Acceptability and usefulness of the EORTC 'Write In three Symptoms/Problems' (WISP): a brief open-ended instrument for symptom assessment in cancer patients.

BACKGROUND: The use of open-ended questions supplementing static questionnaires with closed questions may facilitate the recognition of symptoms and toxicities. The open-ended 'Write In three Symptoms/Problems (WISP)' instrument permits patients to report additional symptoms/problems not covered by selected EORTC questionnaires. We evaluated the acceptability and usefulness of WISP with cancer patients receiving active and palliative care/treatment in Austria, Chile, France, Jordan, the Netherlands, Norway, Spain and the United Kingdom. METHODS: We conducted a literature search on validated instruments for cancer patients including open-ended questions and analyzing their responses. WISP was translated into eight languages and pilot tested. WISP translations were pre-tested together with EORTC QLQ-C30, QLQ-C15-PAL and relevant modules, followed by patient interviews to evaluate their understanding about WISP. Proportions were used to summarize patient responses obtained from interviews and WISP. RESULTS: From the seven instruments identified in the literature, only the free text collected from the PRO-CTAE has been analyzed previously. In our study, 161 cancer patients participated in the pre-testing and interviews (50% in active treatment). Qualitative interviews showed high acceptability of WISP. Among the 295 symptoms/problems reported using WISP, skin problems, sore mouth and bleeding were more prevalent in patients in active treatment, whereas numbness/tingling, dry mouth and existential problems were more prevalent in patients in palliative care/treatment. CONCLUSIONS: The EORTC WISP instrument was found to be acceptable and useful for symptom assessment in cancer patients. WISP improves the identification of symptoms/problems not assessed by cancer-generic questionnaires and therefore, we recommend its use alongside the EORTC questionnaires.

Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data.

BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.

Adjuvant and neoadjuvant approaches in pancreatic cancer.

PURPOSE OF REVIEW: Pancreatic cancer treatment remains a challenging problem for surgeons and oncologists. This review aims to summarize the current advances on adjuvant and neoadjuvant treatment approaches for resectable pancreatic cancer. RECENT FINDINGS: Recent phase III randomized trials of adjuvant therapy showed improvement of overall survival in both experimental and control groups. Effectiveness of adjuvant therapy in specific subgroups as elderly patients, intraductal papillary mucinous neoplasms, stage I, and DNA damage repair gene germline variants has been reported. Completion of all cycles of planned adjuvant chemotherapy is confirmed as an independent prognostic factor. Adjuvant chemotherapy remains underutilized, mainly because of early recurrence, prolonged recovery, or older age older than 75 years. So, neoadjuvant treatment is a logical approach to administer systemic treatment to more patients. Meta-analysis did not demonstrate an overall survival benefit of neoadjuvant treatments in resectable pancreatic cancer, and definitive conclusions cannot be drawn from available randomized controlled trials. Upfront surgery and adjuvant chemotherapy should still be considered a standard approach in resectable pancreatic cancer. SUMMARY: Adjuvant chemotherapy with mFOLFIRINOX remains the standard of care in fit patients with resected pancreatic cancer, and limited high-level evidence support the use of neoadjuvant therapy in upfront resectable pancreatic cancer.

Effect of Adapted Physical Activity in Patients With Advanced Pancreatic Cancer: The APACaP GERCOR Randomized Trial.

BACKGROUND: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. PATIENTS AND METHODS: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. RESULTS: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were -0.98 (SD, 23.9; P=.39), -2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non-statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. CONCLUSIONS: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.

When a joint model should be preferred over a linear mixed model for analysis of longitudinal health-related quality of life data in cancer clinical trials.

BACKGROUND: Patient-reported outcomes such as health-related quality of life (HRQoL) are increasingly used as endpoints in randomized cancer clinical trials. However, the patients often drop out so that observation of the HRQoL longitudinal outcome ends prematurely, leading to monotone missing data. The patients may drop out for various reasons including occurrence of toxicities, disease progression, or may die. In case of informative dropout, the usual linear mixed model analysis will produce biased estimates. Unbiased estimates cannot be obtained unless the dropout is jointly modeled with the longitudinal outcome, for instance by using a joint model composed of a linear mixed (sub)model linked to a survival (sub)model. Our objective was to investigate in a clinical trial context the consequences of using the most frequently used linear mixed model, the random intercept and slope model, rather than its corresponding joint model. METHODS: We first illustrate and compare the models on data of patients with metastatic pancreatic cancer. We then perform a more formal comparison through a simulation study. RESULTS: From the application, we derived hypotheses on the situations in which biases arise and on their nature. Through the simulation study, we confirmed and complemented these hypotheses and provided general explanations of the bias mechanisms. CONCLUSIONS: In particular, this article reveals how the linear mixed model fails in the typical situation where poor HRQoL is associated with an increased risk of dropout and the experimental treatment improves survival. Unlike the joint model, in this situation the linear mixed model will overestimate the HRQoL in both arms, but not equally, misestimating the difference between the HRQoL trajectories of the two arms to the disadvantage of the experimental arm.

Flexible modeling of longitudinal health-related quality of life data accounting for informative dropout in a cancer clinical trial.

PURPOSE: A joint modeling approach is recommended for analysis of longitudinal health-related quality of life (HRQoL) data in the presence of potentially informative dropouts. However, the linear mixed model modeling the longitudinal HRQoL outcome in a joint model often assumes a linear trajectory over time, an oversimplification that can lead to incorrect results. Our aim was to demonstrate that a more flexible model gives more reliable and complete results without complicating their interpretation. METHODS: Five dimensions of HRQoL in patients with esophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 were analyzed. Joint models assuming linear or spline-based HRQoL trajectories were applied and compared in terms of interpretation of results, graphical representation, and goodness of fit. RESULTS: Spline-based models allowed arm-by-time interaction effects to be highlighted and led to a more precise and consistent representation of the HRQoL over time; this was supported by the martingale residuals and the Akaike information criterion. CONCLUSION: Linear relationships between continuous outcomes (such as HRQoL scores) and time are usually the default choice. However, the functional form turns out to be important by affecting both the validity of the model and the statistical significance. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT00861094.

Joint modelling with competing risks of dropout for longitudinal analysis of health-related quality of life in cancer clinical trials.

PURPOSE: Health-related quality of life (HRQoL) is an important endpoint in cancer clinical trials. Analysis of HRQoL longitudinal data is plagued by missing data, notably due to dropout. Joint models are increasingly receiving attention for modelling longitudinal outcomes and the time-to-dropout. However, dropout can be informative or non-informative depending on the cause. METHODS: We propose using a joint model that includes a competing risks sub-model for the cause-specific time-to-dropout. We compared a competing risks joint model (CR JM) that distinguishes between two causes of dropout with a standard joint model (SJM) that treats all the dropouts equally. First, we applied the CR JM and SJM to data from 267 patients with advanced oesophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 to analyse HRQoL data in the presence of dropouts unrelated and related to a clinical event. Then, we compared the models using a simulation study. RESULTS: We showed that the CR JM performed as well as the SJM in situations where the risk of dropout was the same whatever the cause. In the presence of both informative and non-informative dropouts, only the SJM estimations were biased, impacting the HRQoL estimated parameters. CONCLUSION: The systematic collection of the reasons for dropout in clinical trials would facilitate the use of CR JMs, which could be a satisfactory approach to analysing HRQoL data in presence of both informative and non-informative dropout. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT00861094.

Utility values and its time to deterioration in breast cancer patients after diagnosis and during treatments.

BACKGROUND: The potential effects of breast cancer (BC) on health-related quality of life (HRQoL) should be considered in clinical and policy decision-making, as the economic burden of BC management is currently assessed. In the last decades, time-to-HRQoL score deterioration (TTD) has been proposed as an approach to the analysis of longitudinal HRQoL in oncology. The main objectives of the current study were to investigate the evolution of the utility values in BC patients after diagnosis and during follow-ups and to evaluate the TTD in utility values among women in all stages of BC. METHODS: Health-state utility values (HSUV) were assessed using the EuroQol 5-Dimension 3-Level at diagnosis, at the end of the first hospitalization and 3 and 6 months after the first hospitalization. For a given baseline score, HSUV was considered to have deteriorated if this score decreased by ≥ 0.08 points of the EQ-5D utility index score and ≥ 7 points of the EQ visual analogue scale. TTD curves were calculated using the Kaplan-Meier estimation method. RESULTS: Overall 381 patients were enrolled between February 2006 and February 2008. The highest proportions of respondents at the baseline and all follow-ups reporting some and extreme problems were in pain discomfort and anxiety/depression dimensions; more than 80% of patients experienced a deterioration in EQ-5D utility index score and EQ VAS score with a median TTD of 3.15 months and 6.24 Months, respectively. CONCLUSIONS: BC patients undergoing therapy need psychological support to cope with their discomfort, pain, depression, anxiety, and fear during the process of diagnosis and treatment to improve their QoL.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. METHODS: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. FINDINGS: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). INTERPRETATION: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. FUNDING: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).

Longitudinal analysis of health-related quality of life in cancer clinical trials: methods and interpretation of results.

PURPOSE: Health-related quality of life (HRQoL) is assessed by self-administered questionnaires throughout the care process. Classically, two longitudinal statistical approaches were mainly used to study HRQoL: linear mixed models (LMM) or time-to-event models for time to deterioration/time until definitive deterioration (TTD/TUDD). Recently, an alternative strategy based on generalized linear mixed models for categorical data has also been proposed: the longitudinal partial credit model (LPCM). The objective of this article is to evaluate these methods and to propose recommendations to standardize longitudinal analysis of HRQoL data in cancer clinical trials. METHODS: The three methods are first described and compared through statistical, methodological, and practical arguments, then applied on real HRQoL data from clinical cancer trials or published prospective databases. In total, seven French studies from a collaborating group were selected with longitudinal collection of QLQ-C30. Longitudinal analyses were performed with the three approaches using SAS, Stata and R software. RESULTS: We observed concordant results between LMM and LPCM. However, discordant results were observed when we considered the TTD/TUDD approach compared to the two previous methods. According to methodological and practical arguments discussed, the approaches seem to provide additional information and complementary interpretations. LMM and LPCM are the most powerful methods on simulated data, while the TTD/TUDD approach gives more clinically understandable results. Finally, for single-item scales, LPCM is more appropriate. CONCLUSION: These results pledge for the recommendation to use of both the LMM and TTD/TUDD longitudinal methods, except for single-item scales, establishing them as the consensual methods for publications reporting HRQoL.

Factors of the evolution of fatigue dimensions in patients with breast cancer during the 2 years after surgery.

Women with breast cancer are increasingly being cured of the disease but fatigue remains the most frequently reported symptom. The aims of our study were to identify distinct trajectories in four fatigue dimensions during 2 years after breast cancer surgery and to explore the demographic, clinical and personality characteristics associated with these profiles. We included women from the prospective longitudinal multicenter FATSEIN cohort in France. They completed the Multidimensional Fatigue Inventory for nine follow-ups over 24 months after surgery. A group-based trajectory model identified distinct trajectories in each fatigue dimension. Multinomial logistic regression determined the factors associated with each profile. From the 459 women followed, 3-5 fatigue trajectories were revealed in each fatigue dimension, from its absence to its severest degree. In our multivariate analysis, the risk of severe fatigue was decreased in all dimensions by a high quality of life before surgery (measured by the European Organization for Research and Treatment of Cancer 30-item QoL questionnaire; e.g., for general and physical fatigue: OR = 0.93, 95% CI 0.91, 0.96), especially a high physical and emotional functions for general and physical fatigue, and a high cognitive function for mental fatigue. Both severe mental fatigue and severely reduced motivation worsened with low optimism before surgery (e.g., for mental fatigue: OR = 0.93, 95% CI 0.89, 0.97). Severely reduced activities increased by having chemotherapy (OR = 9.41, 95% CI 2.28, 38.79). Targeting women at risk for severe fatigue can provide early preventive and curative treatment and appropriate psychological support.

International validation of the EORTC CAT Core: a new adaptive instrument for measuring core quality of life domains in cancer.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group (QLG) has developed computerised adaptive tests (CATs) for the 14 functional and symptom domains of the EORTC QLQ-C30 quality of life questionnaire. This is expected to optimise measurement precision, relevance to patients and flexibility. Here, we present the first international validation of the EORTC CAT Core. METHODS: A heterogeneous sample of 699 cancer patients scheduled for chemotherapy and/or radiotherapy was recruited across seven European countries. The EORTC CAT Core and all QLQ-C30 items were administered to participants before and after initiating treatment. Correlations between CAT and QLQ-C30 scores and floor/ceiling effects were calculated. Using several grouping variables, relative validity (cross-sectional known groups difference), responsiveness (changes over time) and relative sample size requirements of the CAT compared to the QLQ-C30 were estimated. RESULTS: Correlations of the CAT and QLQ-C30 ranged from 0.81 to 0.93 across domains. The mean relative reduction in floor and ceiling effects using the CAT was 42% (range 3-99%). Analyses of known groups validity and responsiveness indicated that, across domains, mean sample size requirements for the CAT were 72% and 70%, respectively, of those using the QLQ-C30. CONCLUSIONS: The EORTC CAT Core measures the same domains as the QLQ-C30 with reduced floor/ceiling effects. The CAT generally facilitated the use of smaller samples (about 30% smaller on average) without loss of power compared to the QLQ-C30. Based on this study, the EORTC QLG will release the EORTC CAT Core for general use.

Adjuvant treatment of pancreatic cancer.

PURPOSE OF REVIEW: Pancreatic cancer will soon become one of the most common causes of cancer death. Early detection of pancreatic cancer remains impossible and only 20% of patients are suitable for surgery once diagnosed. Even in this specific subgroup of patients, and despite improvements in surgery, overall survival remains poor, with an 80% recurrence rate. Consequently, many attempts have been made to prevent recurrence by adding chemotherapy, radiotherapy, or both. RECENT FINDINGS: Here, we will focus on results of randomized trials evaluating the role of different postoperative treatments. Over 15 years ago, a trial demonstrated that chemoradiotherapy has a deleterious effect on survival. The same trial recommended adjuvant chemotherapy with fluorouracil as standard of care. Subsequent trials sought to identify better chemotherapy regimens. Two recently published trials evaluated the role of combination therapies for resected pancreatic cancer and demonstrated better outcomes with a gemcitabine and capecitabine combination and a fluorouracil, oxaliplatin, and irinotecan combination (FOLFIRINOX) versus gemcitabine alone. SUMMARY: Results from recent trials suggest that FOLFIRINOX should be considered standard of care for fit patients.

Sensitivity to change of the EORTC quality of life module measuring cancer-related fatigue (EORTC QlQ-Fa12): Results from the international psychometric validation.

OBJECTIVE: The European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) has developed a multidimensional instrument measuring cancer-related fatigue, the EORTC QLQ-FA12. The analysis of sensitivity to change is an essential part of psychometric validation. With this study, we investigated the EORTC QLQ-FA12's sensitivity to change. METHODS: The methodology follows the EORTC guidelines of EORTC QLG for phase IV validation of modules. We included cancer patients undergoing curative and palliative treatment at t1 and followed them up prospectively over the course of their treatment (t2) and 4 weeks after completion of treatment (t3). Data were collected prospectively at 17 sites in 11 countries. Sensitivity to change was investigated using analysis of variance. RESULTS: A total sample of 533 patients was enrolled with various tumour types, different stages of cancer, and receiving either curative treatment (n=311) or palliative treatment (n=222). Over time all fatigue scores were significantly higher in the palliative treatment group compared with the curative group (p < .001). Physical fatigue increased with medium effect size over the course of treatment in the curative group (standardized response mean [SRM] (t1,t2) = 0.44]. After treatment physical [SRM (t2,t3) = 0.39], emotional [SRM (t2,t3)= 0.28] and cognitive fatigue (SRM [t2,t3] = 0.22) declined significantly in the curative group. In the palliative group, emotional (SRM [t2,t3] = 0.18) as well as cognitive [SRM [t2,t3] = 0.26) fatigue increases significantly. CONCLUSIONS: The EORTC-QLQ-FA12 proved to identify clinically significant changes in fatigue in the course of curative and palliative cancer treatment.

Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease.

Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

The impact of physical activity on fatigue and quality of life during and after adjuvant treatment for breast cancer.

BACKGROUND: Although physical activity (PA) can alleviate fatigue and improve quality of life (QoL) in patients with breast cancer (BC), not all domains of PA may have equal impact. The objective of the current study was to examine the longitudinal impact of PA components on the evolution of fatigue and QoL during and after adjuvant treatment for BC. METHODS: The women included in the study were participants in the 2-year longitudinal FATSEIN ("Fatigue dans le cancer du Sein") study. Fatigue and QoL were measured using the Multidimensional Fatigue Inventory and the European Organization for Research and Treatment of Cancer 30-item QoL questionnaire, respectively. Group-based trajectory analysis was used to determine patterns of PA evolution (frequency, duration, and intensity). Cross-sectional and longitudinal associations between PA patterns and fatigue and QoL were analyzed by using multivariable linear regression and a mixed model. RESULTS: Among the 424 women who were included (mean ± standard deviation age, 57.1 ± 10.4 years), 2 trajectories were identified for each of the 3 PA components: low and insufficient frequency (51.2%) or regular and moderate frequency (48.8%), low and insufficient duration (47.6%) or regular and moderate duration (52.4%), and low intensity (47.2%) or low to moderate intensity (52.8%). Overall, during treatment, fatigue was increased and QoL was decreased, and the reverse was observed after treatment. During treatment, increased fatigue and decreased QoL were limited by regular PA frequency (ß = -8.71 for total fatigue; ß = 14.59 for emotional function), but the results were less significant after treatment. CONCLUSIONS: PA, especially its frequency, is an important determinant of fatigue and QoL during adjuvant treatment for BC. The promotion of regular PA among women who are receiving treatment for BC may be an effective way to reduce fatigue and improve QoL. Cancer 2018;124:797-806. © 2017 American Cancer Society.

Retrospective Analysis of CA19-9 Decrease in Patients with Metastatic Pancreatic Carcinoma Treated with FOLFIRINOX or Gemcitabine in a Randomized Phase III Study (ACCORD11/PRODIGE4).

OBJECTIVES: Carbohydrate antigen 19-9 (CA19-9) is a sensitive and specific serum marker in pancreatic cancer. Our retrospective analysis aims to evaluate CA19-9 decrease in patients with metastatic pancreatic cancer treated in ACCORD11/PRODIGE4 (FOLFIRINOX vs. gemcitabine). METHODS: A total of 342 patients were treated. CA19-9 was measured at 8 weeks (±2) in 160 patients from a total of 282 with abnormal CA19-9 values at baseline (gemcitabine arm, n = 75; FOLFIRINOX arm, n = 85). In the present study, 8-week CA19-9 decrease or greater CA19-9 decrease according to the 20 and 90% thresholds were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated in each subgroup. RESULTS: In the FOLFIRINOX arm, patients with an 8-week CA19-9 decrease or greater CA19-9 decrease ≥20% showed improved median OS, PFS, and objective response rate. In the overall study population, median OS and PFS were significantly improved in patients with an 8-week CA19-9 decrease ≥20% (vs. <20%). The 8-week CA19-9 decrease was predictive of PFS (interaction test significant according to treatment arm; p = 0.006). CONCLUSION: An 8-week CA19-9 decrease ≥20% is a prognostic factor for OS and PFS. The 8-week CA19-9 decrease (20% threshold) is predictive of PFS. It could help to evaluate the efficacy of FOLFIRINOX and gemcitabine regimens.

Item response models for the longitudinal analysis of health-related quality of life in cancer clinical trials.

BACKGROUND: The use of health-related quality of life (HRQoL) as an endpoint in cancer clinical trials is growing rapidly. Hence, research into the statistical approaches used to analyze HRQoL data is of major importance, and could lead to a better understanding of the impact of treatments on the everyday life and care of patients. Amongst the models that are used for the longitudinal analysis of HRQoL, we focused on the mixed models from item response theory, to directly analyze raw data from questionnaires. METHODS: We reviewed the different item response models for ordinal responses, using a recent classification of generalized linear models for categorical data. Based on methodological and practical arguments, we then proposed a conceptual selection of these models for the longitudinal analysis of HRQoL in cancer clinical trials. RESULTS: To complete comparison studies already present in the literature, we performed a simulation study based on random part of the mixed models, so to compare the linear mixed model classically used to the selected item response models. As expected, the sensitivity of the item response models to detect random effects with lower variance is better than that of the linear mixed model. We then used a cumulative item response model to perform a longitudinal analysis of HRQoL data from a cancer clinical trial. CONCLUSIONS: Adjacent and cumulative item response models seem particularly suitable for HRQoL analysis. In the specific context of cancer clinical trials and the comparison between two groups of HRQoL data over time, the cumulative model seems to be the most suitable, given that it is able to generate a more complete set of results and gives an intuitive illustration of the data.