Prevalence, trends, and characteristics of trials investigating local therapy in contemporary phase 3 clinical cancer research.

BACKGROUND: Although most patients with cancer are treated with local therapy (LT), the proportion of late-phase clinical trials investigating local therapeutic interventions is unknown. The purpose of this study was to determine the proportion, characteristics, and trends of phase 3 cancer clinical trials assessing the therapeutic value of LT over time. METHODS: This was a cross-sectional analysis of interventional randomized controlled trials in oncology published from 2002 through 2020 and registered on ClinicalTrials.gov. Trends and characteristics of LT trials were compared to all other trials. RESULTS: Of 1877 trials screened, 794 trials enrolling 584,347 patients met inclusion criteria. A total of 27 trials (3%) included a primary randomization assessing LT compared with 767 trials (97%) investigating systemic therapy or supportive care. Annual increase in the number of LT trials (slope [m] = 0.28; 95% confidence interval [CI], 0.15-0.39; p < .001) was outpaced by the increase of trials testing systemic therapy or supportive care (m = 7.57; 95% CI, 6.03-9.11; p < .001). LT trials were more often sponsored by cooperative groups (22 of 27 [81%] vs. 211 of 767 [28%]; p < .001) and less often sponsored by industry (5 of 27 [19%] vs. 609 of 767 [79%]; p < .001). LT trials were more likely to use overall survival as primary end point compared to other trials (13 of 27 [48%] vs. 199 of 767 [26%]; p = .01). CONCLUSIONS: In contemporary late-phase oncology research, LT trials are increasingly under-represented, under-funded, and evaluate more challenging end points compared to other modalities. These findings strongly argue for greater resource allocation and funding mechanisms for LT clinical trials. PLAIN LANGUAGE SUMMARY: Most people who have cancer receive treatments directed at the site of their cancer, such as surgery or radiation. We do not know, however, how many trials test surgery or radiation compared to drug treatments (that go all over the body). We reviewed trials testing the most researched strategies (phase 3) completed between 2002 and 2020. Only 27 trials tested local treatments like surgery or radiation compared to 767 trials testing other treatments. Our study has important implications for funding research and understanding cancer research priorities.

The influence of radiation dose on taste impairment in a prospective observational study cohort of oropharyngeal cancer patients.

BACKGROUND: To analyze the influence of radiation dose on late radiation-associated taste impairment in oropharyngeal cancer (OPC) patients treated with intensity-modulated radiotherapy (IMRT) using the taste bud bearing tongue mucosa as organ at risk. MATERIAL AND METHODS: This study is part of an ongoing, prospective observational study. Cancer-free OPC survivors with at least 24 months from IMRT were included in this analysis. Scores for taste impairment and dry mouth were extracted from the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN) with scores of ≥5 considered as moderate-to-severe symptoms. The mean dose, minimum and maximum dose to the taste bud bearing tongue mucosa, the ipsi- and contralateral parotid and submandibular glands were extracted and analyzed for correlation with moderate-to-severe taste impairment. RESULTS: One hundred sixteen T1-4 OPC patients were included (81% males, median age: 55). The primary tumor was in the tonsil in 92 cases (79%) and in the base of tongue in 21 cases (18%). Patients were treated with 64.2-72.0 Gy; 37 patients (32%) received concurrent chemotherapy and 22 (19%) concurrent targeted therapy. After a median of 58 months from RT (IQR: 43-68) 38 patients (33%) suffered from moderate-to-severe long-term radiation-associated taste impairment. No dose volume parameter of the taste bud bearing tongue mucosa and the salivary glands was significantly associated with moderate-to-severe taste impairment for the whole patient cohort. For patients without concurrent chemotherapy, the minimum and mean dose to the ipsilateral parotid gland, and the maximum dose to the submandibular gland was significantly associated with late taste impairment (all p < 0.05). A significant correlation was found between taste impairment and dry mouth (p < 0.001). CONCLUSION: The dose to the ipsilateral parotid gland seems to play an important role in the development of late taste impairment. The influence of dose to the taste bud bearing tongue mucosa remains unclear and needs further investigation.

Food and Drug Administration approvals in phase 3 Cancer clinical trials.

BACKGROUND: Phase 3 oncologic randomized clinical trials (RCTs) can lead to Food and Drug Administration (FDA) approvals. In this study, we aim to identify trial-related factors associated with trials leading to subsequent FDA drug approvals. METHODS: We performed a database query through the ClinicalTrials.gov registry to search for oncologic phase 3 RCTs on February 2020. We screened all trials for therapeutic, cancer-specific, phase 3, randomized, multi-arm trials. We then identified whether a trial was used for subsequent FDA drug approval through screening of FDA approval announcements. RESULTS: In total, 790 trials were included in our study, with 225 trials (28.4%) generating data that were subsequently used for FDA approvals. Of the 225 FDA approvals identified, 65 (28.9%) were based on trials assessing overall survival (OS) as a primary endpoint (PEP), two (0.9%) were based on trials with a quality of life (QoL) PEP, and 158 approvals (70.2%) were based on trials with other PEP (P = 0.01). FDA approvals were more common among industry funded-trials (219, 97.3%; P < 0.001), and less common among trials sponsored by national cooperative groups (21, 9.3%; P < 0.001). Finally, increased pre-hoc power and meeting patients' accrual target were associated with FDA approvals (P < 0.001). CONCLUSIONS: The majority of FDA approvals are based on data generated from trials analyzing surrogate primary endpoints and trials receiving industry funding. Additional studies are required to understand the complexity of FDA approvals.

Proton Therapy for HPV-Associated Oropharyngeal Cancers of the Head and Neck: a De-Intensification Strategy.

OPINION STATEMENT: The rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT-all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway-the "Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck" and the "TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)" trial-are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Exclusion of Men from Randomized Phase III Breast Cancer Clinical Trials.

Male breast cancer treatment regimens are often extrapolated from female-based studies because of a paucity of literature analyzing male breast cancer. Using ClinicalTrials.gov, we analyzed breast cancer randomized clinical trials (RCTs) to determine which factors were associated with male-gender inclusion. Of 131 breast cancer RCTs identified, male patients represented 0.087% of the total study population, which is significantly less than the proportion of male patients with breast cancer in the U.S. (0.95%; p < .001). Twenty-seven trials included male patients (20.6%). Lower rates of male inclusion were seen in trials that randomized or mandated hormone therapy as part of the trial protocol compared with trials that did not randomize or mandate endocrine therapy (2.5% vs. 28.6% male inclusion; p < .001). It is imperative for breast cancer clinical trials to include men when allowable in order to improve generalizability and treatment decisions in male patients with breast cancer.

Performance Status Restriction in Phase III Cancer Clinical Trials.

BACKGROUND: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. METHODS: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. RESULTS: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. CONCLUSIONS: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.

Non-English language validation of patient-reported outcome measures in cancer clinical trials.

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

Roses Have Thorns: Understanding the Downside of Oncological Care Delivery Through Visual Analytics and Sequential Rule Mining.

Personalized head and neck cancer therapeutics have greatly improved survival rates for patients, but are often leading to understudied long-lasting symptoms which affect quality of life. Sequential rule mining (SRM) is a promising unsupervised machine learning method for predicting longitudinal patterns in temporal data which, however, can output many repetitive patterns that are difficult to interpret without the assistance of visual analytics. We present a data-driven, human-machine analysis visual system developed in collaboration with SRM model builders in cancer symptom research, which facilitates mechanistic knowledge discovery in large scale, multivariate cohort symptom data. Our system supports multivariate predictive modeling of post-treatment symptoms based on during-treatment symptoms. It supports this goal through an SRM, clustering, and aggregation back end, and a custom front end to help develop and tune the predictive models. The system also explains the resulting predictions in the context of therapeutic decisions typical in personalized care delivery. We evaluate the resulting models and system with an interdisciplinary group of modelers and head and neck oncology researchers. The results demonstrate that our system effectively supports clinical and symptom research.