Outcomes and endpoints in trials of cancer treatment: the past, present, and future

doi:10.1016/S1470-2045(14)70375-4

The Lancet Oncology

Volume 16, Issue 1, January 2015, Pages e32-e42

https://doi.org/10.1016/S1470-2045(14)70375-4 Get rights and content

Summary

Cancer treatment should allow patients to live better or longer lives, and ideally, both. Trial endpoints should show clinically meaningful improvements in patient survival or quality of life. Alternative endpoints such as progression-free survival, disease-free survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is controversial. In this Review we discuss the measurement, assessment, and benefits and limitations of trial endpoints in use for cancer treatment. Many stakeholders are affected, including regulatory agencies, industry partners, clinicians, and most importantly, patients. In an accompanying Review, reflections from individual stakeholders are incorporated into a discussion of what the future holds for clinical trial endpoints and design.

Introduction

Cancer treatment aims to enable patients to live longer and better lives than they would without treatment.¹ Accordingly, the gold standard to assess therapeutic efficacy is a statistically signifant and clinically meaningful improvement in overall survival, quality of life, or decrease in cancer-related symptoms. The issue is who defines what is clinically meaningful, with substantial variation in opinions between patients, clinicians, and regulatory agencies.¹

Overall survival is an unambiguous outcome measure. However, as an unequivocal marker of therapeutic benefit, it is controversial. Improvement in the efficacy of cytotoxic and novel treatments, and a better understanding of disease biology, means that some cancers now behave like chronic diseases. The detection of differences in overall survival in trials can be complex with confounding results related to trial duration, cost, sample size, and treatment choices after progression.² If cancer is regarded as a chronic disease, new treatments need to have clinically meaningful outcomes for patients, such as improved quality of life, symptom control, and tolerability of treatment.

Endpoints such as progression-free survival (PFS) and time to progression are used because they provide more rapid measures of difference in treatment effect than overall survival. A robust debate continues on whether these are meaningful outcomes in their own right, or purely surrogate endpoints for overall survival and disease control. Unlike overall survival, endpoints such as PFS and time to progression are less affected by subsequent treatments, palliative care, and comorbidities.² By contrast with death, disease progression as an endpoint is continuous, but is identified and measured by discrete clinical or radiological assessments, and hence is dependent on the timing of these investigations. In routine practice, disease status is established by clinical, biochemical, and radiological factors; conversely, trial outcomes are often defined by radiological measures alone to increase objectivity.

Cancer is a multitude of diseases with different natural histories and clinical characteristics.3, 4 Therefore, trial design needs to accommodate the inherent properties of the disease and patient population to ensure meaningful clinical outcomes. This approach will help with the identification of smaller homogenous subpopulations that benefit from a treatment.3, 5 We review present practices in the measurement of clinical outcomes in oncology trials and assess these practices in the context of modern clinical oncology. This Review also addresses the objectivity, reliability, and validity of the methods used to assess endpoints in clinical trials and the importance of integration of these techniques into the study design.

Section snippets

Endpoints in clinical trials

Views on the importance of overall survival and PFS as outcome measures in trials are polarised. Treatment effectiveness has been defined as a clinically meaningful benefit to the patient with the objective of the patient living for longer or better, or both, than if they did not receive the treatment.¹ This measure of efficacy might be shown by symptomatic improvement, or improvement in established disease progression endpoints. The characteristics of the disease and treatment (prognosis,

Overall survival and surrogate endpoints

Overall survival is a precise endpoint that shows patients alive after a fixed duration of time (table).8, 9, 11 Effects from crossover, supportive care, and treatment after progression make measurement of overall survival increasingly protracted.² To measure more modest differences in overall survival, phase 3 trials have become larger, and more resource intensive; present trial designs are challenging this approach.

Surrogate endpoints (table) have garnered interest as indirect measures of

Time to disease progression or treatment

Times to second or third progression have been used as alternative endpoints for overall survival in several trials (figure 1), and are recognised by the European Medicines Agency¹⁰ as a viable endpoint for registered clinical drug trials. Time to second progression is defined as time from randomisation to the second objective disease progression (or death from any cause), and time to third progression is defined as time from randomisation to the third objective disease progression (or death

Technological implications

Accurate determination of clinical outcomes is dependent on the robustness of the methods used in their measurement. Clinical, biochemical, and radiological assessments of patients are used in day-to-day practice but traditionally in trials, responses in solid cancers, are based only on radiological measures in an attempt to ensure objectivity. Additionally, masked independent central and objective review of radiological findings is increasingly needed if the primary outcome is dependent on

RECIST

In 1979 WHO established the first internationally recognised criteria for the radiological assessment of the response of solid malignancies to therapy that required 2D imaging and summation of tumour burden.68, 69 The objective Response Evaluation Criteria In Solid Tumours (RECIST) were established in 2000 (version 1.0)68, 70 and updated in 2009 (version 1.1).²⁰ By contrast with WHO criteria, RECIST used 1D radiological assessment and defined a partial response as a 30% reduction in the sum of

Imaging advances

Differentiation of viable tumour tissue from treatment-induced fibrosis or necrosis on conventional CT is difficult.⁶⁸ A growing interest exists in ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET and dynamic contrast enhanced MRI to distinguish active from inactive disease.

A PET scan after one to two cycles of chemotherapy has been shown to predict the response in lymphoma and is proposed to be a better marker of tumour response to some targeted drugs than is RECIST.85, 86, 87 For example, in patients

Circulating tumour cells and DNA

New indicators of disease progression continue to be identified, and might, in future, challenge traditional definitions of a clinical response. In some cancers, circulating tumour cells are postulated to provide real-time characterisation of disease status during therapy,⁹⁶ and have shown predictive and prognostic value among patients with metastatic breast, prostate, and colorectal cancers.97, 98, 99, 100 In metastatic breast cancer, circulating tumour cell quantification has been shown to be

Statistical considerations

Clinical trial outcomes are reflective of the appropriateness of the questions that are being asked. Preplanned statistical analyses provide an essential method to determine trial outcomes. Post-hoc analyses, although useful to generate hypotheses, are subject to bias. Statistics provide a formal framework to assess the strength of evidence,¹⁰⁹ but a significant result is still at risk of error. The probability of a research claim being true is dependent on study power and bias, the prior

New horizons

Appropriate endpoints in trials depend on the clinical context, and require careful interpretation. The conundrum is how to intelligently use these endpoints to improve patient outcomes, define inter-tumour and inter-patient heterogeneity, and be clinically meaningful. Endpoints should ideally be of tangible benefit for patients, which in itself might be a challenge to show.

Quality-of-life scores need meticulous assessment and similar criteria and guidelines as used for clinical response to

Search strategy and selection criteria

References were identified through searches of PubMed with the search terms “endpoints”, “outcomes”, “oncology”, and “trial design”. Only papers published in English were reviewed without any date restrictions. Articles were also identified through searches of the authors' own files and cited articles. The final reference list was generated on the basis of originality and relevance to the broad scope of this topic.

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The impact of palliative radiotherapy on health-related quality of life in patients with head and neck cancer – Results of a multicenter prospective cohort study
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Palliative radiotherapy for patients with head and neck cancer can be used to alleviate symptoms. Only a few studies have investigated its impact on patient-reported outcomes (PRO). Therefore, we conducted a prospective multicenter observational study. The primary objective was to assess changes in health-related quality of life (HrQoL) per PRO.
Eligibility criteria included i.) head and neck cancer and ii.) palliative radiotherapy indicated (EQD_2Gy < 60 Gy). The primary follow-up date was eight weeks after radiotherapy (t_8w). PRO measures included the EORTC QLQ-C30 and EORTC QLQ-H&N43 and pain per Numeric Rating Scale (NRS). Per protocol, five PRO domains were to be reported in detail as well as PRO domains corresponding to a primary and secondary symptom as determined by the individual patient. We defined a minimal important difference (MID) of 10 points.
From 06/2020 to 06/2022, 61 patients were screened and 21 patients were included. Due to death or decline in health-status, HrQoL data was available for 18 patients at the first fraction and for eight patients at t_8w. The MID was not met for the predefined domains in terms of mean values as compared from first fraction to t_8w. Individually in those patients with available HrQoL data at t_8w, 71% (5/7) improved in their primary and 40% (2/5) in their secondary symptom domain reaching the MID from first fraction to t_8w, respectively. There was a significant improvement in pain per NRS in those patients with available data at t_8w per Wilcoxon signed rank test (p = 0.041). Acute mucositis of grade ≥3 per CTCAE v5.0 occurred in 44% (8/18) of the patients. The median overall survival was 11 months.
Despite low patient numbers and risk of selection bias, our study shows some evidence of a benefit from palliative radiotherapy for head and neck cancer as measured by PRO.
German Clinical Trial Registry identifier: DRKS00021197.
Comprehensive evaluation of surrogate endpoints to predict overall survival in trials with PD1/PD-L1 immune checkpoint inhibitors plus chemotherapy
2023, Cancer Treatment Reviews
PD1/PD-L1 immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. Although there is controversy about the accuracy of surrogate endpoints in the ICI setting to predict overall survival (OS), these endpoints are commonly used in confirmatory trials. Here we aimed to explore the validity of classical and novel surrogate endpoints in randomised controlled trials (RCT) that combine ICI plus chemotherapy (CT) in the first-line setting.
A systematic review was conducted to identify RCT investigating anti-PD1/PD-L1 drugs plus CT versus CT alone. We performed (i) arm-level analysis to evaluate predictors of median OS (mOS) and (ii) comparison-level analysis for OS hazard ratio (HR) estimations. Linear regression models weighted by trial size were fitted and adjusted R² values were reported.
Thirty-nine RCTs involving 22,341 patients met the inclusion criteria (17 non-small cell lung, 9 gastroesophageal and 13 in other cancers) with ten different ICI under study. Overall, ICI plus CT improved OS (HR = 0.76; 95%CI: 0.73–0.80). In the arm-level analysis, the best mOS prediction was obtained with a new endpoint that combines median duration of response and ORR (mDoR-ORR) and with median PFS (R² = 0.5 both). In the comparison-level analysis, PFS HR showed a moderate association with OS HR (R² = 0.52). Early OS read-outs were highly associated with final OS outcomes (R² = 0.80).
The association between surrogate endpoints and OS in first-line RCT combining anti-PD1/PD-L1 and CT is moderate-low. Early OS read-outs showed a good association with final OS HR while the mDOR-ORR endpoint could help to better design confirmatory trials after single-arm phase II trials.
Surrogate Endpoints as Predictors of Overall Survival in Metastatic Urothelial Cancer: A Trial-level Analysis
2023, European Urology Open Science
Surrogate endpoints (SEs), such as progression-free survival (PFS) and objective response rate (ORR), are frequently used in clinical trials. The relationship between SEs and overall survival (OS) has not been well described in metastatic urothelial cancer (MUC).
We evaluated trial-level data to assess the relationship between SEs and OS. We hypothesize a moderate surrogacy relationship between both PFS and ORR with OS.
We systematically reviewed phase 2/3 trials in MUC with two or more treatment arms, and report PFS and/or ORR, and OS.
Linear regression was performed, and the coefficient of determination (R²) and surrogate threshold effect (STE) estimate were determined between PFS/ORR and OS.
Of 3791 search results, 59 trials and 62 comparisons met the inclusion criteria. Of the 53 trials that reported PFS, 31 (58%) reported proportional hazard regression for PFS and OS. Linear regression across trials demonstrated an R² of 0.60 between hazard ratio (HR) for PFS (HR^PFS) and HR for OS (HR^OS), and an STE of 0.41. Linear regression of ΔPFS (median PFS in months of the treatment arm – that of the control arm) and ΔOS demonstrated an R² of 0.12 and an STE of 14.1 mo. Thirty trials reported ORRs. Linear regression for ORR^ratio and HR^OS among all trials found an R² of 0.08; an STE of 95% was not reached at any value and ΔORR and HR^OS similarly demonstrated a poor correlation with an R² value of 0.03.
PFS provides only a moderate level of surrogacy for OS; An HR^PFS of ≤0.41 provides 95% confidence of OS improvement. ORR is weakly correlated with OS and should be de-emphasized in MUC clinical trials. When PFS is discussed, proportional hazard regression should be reported.
We examined the relationship between surrogate endpoints, common outcomes in clinical trials, with survival in urothelial cancer trials. Progression-free survival is moderately correlated, while objective response rate had a poor correlation with survival and should be de-emphasized as a primary endpoint.
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Up to 50% of radiotherapy courses are delivered in palliative intent for various indications. Despite the large number of treated patients, we know little about the choice of endpoints in trials of palliative radiotherapy. Our primary aim was, therefore, to analyze primary endpoints in trials of palliative radiotherapy.
We conducted a pre-registered (https://doi.org/10.17605/OSF.IO/GMCAF) meta-research analysis searching Pubmed/MEDLINE, EMBASE, CENTRAL, and “ClinicalTrials.gov” for clinical trials of palliative radiotherapy published 1990–2020. Endpoints were categorized in “patient-centered endpoints”, including overall survival and patient-reported outcomes, and “tumor-centered endpoints” such as local control. The remainder were “other endpoints” including toxicity or observer-rated symptoms. We applied descriptive statistics to summarize data and logistic regression to assess if year of publication predicted the choice of primary endpoints.
Of 7379 records screened, 292 were eligible. Trials were characterized by small sample sizes and use of external beam radiotherapy for metastases or thoracic primaries. Median patient age was 64 and median ECOG was 1. Only 64.4%(145/225) of published trials clearly stated their primary endpoint. Published trials employed a “patient-centered primary endpoint” in 45.5%(66/145) and a “tumor-centered primary endpoint” in 17.3%(25/145) of the cases. There was no statistically significant trend in time for the use of “patient-centered primary endpoints”. Registered ongoing trials used a “patient-centered primary endpoint” in 32.8%(22/67) and a “tumor-centered primary endpoint” in 26.9%(18/67) of the cases.
Although “patient-centered primary endpoints” appear relatively prevalent in published trials of palliative radiotherapy, their use is still suboptimal and appears to be lower in currently ongoing trials.
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ReviewOutcomes and endpoints in trials of cancer treatment: the past, present, and future

Summary

Introduction

Section snippets

Endpoints in clinical trials

Overall survival and surrogate endpoints

Time to disease progression or treatment

Technological implications

RECIST

Imaging advances

Circulating tumour cells and DNA

Statistical considerations

New horizons

Search strategy and selection criteria

Gynecol Oncol

Eur J Cancer

Lancet Oncol

Lancet Oncol

Lancet

Lancet

Ann Oncol

Lancet Oncol

Eur J Cancer

Lancet

Ann Oncol

Clin Lung Cancer

Eur J Cancer

Ann Oncol

Lancet Oncol

Reflections on medical oncology: 25 years of clinical trials—where have we come and where are we going?

J Clin Oncol

Overall survival: a gold standard in search of a surrogate: the value of progression-free survival and time to progression as end points of drug efficacy

Cancer J

Equipoise lost: ethics, costs, and the regulation of cancer clinical research

J Clin Oncol

Taking the long view: how to design a series of phase III trials to maximize cumulative therapeutic benefit

ClinTrials

Fool's gold, lost treasures, and the randomized clinical trial

BMC Cancer

State-of-the-art in the management of locally advanced and metastatic gallbladder cancer

Curr Opin Oncol

Endpoints for assessing drug activity in clinical trials

Oncologist

The role of the US Food and Drug Administration review process: clinical trial endpoints in oncology

Oncologist

Answers from the CHMP Scientific Advisory Group (SAG) for Oncology for Revision of the anticancer guideline

Overall survival: still the gold standard: why overall survival remains the definitive end point in cancer clinical trials

Cancer J

Surrogate endpoint analysis: an exercise in extrapolation

J Natl Cancer Inst

Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

Clin Pharmacol Ther

Surrogate endpoints in clinical trials: definition and operational criteria

Stat Med

Predicting treatment effect from surrogate endpoints and historical trials: an extrapolation involving probabilities of a binary outcome or survival to a specific time

Biometrics

Reporting of serious adverse drug reactions of targeted anticancer agents in pivotal phase III clinical trials

J Clin Oncol

Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials

Cancer

Progression-free survival: meaningful or simply measurable?

J Clin Oncol

Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab

Br J Cancer

Detecting an overall survival benefit that is derived from progression-free survival

J Natl Cancer Inst

Progression-free survival is a surrogate for survival in advanced colorectal cancer

J Clin Oncol

Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy

J Clin Oncol

Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials

Cancer

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology

Onco Targets Ther

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

N Engl J Med

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer

N Engl J Med

Early palliative care for patients with metastatic non-small-cell lung cancer

N Engl J Med

Review
Outcomes and endpoints in trials of cancer treatment: the past, present, and future