Treatment efficacy and tolerance in geriatric oncology

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6115-6115 ◽  
Author(s):  
A. Kumar ◽  
H. P. Soares ◽  
L. Balducci ◽  
B. Djulbegovic
Keyword(s):  
Clinical Trials ◽  
Elderly Patients ◽  
Randomized Clinical Trials ◽  
Geriatric Oncology ◽  
Cochrane Collaboration ◽  
Phase Iii ◽  
General Notion ◽  
Event Free Survival ◽  
Free Survival ◽  
Study Protocols

6115 Background: Elderly patients share the majority of the disease burden in cancer. Although 61% of new cancer cases occur among elderly, yet elderly comprise only 25% of the patients enrolled in clinical trials. A systematic review to assess the accurate participation of elderly in randomized clinical trials (RCT) has not been done. Methods: We reviewed all consecutively completed phase III RCTs conducted by 5 National Cancer Institute sponsored cooperative groups. Published papers and study protocols were used to ensure the accuracy of the data extraction. We used a cut-off of age ≥65 to define elderly patients. For trials that did not have an exclusive ≥65 age criteria for enrollment, data were extracted on number of participants ≥65. Outcome between the innovative and the standard treatment was compared. Data were extracted as per the methods recommended by the Cochrane Collaboration. Results: Out of 413 studies, only two trials exclusively enrolled elderly patients (0.5%). 57% (n=235) of the trials did not have any stratification by age. Only 10% of the studies had a stratification age at ≥65 (n=42). Contrary to the general notion that elderly may not respond well to newer chemotherapy combination treatments, overall survival in these two trials exclusively enrolling elderly favored the newer treatments [Hazard ratio (HR) 0.62(95%CI 0.44, 0.87)]. In addition, trials enrolling >40% of elderly had favorable outcomes involving innovative treatments for survival and event-free survival [HR survival 0.85(95%CI 0.77, 0.94), HR event-free survival was 0.76(95%CI 0.64, 0.92)]. Treatment related mortality was similar in the innovative and the standard arms [HR 0.87(95%CI 0.39, 1.96)]. Conclusions: Our data indicate that enrollment of elderly in experimental RCTs is not associated with increased harms to this patient population. Increased participation of elderly may help in finding new treatments that are clinically applicable specifically to this cohort of patients. No significant financial relationships to disclose.

Treatment Tolerance and Efficacy in Geriatric Oncology: A Systematic Review of Phase III Randomized Trials Conducted by Five National Cancer Institute–Sponsored Cooperative Groups

2007 ◽  
Vol 25 (10) ◽  
pp. 1272-1276 ◽  
Author(s):  
Ambuj Kumar ◽  
Heloisa P. Soares ◽  
Lodovico Balducci ◽  
Benjamin Djulbegovic
Keyword(s):  
Systematic Review ◽  
Elderly Patients ◽  
National Cancer Institute ◽  
Randomized Clinical Trials ◽  
Standard Treatment ◽  
Geriatric Oncology ◽  
Phase Iii ◽  
Cooperative Groups ◽  
Event Free Survival ◽  
Free Survival

Purpose Elderly patients share the majority of the disease burden in cancer. Although 61% of new cancer cases occur among elderly, they comprise only 25% of the patients enrolled onto randomized clinical trials (RCTs). A systematic review to assess the accurate participation of elderly patients in RCTs has not been performed. Patients and Methods We reviewed all consecutively completed phase III RCTs conducted by five National Cancer Institute–sponsored cooperative groups. Published papers and study protocols were used for data extraction. We used a cutoff age of ≥ 65 years to define elderly patients. For trials that did not exclusively enroll elderly, data were extracted on number of participants ≥ 65 years of age. Outcome between the innovative and the standard treatment was compared. Results Of 345 studies, only one trial exclusively enrolled elderly patients (0.28%); 57% of the trials (n = 197) had no stratification by age, and 12% of the studies had a stratification age ≥ 65 years (n = 42). Overall survival in the trial exclusively enrolling elderly favored the newer treatments (hazard ratio [HR], 0.69; 95% CI, 0.47 to 1.02; P = .06). Additionally, in trials enrolling more than 40% of elderly, survival and event-free survival favored the innovative treatments (HR for survival, 0.91; 95% CI, 0.84 to 0.99; P = .03; HR for event-free survival, 0.85; 95% CI, 0.72 to 1.01; P = .07). Treatment-related mortality was similar in both the innovative and standard treatment groups (HR, 0.91; 95% CI, 0.47 to 1.78; P = .8). Conclusion Our data indicate that enrollment of elderly in experimental RCTs is not associated with increased harm to this patient population. Increased participation of elderly may help in finding new treatments that are clinically applicable specifically to this cohort of patients.

scholarly journals Blinded Independent Central Review of Progression-Free Survival in Phase III Clinical Trials: Important Design Element or Unnecessary Expense?

2008 ◽  
Vol 26 (22) ◽  
pp. 3791-3796 ◽  
Author(s):  
Lori E. Dodd ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
C. Carl Jaffe ◽  
Lawrence V. Rubinstein ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Treatment Effectiveness ◽  
Progression Free Survival ◽  
Informative Censoring ◽  
Phase Iii ◽  
General Strategy ◽  
Design Element ◽  
Free Survival ◽  
Using Data

Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results.

Impact of the Timing of Complete Remission and Transplantation on Estimates of Event-Free Survival in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 214-214 ◽  
Author(s):  
Jun Yin ◽  
Betsy R. Laplant ◽  
Geoffrey L. Uy ◽  
Guido Marcucci ◽  
William Blum ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Complete Remission ◽  
Board Of Directors ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Phase Iii Study ◽  
Induction Failure

Abstract Background: Event free survival (EFS) is often used as an endpoint in AML clinical trials. EFS-based endpoints are controversial due to the lack of a consistent definition for the timing of complete remission (CR), and consideration of hematopoietic cell transplantation (HCT). Here, we examined the impact of the timing of achievement of CR and censoring for HCT in the estimation of the EFS, and assessed its robustness as an endpoint in AML. Methods: All prospective trials since 2003 using anthracycline and cytarabine chemotherapy for newly diagnosed patients (pts) with AML conducted through the Alliance for Clinical Trials in Oncology, and whose primary endpoint data has been reported, were included (5 trials total). Trial 1 - randomized phase III study in older AML pts (n=504, median age 69, 61% male); trial 2 - single-arm phase II study in older FLT3-mutated AML pts (n=54, median age 67, 56% male); trial 3 - randomized phase III study in younger AML pts (n=546, median age 48, 55% male); trial 4 - randomized phase III study in younger FLT3-mutated AML pts (n=717, median age 48, 45% male); and trial 5 - single arm phase II study in core-binding factor AML pts with no restriction on age (n=61, median age 51, 51% male). Induction failure was defined as one of: no CR by 60 days (Definition 1), no CR by the end of all protocol induction courses (Definition 2), or no CR by the end of all protocol treatment (Definition 3). CR was defined as <5% blasts in a cellular marrow with recovery of >1000 neutrophils/ul (>1500 neutrophils/ul for trial 1), >100,000 platelets/ul, and no red cell transfusion requirement. EFS was defined as the time from randomization / registration to the first evidence of induction failure using each of the 3 methods above, relapse, or death from any cause. Patients last known to be alive without relapse were censored at the date of last contact. Including the 3 induction failure definitions and consideration of censoring or no censoring for HCT, the Kaplan Meier estimates of EFS were computed for the six different definitions of EFS. Results: The number of deaths was respectively 464, 38, 307, 357, and 13 across the 5 trials, with a median follow-up of 99.7, 28.2, 60.1, 58.2, and 33.5 months on the alive patients, respectively. Not considering HCT, in trial 1, the median EFS ranged from 2.0 to 4.3 months (115% difference); in trial 2, the median EFS ranged from 6.9 to 8.3 months (20% difference); in trial 3, the median EFS ranged from 9.8 to11.2 months (14% difference); and in trial 4, the median EFS ranged from 5.5 to 9.7 months (76% difference). The median EFS was not achieved in trial 5; however the 1-year EFS estimates ranged from 78 to 83% (6% difference). Consistently across all trials, as expected, the EFS estimate using the 60-day induction failure yielded the shortest estimates, whereas the end-of-treatment induction failure yielded the longest estimates. Results were similar both with and without censoring at the time of HCT as the event of interest occurred prior to transplantation in most cases. Conclusions: Although relapse and death are firm endpoints, the determination of failure to achieve CR is not consistent across studies. While there is minimal impact of censoring at HCT on EFS estimates, the median EFS estimates differed considerably based on the timing of CR used to define induction failure, with the magnitude of difference being large enough in most cases (observed range: 14% to >100%) to lead to incorrect conclusions about efficacy in a single arm trial if the trial definition was not consistent with the definition used for the historical control. The timing of CR should be carefully examined in the historical control data used to guide the design of the next trial. Table. Table. Disclosures Uy: Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy. Stone:Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy.

Intensified CHOP with Rituximab for Intermediate or High-Risk Non-Hodgkin’s Lymphoma: Interim Analysis of a Randomized Phase III Trial in Elderly Patients by the Dutch HOVON and Nordic Lymphoma Groups.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 16-16 ◽  
Author(s):  
Pieter Sonneveld ◽  
Wim van Putten ◽  
Harald Holte ◽  
Douwe Biesma ◽  
Marinus van Marwijk-Kooy ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Incomplete Data ◽  
Interim Analysis ◽  
Cell Lymphoma ◽  
Phase Iii ◽  
Event Free Survival ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Significant Difference

Abstract High-risk Non-Hodgkin lymphoma (NHL) in elderly patients (&gt; 60 yrs) is associated with a relatively low complete response (CR) rate and a poor overall survival (OS). Previous studies have shown that addition of Rituximab to standard CHOP chemotherapy may improve CR and/or OS. A similar improvement has been shown for intensification of CHOP from 21 day intervals to 14 day intervals. The Dutch HOVON group and the Nordic lymphoma group have performed a multi-center, randomized phase III trial to compare 8 cycles of intensified CHOP (CHOP14) with the same regimen plus 6 administrations of Rituximab in previously untreated elderly patients with intermediate or high-risk NHL. Inclusion criteria were diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma grade III; intermediate or high-risk NHL according to age adjusted IPI score; CD20-positive NHL; age 65 yrs or higher. The target number was 400 patients to be accrued in 5 years based on an expected increase in event-free survival with hazard ratio HR=0.70. Aplanned interim analysis was performed after inclusion of 250 patients, restricted to 211 patients included from 1st September 2001 to 1st October 2004. Forty patients had to be excluded because of lack of treatment and evaluation data, leaving 171 patients for the analysis. The median time off protocol treatment was 119 days (range 4–468 days). The median age was 73 years (range 62–88 years). There was no difference between the two treatment arms regarding histology, age, WHO classification of NHL, age-adjusted IPI score, Ann Arbor stage, WHO performance status and serum LDH. There was no significant difference of toxicity or CR between the two treatment arms. However, a highly significant difference was observed for event-free survival and overall survival in favor of the treatment arm with CHOP plus Rituximab. Based on this interim analysis, the randomization was halted and patients in the control arm were further treated with CHOP plus Rituximab. Since the outcome of the interim analysis could be biased due to incomplete data, a final decision to stop the trial awaits a new analysis which is planned for 26th August 2005 after collection of missing or incomplete data. If the new analysis confirms the results of the interim analysis, i.e. that Rituximab significantly improves the outcome of treatment in elderly patients with intermediate or high-risk NHL, even when an intensified CHOP regimen is used, the study will be closed and outcomes will be presented.

scholarly journals Sequencing Therapy for Elderly Chronic Lymphocytic Leukemia Patients in the Era of Novel Therapies: An Overview of Randomized Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5559-5559
Author(s):  
Malik Qistas Ahmad ◽  
Chaudhry Saad Sohail ◽  
Muhammad Yasir ◽  
Muhammad Junaid Tariq ◽  
Arshia Akbar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Randomized Clinical Trials ◽  
Conflicts Of Interest ◽  
The Elderly ◽  
Phase Iii ◽  
Female Ratio ◽  
Tp53 Mutations

Abstract Background: For most of the elderly or unfit CLL patients, treatment algorithms focus on achievement of clinical response, relief of symptoms and prolongation of life expectancy. Comorbidities, frailty and reduced functional status in elderly patients make some of the standard treatments intolerable and less efficacious. However, recent advancements in understanding of CLL biology, approval of target agents including novel monoclonal antibodies and kinase inhibitors have expanded the horizons for treatment of CLL in elderly. Methods: We conducted a literature search on PubMed, Embase, Web of Science and ClinicalTrials.gov which was completed on July 1, 2018. To assess the CLL treatment protocols in the elderly population, we included data from phase II and phase III clinical trials from the last decade (Jan 2008 to Jan 2018). Results: From a total of 1259 studies, we selected 34 studies (n=3122) after inclusion criteria were met. The patients included are from the age group of ≥65 years with the mean age of 68.8 years. Male to female ratio was 3:2. On comparison of different parameters to look for the drug or regimen efficacy, we found that ibrutinib is very effective and tolerable in older (aged ≥65 years) treatment-naïve (TN) as well as relapsed refractory patients (RR), with overall response rate (ORR) of 91% for combined group in one study when compared to ofatumumab. When used in combination with ublituximab, the ORR peaked to 80% as compared to ibrutinib alone in patients with high risk cytogenetics (ORR=47%, p<0.001). Phase III RESONATE trial showed a comparison between ibrutinib and chlorambucil treated del 17p negative elderly patients; ibrutinib was superior in terms of ORR (86% vs. 35%) and overall survival (OS) (2-year OS, 98% vs. 85%, p=0.001). The OS with ibrutinib turned out to be 89% showing better disease control as compared to idelalisib (OS= 61%) when used in combination with rituximab, with a 33% reduction in mortality with ibrutinib as compared with idelalisib in RR patients. The combination of rituximab with idelalisib has shown promising results in patients with specific mutations (i.e. 100% ORR in those with del (17)/ Tp53 mutations, 97% ORR in those with unmutated IGHV). Similarly, when compared with placebo and rituximab combination progression free survival (PFS) was 13%, idelalisib is found to have PFS of 66% at 12 months in patients with del 17p/ Tp53 mutations and unmutated IGHV status. Moreover, in a phase II study, ofatumumab monotherapy showed ORR of 72%. In newly diagnosed (ND) CLL, an ORR of 98% is found with the pentostatin, cyclophosphamide, rituximab, and lenalidomide regimen. Other worth sharing results include; complete remission (CR) in 71% (24 out of 34 included) patients who were given lenalidomide as an initial therapy, with OS of 88% and ORR of 65%. The OS is surprisingly as high as 97.9% in those who were given pentostatin and cyclophosphamide in combination with ofatumumab. Traditional chemotherapy with fludarabine and rituximab (FR) showed OS of 67% in one study with rates of grades II and III-IV acute GVHD as 60% and 15% respectively. The most common hematological side effects seen with ibrutinib in one of the studies are neutropenia (12%), thrombocytopenia (4%) and anemia (7%). The non-hematological complications may be secondary due to cytopenias (infections, pneumonia, bleeding, and neutropenic fever) or due to constitutional symptoms like myalgia, fatigue, vomiting, or nausea. Conclusion: The rapid clinical development of novel therapy agents has changed the prognosis for CLL patients. Ibrutinib is considered as a standard option and an up front therapy for high risk CLL patients especially who are elderly and have del 17p, despite its significant toxicity profile in very elderly patients (80 years and above) where multiple deaths were reported. Future prospects include ibrutinib combinations with frontline chemo-immunotherapy (CIT) and other novel agents for TN and RR del 17p negative patients. Disclosures No relevant conflicts of interest to declare.

End Points and Trial Design in Geriatric Oncology Research: A Joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology Position Article

2013 ◽  
Vol 31 (29) ◽  
pp. 3711-3718 ◽  
Author(s):  
Hans Wildiers ◽  
Murielle Mauer ◽  
Athanasios Pallis ◽  
Arti Hurria ◽  
Supriya G. Mohile ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Geriatric Oncology ◽  
New Drugs ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Global Functioning ◽  
End Points ◽  
Advantages And Disadvantages ◽  
Oncology Research

Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals.Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.

What are the reciprocal influences of randomized clinical trials and the patient–psychiatrist relationship?

1999 ◽  
Vol 14 (2) ◽  
pp. 93-100
Author(s):  
J. Catteau ◽  
C. Cyran ◽  
R. Bordet ◽  
C.E. Thomas ◽  
B.A. Dupuis
Keyword(s):  
Clinical Trials ◽  
Depressive Disorders ◽  
Randomized Clinical Trials ◽  
Antidepressant Drugs ◽  
Antidepressant Medication ◽  
Study Data ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Clinical Trials ◽  
Reciprocal Influences

SummaryThe goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

scholarly journals Is Bayesian Analysis Ready for Use in Phase III Randomized Clinical Trials?

Stroke ◽  
2005 ◽  
Vol 36 (7) ◽  
pp. 1622-1623 ◽  
Author(s):  
George Howard ◽  
Christopher S. Coffey ◽  
Gary R. Cutter
Keyword(s):  
Clinical Trials ◽  
Bayesian Analysis ◽  
Randomized Clinical Trials ◽  
Phase Iii

Positron Emission Tomography–Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial

2018 ◽  
Vol 36 (20) ◽  
pp. 2024-2034 ◽  
Author(s):  
Ulrich Dührsen ◽  
Stefan Müller ◽  
Bernd Hertenstein ◽  
Henrike Thomssen ◽  
Jörg Kotzerke ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Survival Rates ◽  
Hazard Ratio ◽  
Emission Tomography ◽  
Phase Iii ◽  
Event Free Survival ◽  
Free Survival ◽  
Interim Pet ◽  
Positron Emission ◽  
To Receive

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt’s lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

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