Quality of life and experiences of sarcoma trajectories (the QUEST study): protocol for an international observational cohort study on diagnostic pathways of sarcoma patients

IntroductionSarcomas are rare tumours with considerable heterogeneity. Early and accurate diagnosis is important to optimise patient outcomes in terms of local disease control, overall survival (OS) and health-related quality of life (HRQoL). Time to diagnosis is variable in bone as well as soft tissue sarcoma. Possible factors for a long time from first symptom to diagnosis (the total interval) include patient, tumour and healthcare characteristics, but until now the most relevant risk factors and its association with outcomes remain unknown. Our study aims to (1) quantify total interval, the time interval from first symptom until (histological) diagnosis; (2) identify factors associated with interval length and (3) determine the association between total interval and HRQoL, stage and tumour size at diagnosis, progression-free survival (PFS) and OS.Methods and analysisWe will conduct a longitudinal, prospective, international, multicentre cohort study among patients aged ≥18 years with newly diagnosed bone or soft tissue sarcoma at eight centres (three in UK, five in The Netherlands). Patients will be asked to complete questionnaires at five points in time; one at diagnosis and at follow-up points of 3, 6, 12 and 24 months. Questionnaire data is collected within the Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship (PROFILES) registry: an international data management system for collection of patient-reported outcomes. Clinical data will be extracted from patient records. The primary endpoint is HRQoL at diagnosis, measured with the EORTC QLQ-C30. Secondary endpoints are stage and tumour size at diagnosis, PFS, OS, additional patient-reported outcomes, such as quality-adjusted life years and psychological distress.Ethics and disseminationEthical approval was given by the Health Research Authority and Research Ethics Committee for the United Kingdom (18/WA/0096) and medical ethical committee of Radboudumc for The Netherlands (2017-3881). Results will be presented in peer-reviewed journals and presented at meetings.Trial registration numberNCT03441906.

The Perceived Impact of Length of the Diagnostic Pathway Is Associated with Health-Related Quality of Life of Sarcoma Survivors: Results from the Dutch Nationwide SURVSARC Study

Background: Sarcoma patients often experience a long time to diagnosis, known as the total interval. This interval can be divided into the patient (time from symptoms to doctor consultation) and diagnostic intervals (time from first consultation to diagnosis). In other cancers, a long total interval has been associated with worse outcomes, but its effect on health-related quality of life (HRQoL) has never been investigated among sarcoma patients. This study investigates the association between (1) the actual time to diagnosis and HRQoL; (2) the perceived impact of the diagnostic interval length and HRQoL; (3) the actual length and perceived impact of the length and the HRQoL of sarcoma survivors. Methods: A cross-sectional study was performed among sarcoma patients aged ≥18, diagnosed 2–10 years ago in the Netherlands. The participants completed a questionnaire on HRQoL, the time to diagnosis, the perceived impact of the diagnostic interval on HRQoL, and coping. Results: 1099 participants were included (response rate, 58%). The mean time since diagnosis was 67.4 months. More than half reported a patient (60%) or diagnostic interval (55%) ≥1 month. A third (31%) perceived a negative impact of the diagnostic interval length on HRQoL. Patient or diagnostic interval length was not associated with HRQoL. By contrast, participants perceiving a negative impact (32%) had lower HRQoL scores than those perceiving a positive (11%) or no impact (58%) (p = 0.000). This association remained significant in a multivariable model, in which maladaptive coping strategies and tumour characteristics were also found to be associated with HRQoL. Participants perceiving a negative impact of the length of the diagnostic interval related this to high psychological distress levels, more physical disabilities, and worse prognosis. Conclusion: The perceived impact of the diagnostic interval length was associated with the HRQoL of sarcoma survivors, whereas the actual length was not associated with HRQoL. Maladaptive coping strategies were independently associated with HRQoL. This offers opportunities for early intervention to improve HRQoL.

The sarcoma diagnostic interval: a systematic review on length, contributing factors and patient outcomes

Sarcomas are rare and heterogeneous mesenchymal tumours of soft tissue or bone, making them prone to late diagnosis. In other malignancies, early diagnosis has an impact on stage of disease, complexity of therapeutic procedures, survival and health-related quality of life (HRQoL). Little is known about what length of diagnostic interval should be considered as delay in patients with bone (BS) or soft tissue sarcomas (STS). To quantify total interval (defined as time from first symptom to histological diagnosis) and its components, identify contributing factors to its length and determine the impact on patients’ outcome in terms of mortality and HRQoL. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Seventy-six articles out of 2310 met the predefined inclusion criteria. Total intervals, varied broadly; 9–120.4 weeks for BS and 4.3–614.9 weeks for STS. Older age and no initial radiological examinations were contributing factors for a long interval in BS, while in STS results were conflicting. The impact of length of total interval on clinical outcomes in terms of survival and morbidity remains ambiguous; no clear relation could be identified for both BS and STS. No study examined the impact on HRQoL. The length of total interval is variable in BS as well as STS. Its effect on outcomes is contradictory. There is no definition of a clinically relevant cut-off point that discriminates between a short or long total interval. Prospero: CRD42017062492.

Diagnostic timeliness in adolescents and young adults with cancer: Cross-sectional findings from the BRIGHTLIGHT cohort

BackgroundAdolescents and young adults (AYA) with cancer are thought to experience prolonged diagnostic intervals but robust evidence quantifying such associations is lacking.AimTo examine diagnostic timeliness in a cohort of young people, identifying sociodemographic factors and cancer sites associated with variation in timeliness.MethodWe analysed data from 830 patients with cancer aged 12–24 who completed BRIGHTLIGHT face-to-face interviews, for variation in the patient interval (time from symptom onset to first healthcare presentation); the number of pre-referral GP consultations; and the total interval (time from symptom onset to diagnosis). We present descriptive statistics of these outcomes by patient characteristics and cancer site and multivariable regression models for adjusted estimates of associations.ResultsAmong participants, 27% experienced a patient interval of >1 month and 35% of those consulting a GP had 3 or more (3+) pre-referral consultations. The median total interval was 62 days. We hereafter highlight significant associations (<0.05). Females were more likely to have 3+ consultations and longer total intervals compared with males. Patients with lymphoma or bone tumours were most likely to have 3+ pre-referral consultations and those with melanoma least likely. Females and patients with bone tumours had the longest median total intervals and those with leukaemia the shortest.ConclusionThese data benchmark diagnostic timeliness for young people with cancer and identify subgroups at higher risk of prolonged diagnostic journeys. Further work is now required to prioritise and stratify early diagnosis initiatives for these subgroups.FundingNational Institute for Health Research (RP-PG-1209-10013); Teenage Cancer Trust; Cancer Research UK (A18180).

Applied-Information Technology and Data Processing for Multi-Objective Interval Job Shop Scheduling Problem with Flexible Preventive Maintenance

Interval job shop scheduling problem with flexible preventive maintenance is considered and an multi-objective swarm-based neighborhood search (MOSNS) is proposed for minimizing interval makespan and total interval tardiness. A dominance based greedy principle is utilized to decide if the old solution is replaced with the new one. A solution with the highest rank is replaced with a randomly chosen member of the non-dominated set every few number of iterations. Computational results show that MOSNS is an effective approach to solve the considered problem.

Prospective Study Of Mobilization Kinetics Up To 18 Hours After Late Afternoon Dosing Of Plerixafor

Background Plerixafor (Mozobil®, Genzyme, Cambridge, MA) is approved for hematopoietic progenitor cell (HPC) mobilization into peripheral blood (PB) in combination with granulocyte colony stimulating factor (G-CSF) at ∼11 hours (hr) prior to apheresis initiation. Since apheresis facilities typically open at 8-9 AM, this 11 hr interval requires plerixafor dosing between 9-10 pm, impractical unless the patient self-administers the drug. No studies have examined mobilization kinetics beyond 15 hr in the target MM and NHL patient population. This is the first study in this target population to examine a total interval time of 17-18 hr post-plerixafor, important because, practically, leukapheresis may not be initiated until 10-11 AM. Even if initiated earlier between 8-9 AM, a standard leukapheresis typically lasts ∼3 hr. Therefore, it is important to rule out a significant decrease in PB [CD34+] extending through this interval. Study Design and Methods A single-center, prospective cohort, IRB-approved study where 11 patients with NHL and MM underwent HPC mobilization from March 2010 to October 2011. Patients met the same entry criteria specified in the initial studies leading to FDA approval. Plerixafor 240 ug/kg was administered at 5pm on day 4 of AM G-CSF 10 ug/kg. PB [CD34+] and [CD34+CD38-] concentrations were enumerated every 2 hours from 5PM to 7AM and immediately pre-apheresis on day 5, for a total interval time of 17-18 hr post-plerixafor. Leukapheresis (3 total blood volumes) was performed if the 7 am peripheral blood CD34+ concentration was ≥10/uL. Data was analyzed used mixed model analysis of repeated measures. Results 9 of 11 subjects , including all 5 patients who had received 3-9 cycles of lenalidomide, achieved a CD34+ product count of >5x106/kg with a single leukapheresis. All 9 patients (in contrast to the other 2) had a pre-plerixafor PB CD34+ concentration > 10/uL. PB [CD34+] did not differ between 10-18 hours post-plerixafor (p≈0.8). In contrast, PB [CD34+CD38-] increased from 10 to 18 hours post-plerixafor (p=0.03). 10 subjects underwent transplant with a median CD34+ dose of 6.0x106/kg (range 3.8-10.8x 106/kg) and engrafted within normal time frames. Using post- to (5PM) pre-plerixafor [CD34+] ratios to compare efficacy of plerixafor kinetics, the median ratio of the 17-18hr post/pre-plerixafor [CD34+] was 4.0 (range 1.8-6.8), not significantly different (p=0.09) from that of the peak post/pre-plerixafor [CD34+] of 4.7 (range 1.9-9). The 3 subjects with lowest mobilization had diabetes, but the peak post/pre [CD34+] ratio was not adversely affected. Two of these three reached their peak [CD34+] mobilization at 8hr post-plerixafor, whereas all other donors reached their peak [CD34+] ≥ 10hr post-plerixafor. The correlation coefficient of 0.54 between the PB [CD34+] and [CD34+CD38-] was weak. Conclusions In MM and NHL patients with adequate pre-plerixafor CD34+ concentration, which includes those with prior lenalidomide, leukapheresis initiated 17-18 hours post-plerixafor may not impair CD34+ product yield and may increase more primitive CD34+CD38- yield. Patient with risk factors for poor mobilization, such as diabetes or salvage chemotherapy, may be an exception. The three donors with post-plerixafor PB [CD34+] < 100/uL all had diabetes, which has been established to impair G-CSF induced stem cell mobilization. Our data supports murine data that plerixafor overcomes sympathetic nervous system-related defects in mobilization, since the peak post/pre plerixafor [CD34+] ratio was > 4 in all 3 patients. Interestingly, the donor with the second highest mobilization also had diabetes but a low peak/pre [CD34+] ratio of 2.9 (i.e. excellent mobilization with G-CSF alone); her mobilization impairment from diabetes may have been overcome by concurrent use (for asthma) of the β2-adrenergic agonist albuterol, previously associated with high mobilization. Consistent with previous studies, the 2 patients with poor [CD34+] mobilization reached their peak PB [CD34+] < 11 hours post-plerixafor. Finally, given the weak correlation between PB [CD34+] and [CD34+CD38-] , the utility of using PB [CD34+CD38-] to help determine the optimal time for collection may be worth exploring, given the correlation between CD34+CD38- graft content and long-term hematopoietic reconstitution in autologous transplantation. Disclosures: Off Label Use: Plerixafor administered up to 18 hours prior to apheresis initiation, rather than the FDA-approved 11 hours.