Setting the international research agenda for sarcomas with patients and carers: results of phase II of the Sarcoma Patient Advocacy Global Network (SPAGN) priority setting partnership.

BACKGROUND: Typically, researchers and clinicians determine the agenda in sarcoma research. However, patient involvement can have a meaningful impact on research. Therefore, the Patient-Powered Research Network (PPRN) of the Sarcoma Patient Advocacy Global Network (SPAGN) set up a Priority Setting Partnership (PSP). The primary objective of this partnership is to identify priorities for research and patient advocacy topics. METHODS: In the first phase of this PSP, including 264 sarcoma patients and carers from all over the world, 23 research topics regarding sarcomas and 15 patient advocacy topics were identified using an online survey. In the second phase, participants were asked to fill in a top five and a top three of research and patient advocacy topics, respectively. Additionally, sociodemographic characteristics and sarcoma characteristics were collected. Social media channels, local national patient advocacy groups and the SPAGN website were used to distribute the survey. RESULTS: In total, 671 patients (75%) and carers (25%) participated in this survey. The five highest ranked research topics were related to causes of sarcoma (43%), prognosis and risk of recurrence (40%), specific subtypes of sarcoma (33%), the role of immunotherapy, targeted therapy and combined therapy (30%), and hereditary aspects (30%). The three highest ranked patient advocacy topics were improving the diagnostic process of sarcoma (39%), access to tumor DNA analysis (37%) and establishing an international sarcoma registry (37%). CONCLUSIONS: This sarcoma PSP has identified priorities for research and patient advocacy, offering guidance for researchers, assisting funding agencies with assessing project relevance and empowering patient advocates to represent the needs of patients and carers.

Long-term second primary cancer risk in adolescent and young adult (15-39 years) cancer survivors: a population-based study in the Netherlands between 1989 and 2018.

BACKGROUND: Few studies have comprehensively investigated the long-term second cancer risk among adolescent and young adult (AYA, aged 15-39 years) cancer survivors. This study investigated the long-term second cancer risk by including the full range of first and second cancer combinations with at least 10 observations in the Netherlands between 1989 and 2018. MATERIALS AND METHODS: First and second primary cancer data of all 6-month AYA cancer survivors were obtained from the nationwide population-based Netherlands Cancer Registry. Excess cancer risk compared to the general population was assessed with standardized incidence ratio (SIR) and absolute excess risk (AER) statistics up to 25 years after diagnosis. Cumulative incidences were estimated, using death as a competing risk factor. Analyses were carried out with and without applying multiple cancer rules. RESULTS: The cohort included 99 502 AYA cancer survivors. Male survivors had a 2-fold higher risk of developing any cancer compared to the general population, whereas this was around 1.3-fold in females. AERs were 17.5 and 10.1 per 10 000 person-years for males and females. The long-term excess risk of cancer was significantly higher for most first and second primary cancer combinations, but comparable and lower risk estimates were also observed. Application of the multiple cancer rules resulted in a noticeable risk underestimation in melanoma, testicular, and breast cancer survivors. Risk outcomes remained similar in most cases otherwise. The cumulative incidence of second cancer overall increased over time up to 8.9% in males and 10.3% in females at 25 years' follow-up. Highest long-term cumulative incidences were observed among lymphoma survivors (13.3% males and 18.9% females). CONCLUSIONS: AYA cancer survivors have a higher cancer risk compared to the general population for most cancers up to 25 years after their initial cancer diagnosis. Additional studies that investigate risk factors for the specific cancer type combinations are needed to develop personalized follow-up strategies.

The increasing burden of testicular seminomas and non-seminomas in adolescents and young adults (AYAs): incidence, treatment, disease-specific survival and mortality trends in the Netherlands between 1989 and 2019.

BACKGROUND: Testicular cancer incidence among adolescents and young adults (AYAs, aged 18-39 years at diagnosis) is increasing worldwide and most patients will survive the initial disease. Still, detailed epidemiological information about testicular cancer among AYAs is scarce. This study aimed to provide a detailed overview of testicular cancer trends in incidence, treatment, long-term relative survival and mortality by histological subtype among AYAs diagnosed in the Netherlands between 1989 and 2019. MATERIALS AND METHODS: Data of all malignant testicular cancers (ICD-code C62) were extracted from the Netherlands Cancer Registry. Mortality data were retrieved from Statistics Netherlands. European age-standardized incidence and mortality rates with average annual percentage change statistics and relative survival estimates up to 20 years of follow-up were calculated. RESULTS: A total of 12 528 testicular cancers were diagnosed between 1989 and 2019. Comparing 1989-1999 to 2010-2019, the incidence increased from 4.4 to 11.4 for seminomas and from 5.7 to 11.1 per 100 000 person-years for non-seminomas. Rising trends were most prominent for localized disease. Radiotherapy use in localized testicular seminomas declined from 78% in 1989-1993 to 5% in 2015-2019. Meanwhile, there was a slight increase in chemotherapy use. Most AYAs with localized seminomas and non-seminomas received active surveillance only (>80%). Overall, relative survival estimates remained well above 90% even at 20 years of follow-up for both seminomas and non-seminomas. Mortality rates declined from 0.5 to 0.4 per 100 000 person-years between 1989-1999 and 2010-2019. CONCLUSIONS: The incidence of seminoma and non-seminoma testicular cancers significantly increased in AYAs in the Netherlands between 1989 and 2019. There was a shift towards less-aggressive treatment regimens without negative survival effects. Relative survival estimates remained well above 90% at 20 years of follow-up in most cases. Testicular cancer mortality was already low, but has improved further over time, which makes survivorship care an important issue for these young adults.

Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients.

PURPOSE: Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care. METHODS: A retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated. RESULTS: Liver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment. CONCLUSION: Our study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.

Interleukin-6 in relation to early recurrence in primary, localized soft tissue sarcoma: An addition for existing risk classification systems?

BACKGROUND: Several inflammatory markers have gained interest as prognostic factors for cancer. The aim of this study is to evaluate the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as predictive markers for aggressive behavior and early recurrences in primary, localized soft tissue sarcoma (STS). METHODS: 115 STS patients were retrospectively reviewed. IL-6 and CRP blood levels, NLR and PLR were obtained prior to treatment. Early recurrence was defined as disease relapse (local or distant) within the first year after surgery. Cox regression analysis was used to identify prognostic factors for early recurrence. RESULTS: IL-6 elevation was associated with a higher tumor grade, increased size, tumor necrosis and a higher mitotic count. NLR elevation was associated with a higher tumor grade, PLR elevation with a larger tumor size. Early recurrences were found in 24 patients (21 %). Univariable analysis revealed that tumor grade (p = 0.029), tumor size (p = 0.030, >10 cm vs < 5 cm), tumor depth (p = 0.036), necrosis on imaging (p = 0.008), mitotic count (p = 0.045, ≥20 mitoses vs 0-9 mitoses), and IL-6 level (p = 0.044) were associated with early recurrence. The factors age at diagnosis, tumor location, necrosis at pathology, (neo)adjuvant radio- or chemotherapy, resection margin, CRP level, NLR and PLR were not related to early disease recurrence. CONCLUSIONS: Increased inflammatory markers in STS are associated with an aggressive phenotype. STS patients with elevation of IL-6 may be at risk for early disease recurrence.

Sexual quality of life of adolescents and young adult breast cancer survivors.

BACKGROUND: With increasing survival rates of adolescents and young adults (AYAs) with breast cancer, health-related quality of life (HRQoL) becomes more important. An important aspect of HRQoL is sexual QoL. This study examined long-term sexual QoL of AYA breast cancer survivors, compared sexual QoL scores with that of other AYA cancer survivors, and identified factors associated with long-term sexual QoL of AYA breast cancer survivors. MATERIALS AND METHODS: Data of the SURVAYA study were utilized for secondary analyses. Sexual QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life cancer survivorship core questionnaire (EORTC QLQ-SURV100). Descriptive statistics were used to describe sexual QoL of AYA cancer survivors. Linear regression models were constructed to examine the effect of cancer type on sexual QoL and to identify factors associated with sexual QoL. RESULTS: Of the 4010 AYA cancer survivors, 944 had breast cancer. Mean sexual QoL scores of AYA breast cancer survivors ranged from 34.5 to 60.0 for functional domains and from 25.2 to 41.5 for symptom-orientated domains. AYA breast cancer survivors reported significantly lower sexual QoL compared to AYA survivors of other cancer types on all domains. Age, time since diagnosis, relationship status, educational level, chemotherapy, hormonal therapy, breast surgery, body image, and coping were associated with sexual QoL of AYA breast cancer survivors. CONCLUSIONS: AYA breast cancer survivors experience decreased sexual QoL in the long term (5-20 years) after diagnosis and worse score compared to AYA survivors of other cancer types, indicating a clear need to invest in supportive care interventions for those at risk, to enhance sexual well-being.

Sunitinib for the treatment of metastatic gastrointestinal stromal tumors: the effect of TDM-guided dose optimization on clinical outcomes.

BACKGROUND: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity. PATIENTS AND METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing. RESULTS: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002). CONCLUSIONS: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.