Differences in trial knowledge and motives for participation among cancer patients in phase 3 clinical trials

While participants in clinical oncology trials are essential for the advancement of cancer therapies, factors decisive for patient participation have been described but need further investigation, particularly in the case of phase 3 studies. The aim of this study was to investigate differences in trial knowledge and motives for participation in phase 3 clinical cancer trials in relation to gender, age, education levels and former trial experience. The results of a questionnaire returned from 88 of 96 patients (92%) were analysed using the Mann–Whitney U‐test. There were small, barely relevant differences in trial knowledge among patients when stratified by gender, age or education. Participants with former trial experience were less aware about the right to withdraw. Male participants and those aged ≥65 years were significantly more motivated by a feeling of duty, or by the opinions of close ones. Men seem more motivated than women by external factors. With the awareness that elderly and single male participants might be a vulnerable group and participants with former trial experience are less likely to be sufficiently informed, the information consent process should focus more on these patients. We conclude that the informed consent process seems to work well, with good results within most subgroups.     

Intermediate clinical endpoints: A bridge between progression‐free survival and overall survival in ovarian cancer trials

Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum‐based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression‐free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long‐term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy. Cancer 2015;121:1737–1746. © 2015 American Cancer Society.     

Older adult participation in cancer clinical trials: A systematic review of barriers and interventions

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.     

Assessing outcomes in prostate cancer clinical trials: a twenty-first century tower of Babel

BACKGROUND: Because of the osseous distribution of prostate cancer metastases, progression is more readily identified than response in prostate cancer clinical trials. As a result, there is an increased focus on progression-free survival (PFS) as a phase 2 endpoint. PFS, however, is vulnerable to inter-study design variability. The authors sought to identify and quantify this variability and the resultant error in PFS across prostate cancer clinical trials. METHODS: The authors reviewed phase 2 clinical trials of cytotoxic agents in castration-resistant metastatic prostate cancer over 5 years to evaluate the policies determining extent of disease and the definitions of disease progression. A simulation model was created to define the degree of error in estimating PFS in 3 hypothetical cohorts (median PFS of 12, 24, and 36 weeks) when the frequency of outcome assessments varies. RESULTS: Imaging policies for trial entry were heterogeneous, as were the type, timing, and indications for outcome assessments. In the simulation, error in the reported PFS varied according to the interval between assessments. The difference between the detected and the true PFS could vary as much as 6.4 weeks per cycle, strictly resulting from the variability of assessment schedules tested. CONCLUSIONS: Outcome assessment policies are highly variable in phase 2 studies of castration-resistant prostate cancer patients, despite published guidelines designed to standardize authentication of disease progression. The estimated error in PFS can exceed 6 weeks per cycle, exclusively because of variations in the assessment schedules. Comparisons of PFS times from different studies must be made with circumspection.     

Delivered relative dose intensity in adolescent and young adult germ cell tumours in England: Assessment of data quality and consistency from clinical trials compared to national cancer registration data

Adolescent and young adults (AYA) with germ cell tumours (GCT) have poorer survival rates than children and many older adults with the same cancers. There are several likely contributing factors to this, including the treatment received. The prognostic benefit of intended dose intensity is well documented in GCT from trials comparing regimens. However, evidence specific to AYA is limited by poor recruitment of AYA to trials and dose delivery outside trials not being well examined. We examined the utility of cancer registration data and a clinical trials dataset to investigate the delivery of relative dose intensity (RDI) in routine National Health Service practice in England, compared to within international clinical trials. Linked data from the Cancer Outcomes and Services Dataset (COSD) and the Systemic Anti-Cancer Therapy (SACT) dataset, and data from four international clinical trials were analysed. Survival over time was described using Kaplan-Meier estimation; overall, by age category, International Germ-Cell Cancer Collaborative Group (IGCCCG) classification, stage, tumour subtype, primary site, ethnicity and deprivation. Cox regression models were used to determine the fully adjusted effect of RDI on mortality risk. The quality of both datasets was critically evaluated and clinically enhanced. RDI was found to be well maintained in all datasets with higher RDIs associated with improved survival outcomes. Real-world data demonstrated several strengths, including population coverage and inclusion of sociodemographic variables and comorbidity. It is limited in GCT however, by the poor completion of data items enabling risk classification of patients and a higher proportion of missing data.     

Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design

BACKGROUND:

Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents.

METHODS:

The characteristics and outcome of refractory GCT patients enrolled in 7 single‐agent phase 2 trials conducted at Memorial Sloan‐Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all‐transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression‐free survival (PFS), and overall survival (OS).

RESULTS:

Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty‐six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8‐1.3) and 4.7 months (95% CI, 3.5‐6.4), respectively. Eighty‐six of the 90 patients have died. The 12‐ and 16‐week PFS rates were 9% (95% CI, 3‐15%) and 6% (95% CI, 1%‐11%), respectively.

CONCLUSIONS:

Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve‐week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials. Cancer 2012;. © 2011 American Cancer Society.     

Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials

Background:Patients with advanced solid tumors may be includedin phase I clinical trials. In such studies, the benefit expected is generallylower than the likelihood of toxicity and may even be non-existent if thepatient's life expectancy is too short. This study was performed to identifyprognostic variables for toxicity and survival in patients who participate inphase I clinical trials. Patients and methods:One hundred fifty-four patients treated ona phase I clinical trial in our institute were evaluated retrospectively.Univariable and multivariable analyses of patients' characteristics wereundertaken to determine their effects on the probability of grade 3 and 4toxicity and on survival. Results:Grade 3 or 4 toxicity was experienced by 56 patients(36%): dosage level at entry (P < 0.001) and age over 65years (P = 0.03) were independently associated with the risk oftoxicity. Median overall survival was 5 months. The multivariable analysisidentified performance status 2 or 3 (P < 0.001) and lactatedehydrogenase levels greater than 600 UI (P < 0.001) asindependent adverse prognostic variables for overall survival. Using these twoparameters, we determined a prognostic index which allowed us to discriminatethree risk groups of patients with an observed median survival of 8.5, 4.5 and1.5 months, respectively. Conclusions:Subgroups with different survival expectancy can beidentified among patients who are eligible for phase I clinical trials. Ifconfirmed, the proposed prognostic model may be useful for therapeuticdecision making in palliative oncology.eased     

Impact of a previous cancer history on the overall survival of patients with primary gastric cancer: A SEER population-based study

BackgroundThe impact of previous cancers on the survival of gastric cancer (GC) patients is still uncertain. To evaluate the impact of a prior cancer history on the overall survival of patients with primary GC.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database provided data on patients diagnosed with GC as the first or second primary malignancy between 2010 and 2015 in this retrospective cohort study. Cox proportional hazards models, Kaplan-Meier curves and forest plots were utilized to analyze overall survival. Subgroup analysis was performed based on age, gender, race and prior cancer type.ResultsTotally 39,379 were eligible for this study, including 7403 (18.8%) with a previous cancer history. A previous cancer was an independent risk factor for overall survival [hazard ratio (HR) = 1.103, 95% confidence interval (CI): 1.070–1.138]. For GC patients aged 40–60 years (HR = 1.191, 95% CI: 1.084–1.308) and ≥60 years (HR = 1.093, 95% CI: 1.058–1.13) at diagnosis, a previous cancer was significantly associated with worse overall survival. GC patients with previous oral cavity and pharynx cancer (HR = 1.249, 95% CI: 1.038–1.501), respiratory system cancer (HR = 1.177, 95% CI: 1.076–1.286), female genital system cancer (HR = 1.169, 95% CI: 1.011–1.351), or lymphoma cancer (HR = 1.192, 95% CI: 1.023–1.389) had shorter overall survival than GC patients without a previous cancer.ConclusionA previous cancer adversely affected the overall survival of GC patients. Specifically, GC patients aged ≥40 years, or with oral cavity and pharynx cancer, respiratory system cancer, female genital system cancer, or lymphoma cancer had inferior overall survival. These patients should obtain more attention and get individualized treatment to improve prognosis, and clinical trial eligibility criteria could be reconsidered for particular age and cancer types.     

Bridging the gap between the randomised clinical trial world and the real world by combination of population-based registry and electronic health record data: A case study in haemato-oncology

Randomised clinical trials (RCTs) are considered the basis of evidence-based medicine. It is recognised more and more that application of RCT results in daily practice of clinical decision-making is limited because the RCT world does not correspond with the clinical real world. Recent strategies aiming at substitution of RCT databases by improved population-based registries (PBRs) or by improved electronic health record (EHR) systems to provide significant data for clinical science are discussed. A novel approach exemplified by the HemoBase haemato-oncology project is presented. In this approach, a PBR is combined with an advanced EHR, providing high-quality data for observational studies and support of best practice development. This PBR + EHR approach opens a perspective on randomised registry trials.     

Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.     

Triple-negative breast cancer: A run-through of features,classification and current therapies

Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12–20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.     

Hematopoietic stem cell transplantation rates and long-term survival in acute myeloid and lymphoblastic leukemia: real-world population-based data from the Swedish Acute Leukemia Registry 1997-2006

BACKGROUND:

Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population‐based data avoid patient selection and may therefore substitute for lack of randomized trials.

METHODS:

We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow‐up of 6.2 years.

RESULTS:

AlloSCT rates and survival decreased rapidly with age >55 years. The 8‐year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two‐thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two‐thirds of AML patients 40‐59 years had alloSCT in one region compared with one‐third in other regions (P<.001), with improved 8‐year OS among all AML patients in this age cohort (51% vs 30%; P = .005).

CONCLUSIONS:

More Swedish AML patients received alloSCT, and long‐term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long‐term survival, but there was no such correlation in ALL. Cancer 2011;. © 2011 American Cancer Society.     

Impact of prior cancer history on the overall survival of patients newly diagnosed with cancer: A pan‐cancer analysis of the SEER database

The population of cancer survivors with prior cancer is rapidly growing. Whether a prior cancer diagnosis interferes with outcome is unknown. We conducted a pan‐cancer analysis to determine the impact of prior cancer history for patients newly diagnosed with cancer. We identified 20 types of primary solid tumors between 2004 and 2008 in the Surveillance, Epidemiology, and End Results database. Demographic and clinicopathologic variables were compared by χ² test and t‐test as appropriate. The propensity score‐adjusted Kaplan‐Meier method and Cox proportional hazards models were used to evaluate the impact of prior cancer on overall survival (OS). Among 1,557,663 eligible patients, 261,474 (16.79%) had a history of prior cancer. More than 65% of prior cancers were diagnosed within 5 years. We classified 20 cancer sites into two groups (PCI and PCS) according to the different impacts of prior cancer on OS. PCI patients with a prior cancer history, which involved the colon and rectum, bone and soft tissues, melanoma, breast, cervix uteri, corpus and uterus, prostate, urinary bladder, kidney and renal pelvis, eye and orbits, thyroid, had inferior OS. The PCS patients (nasopharynx, esophagus, stomach, liver, gallbladder, pancreas, lung, ovary and brain) with a prior cancer history showed similar OS to that of patients without prior cancer. Our pan‐cancer study presents the landscape for the survival impact of prior cancer across 20 cancer types. Compared to the patients without prior cancer, the PCI group had inferior OS, while the PCS group had similar OS. Further studies are still needed.     

幽门螺杆菌感染与胃癌患者临床特征和生存状况的关系研究

目的：探究幽门螺杆菌（HP）感染与胃癌患者临床特征和生存状况的关系。方法选择就诊的80例胃癌患者,根据患者是否发生HP感染分为感染组患者52例和未感染组患者28例,根据感染组患者的HP感染量又将患者分为A、B、C三组,比较四组患者的临床特征和生存状况。结果四组患者的年龄,淋巴结转移,Lauren分型,局部浸润方面比较,差异均有统计学意义（P﹤0.05）。C组患者淋巴结转移N2期和N3期例数多于其他三组,而未感染组N0、N1期例数较多;C组患者Lauren分型中肠型比例,局部浸润T3、T4期比例大于其他三组;感染组患者胃窦癌比例较大,未感染组患者中胃底癌比例较大,差异均有统计学意义（P﹤0.05）。对照组患者的平均生存期大于感染组,差异具有统计学意义（P﹤0.05）,且感染组患者中HP感染量越大患者生存期越短。Cox回归分析显示,HP感染,淋巴结转移,年龄（﹥60岁）,胃窦癌,浸润深度均是影响胃癌患者生存状况的独立危险因素,具有统计学意义（P﹤0.05）。结论 HP感染与胃癌患者的临床特征有关,且HP感染量越大患者的生存状况越差。