studies were analyzed. Performing a meta-analysis was not entirely possible owing to the heterogeneity of treatment paradigms and the lack of >2 studies for most paradigms; however, because just one paradigm (induction chemotherapy followed by reduced-dose RT and/or systemic therapy) had 4 associated articles, an exploratory meta-analysis was conducted for that subset. Two trials of dose-reduced concurrent chemoradiotherapy (60 Gy/weekly cisplatin) demonstrated 3-year distant metastasis-free survival and overall survival (OS) ranging from 91 to 100% and 95%, respectively; acute grade 3+ mucositis and dysphagia occurred in 33–35% and 21–39%, respectively. In the four trials of induction chemotherapy (platinum/taxane-based) followed by dose-reduced RT, 2-year progression-free and OS ranged from 80 to 95% and 83 to 98%, respectively; acute grade 3+ dysphagia, dermatitis, and mucositis ranged from 9 to 15%, 7 to 20%, and 9 to 30% (excluding one outlier), respectively. For these four trials, the exploratory meta-analysis showed a pooled 2-year PFS and OS of 89% (95% confidence interval, 80–96%) and 96% (92–99%). The pooled rates of grade ≥3 dysphagia, dermatitis, and mucositis were 13% (7–19%), 9% (5–14%), and 28% (9–53%). However, there was significant heterogeneity in the 2-year PFS (I2 = 57%, p = 0.07) and grade ≥3 mucositis (I2 90%, p < 0.01). Next, both randomized trials which replaced concurrent tri-weekly cisplatin with weekly cetuximab illustrated superior outcomes with the former. Lastly, two remaining trials (one using functional imaging to guide reduced-dose RT, and another examining reduced-dose postoperative RT) also showed satisfactory outcomes and toxicities. Taken together, dose-reduced chemoradiotherapy (with or without induction chemotherapy for patient/biology selection purposes) seems to be a promising de-escalation strategy for HPV-associated OPC, although replacement of concurrent cisplatin by cetuximab is not recommended. Long-term follow-up is required for firmer conclusions.
Optimal management of cancer patients relies heavily on late-phase oncology randomized controlled trials. A comprehensive understanding of the key considerations in designing and interpreting ...late-phase trials is crucial for improving subsequent trial design, execution, and clinical decision-making. In this review, we explore important aspects of late-phase oncology trial design. We begin by examining the selection of primary endpoints, including the advantages and disadvantages of using surrogate endpoints. We address the challenges involved in assessing tumor progression and discuss strategies to mitigate bias. We define informative censoring bias and its impact on trial results, including illustrative examples of scenarios that may lead to informative censoring. We highlight the traditional roles of the log-rank test and hazard ratio in survival analyses, along with their limitations in the presence of nonproportional hazards as well as an introduction to alternative survival estimands, such as restricted mean survival time or MaxCombo. We emphasize the distinctions between the design and interpretation of superiority and noninferiority trials, and compare Bayesian and frequentist statistical approaches. Finally, we discuss appropriate utilization of phase II and phase III trial results in shaping clinical management recommendations and evaluate the inherent risks and benefits associated with relying on phase II data for treatment decisions.
In this review, we present the context of older adult (OA) cancer patients within the broader cancer population, including cancer burdens and trial representation. We first describe the proportion of ...older adults in clinical trials, with studies showing strong evidence that the proportion of OA in cancer trials is much less than the proportion of OA in the overall cancer population. We highlight the lack of generalizability that can lead to challenges in treatment decisions for OA as well as concerns regarding health inequity. We then discuss barriers to OA enrollment related to trial structure and design, physician perspective, and patient and/or caregiver perspective. We expand on this further by outlining these barriers throughout the process of trial design, patient enrollment/trial implementation, and data analysis in post-market settings. We summarize guidelines from national societies, regulatory agencies, and other institutional bodies, then present a compilation of on-the-ground actionable recommendations to address the challenges of clinical trial design, focusing on geriatric assessments and OA-specific trials. We conclude by providing an outline for future directions, noting specifically the potential impact that radiotherapy and radiation oncology may have on clinical trials related to OA patients.
Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative ...interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.
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