Molecular Heterogeneity in Leiomyosarcoma and Implications for Personalised Medicine.

OPINION STATEMENT: Leiomyosarcoma (LMS) is one of the more common subtypes of soft tissue sarcomas (STS), accounting for about 20% of cases. Differences in anatomical location, risk of recurrence and histomorphological variants contribute to the substantial clinical heterogeneity in survival outcomes and therapy responses observed in patients. There is therefore a need to move away from the current one-size-fits-all treatment approach towards a personalised strategy tailored for individual patients. Over the past decade, tissue profiling studies have revealed key genomic features and an additional layer of molecular heterogeneity among patients, with potential utility for optimal risk stratification and biomarker-matched therapies. Furthermore, recent studies investigating intratumour heterogeneity and tumour evolution patterns in LMS suggest some key features that may need to be taken into consideration when designing treatment strategies and clinical trials. Moving forward, national and international collaborative efforts to aggregate expertise, data, resources and tools are needed to achieve a step change in improving patient survival outcomes in this disease of unmet need.

Best Overall Response-associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE.

PURPOSE: This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase-3 ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers. EXPERIMENTAL DESIGN: RNA sequencing was performed on pretreatment tumor samples (n=273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was utilized for refinement and validation. RESULTS: A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2 P=2.0e-7) and grade (P=0.002). There were no associations between the BOR signature and gender, age, ethnicity or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma. CONCLUSIONS: The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.

Efficacy and Safety of Ripretinib in Advanced Gastrointestinal Stromal Tumors within an Expanded Access Program: A Cohort Study.

Ripretinib, a novel tyrosine kinase inhibitor used in advanced gastrointestinal stromal tumors (GIST) resistant to standard therapies, was assessed in the United Kingdom (UK) within an Expanded Access Program (EAP). A retrospective review of patients treated between January 2020 and October 2021 within the ripretinib EAP in our Institution was conducted. Clinician-documented and mRECIST 1.1 assessments were collected. The primary endpoints were progression-free survival (PFS) and time to treatment discontinuation (TTD). Treatment beyond progression (TBP), overall survival (OS), objective response rates and safety data were also analyzed. Survival curves were constructed using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were performed. All analyses were performed with R software. Overall, forty-five patients were included. After a median follow-up of 24.2 (95% CI 19.7-29.7) months, the median PFS of the group receiving 150 mg ripretinib once daily (OD) was 7.9 (95% CI 5.6-19.3) months. In the cohort of 22 patients with dose escalation upon tumor progression to 150 mg ripretinib twice daily (BD), the median PFS from BD was 5.4 (95% CI 2.8-9.3) months. Overall, median PFS and OS values for patients on ripretinib were 9.7 (95% CI 8.3-18.1) and 14.0 (95% CI 9.9-NA) months, respectively. TTD was similar to PFS. TBP was observed in about one third of all patients. Objective responses to ripretinib OD and BD treatments were observed in 16.7% and 10.0% of the patients, respectively. No new safety signals were identified. In conclusion, patients with advanced GIST receiving ripretinib in the UK within the EAP reported prolonged benefits, in line with the recent phase III clinical trials.

The patient perspective on sirolimus for epithelioid hemangioendothelioma (EHE): results of a community survey highlighting the importance of equitable access to treatments.

Background: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, vascular sarcoma with clinical presentation ranging from an indolent to an aggressive form. Over 50% of patients present with metastatic disease, requiring systemic therapy, although no systemic therapies are specifically approved for EHE. Retrospective evidence supports the activity of mTOR inhibitors (e.g. sirolimus), although available only off-label. EHE patients and advocates are therefore working to support approval of effective treatments by collecting data on patient perspectives and experiences. Materials and methods: In February 2023, the EHE Rare Cancer Charity (UK) and The EHE Foundation (US), with other advocates, conducted a survey of perspectives and experiences of EHE patients regarding the use and accessibility of sirolimus. The survey consisted of 20 questions designed for individuals undergoing treatment, those who had been treated, or had never been treated with the drug. Widely promoted within the patient community, the online survey categorized patients into three cohorts for the analysis: liver transplant patients, non-transplant patients who had ever taken sirolimus and sirolimus-naïve non-transplant patients. Results: The survey evaluated data from 129 patient responses from 21 countries, mostly from USA, UK, Australia, and Canada (70%). The liver transplant, sirolimus and non-sirolimus cohorts were 16%, 25% and 59%, respectively. In the sirolimus group 66% reported treatment durations exceeding one year, with 16% exceeding five years, indicating the drug's efficacy. In the non-sirolimus group, the drug was not available for 42% and for 11% sirolimus was available but not selected for treatment because of its off-label status. Overall, 87% of all patients across all cohorts expressed the importance of the drug's availability as hugely or very important. Conclusion: The survey responses highlight the activity of sirolimus for EHE and the importance of securing a label extension for the drug delivering equitable access to this treatment for patients.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies.

PURPOSE: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. PATIENTS AND METHODS: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). RESULTS: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). CONCLUSIONS: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings.

Reply to Chen, A.; Zhang, X. Comment on "Golcic et al. Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. Cancers 2023, 15, 4081".

We appreciate the comment made by Chen et al. on our manuscript evaluating the systemic treatment options for gastrointestinal stromal tumours (GIST) [...].

Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas.

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64-1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39-1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma: A Phase 1 Nonrandomized Controlled Trial.

Importance: Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. Objective: To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. Design, Setting, and Participants: This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Interventions: Two doses of IT GLA-SE (5 µg and 10 µg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Main Outcomes and Measures: Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Results: Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. Conclusions and Relevance: In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02180698.

Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.

Pseudoprogression in patients with uterine leiomyosarcoma treated with first-line single-agent doxorubicin.

AIM: To evaluate the incidence of pseudoprogression in patients with metastatic or inoperable uterine leiomyosarcoma (LMS) treated with first-line single-agent doxorubicin. METHODS: The Royal Marsden NHS Foundation Trust Sarcoma Unit database was searched to identify all patients with metastatic or inoperable LMS treated with first-line doxorubicin from January 2006 to January 2022. Patients with available computed tomography scans performed at baseline and during doxorubicin therapy were included. Response evaluation criteria in solid tumours v1.1 and Choi criteria were applied. Any increase in the sum of the longest diameter that decreased on the subsequent scan was labelled as pseudoprogression. RESULTS: The total number of patients evaluated was 52. In total, 19% (n = 10) of patients treated with doxorubicin showed pseudoprogression. However, pseudoprogression at the time of the second scan was not associated with time to doxorubicin failure. Choi criteria identified 30% (n = 3) of pseudoprogressors as responding. CONCLUSION: Despite the use of doxorubicin as first-line therapy for soft-tissue sarcomas for over 40 years, pseudoprogression has not been described. This retrospective study shows that pseudoprogression occurs in 19% of patients with metastatic/inoperable uterine LMS treated with first-line doxorubicin. Choi criteria were not consistently able to differentiate pseudoprogression from true progression. It is imperative that oncologists and radiologists are aware of this as symptomatically stable/improving patients may benefit from continued treatment despite initial radiological growth in tumour size.

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study.

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor after treatment with imatinib: a plain language summary of the phase 3 INTRIGUE trial.

WHAT IS THIS SUMMARY ABOUT?: This document presents a patient-friendly summary of the phase 3 INTRIGUE clinical trial results, which were published in the Journal of Clinical Oncology in August 2022. A phase 3 trial is a study that tests the safety of a proposed treatment and how well it works compared with a standard treatment or a treatment with no active ingredient (also called a placebo). The aim of the INTRIGUE trial was to understand whether treatment with a drug called ripretinib (brand nameQINLOCK®) was superior to treatment with sunitinib (brand name SUTENT®) in participants with advanced gastrointestinal stromal tumor (also known as GIST) who cannot tolerate or whose disease progressed beyond first-line treatment with imatinib (brand name GLEEVEC®). The INTRIGUE trial included 453 participants with advanced GIST who had previously been treated with a tyrosine kinase inhibitor (also known as a TKI) medicine called imatinib. For patients with advanced GIST who cannot tolerate or whose disease progresses while taking imatinib, the recommended second-line TKI medicine is sunitinib. The recommended third-line TKI medicine is called regorafenib (brand name STIVARGA®). Ripretinib is currently the only medication approved for adults with advanced GIST who have previously been treated with 3 or more TKIs (fourth-line). WHAT WERE THE RESULTS?: The trial showed that ripretinib did not significantly increase the time that participants survived without their cancer getting worse (progression-free survival or PFS) over sunitinib. However, participants treated with ripretinib had similar PFS to those treated with sunitinib. Importantly, treatment with ripretinib resulted in fewer severe adverse events, or side effects, compared with sunitinib, and participants reported better quality of life with ripretinib compared with sunitinib. WHAT DO THE RESULTS MEAN?: Treatment with ripretinib, after imatinib stops working or can no longer be tolerated, provided similar PFS for participants with advanced GIST and had fewer severe adverse events compared with sunitinib. Sunitinib is the only medication currently approved for use as a second-line treatment in patients with advanced GIST previously treated with imatinib. With more investigation, ripretinib could be a treatment option for these patients. Patients should always talk to their medical team before making any decisions about their treatment.

The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Pharmacotherapeutic strategies for epithelioid sarcoma: are we any closer to a non-surgical cure?

INTRODUCTION: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma subtype, predominantly occurring in children and young adults. Despite optimal management of localized disease, approximately 50% of patients develop advanced disease. The management of advanced ES remains challenging due to limited response to conventional chemotherapy and despite novel oral EZH2 inhibitors that have better tolerability but similar efficacy to chemotherapy. AREAS COVERED: We performed a literature review using the PubMed (MEDLINE) and Web of Science databases. We have focused on the role of chemotherapy, targeted agents such as EZH2 inhibitors, potential new targets and immune checkpoint inhibitors and combinations of therapies currently undergoing clinical investigation. EXPERT OPINION: ES is a soft tissue sarcoma with a heterogeneous pathological, clinical, and molecular presentation. In the current era of precision medicine, more trials with targeted therapies and a combination of chemotherapy or immunotherapy with targeted therapies are required to establish optimal treatment for ES.

Optimal Delivery of Follow-Up Care Following Treatment for Adults Treated for Ewing Sarcoma.

Ewing sarcoma (ES) is a rare, highly malignant sarcoma. It usually presents in the second decade of life; however, patients can be diagnosed as early as newborns and as late as in their seventies. ES is most frequently found in the long bones of the extremities and the pelvis. In older patients, ES can also arise in the soft tissues. Currently, there is no standard schedule for surveillance of adult patients with ES after their initial treatment for localised disease, not only for the early detection of recurrence but also for long-term side effects. Follow-up is based on group recommendations using extrapolated data obtained primarily from studies with paediatric patients. The main objective of this review is to summarise the data available on treatment-associated complications in long-term survivors. Furthermore, we provide a set of recommendations for optimising the follow-up of adults ES survivors, as well as for managing the sequelae that result from intensive multimodal treatment.

Psychological and social challenges of patients with locally advanced and metastatic gastrointestinal stromal tumours (GIST) on long-term treatment with tyrosine kinase inhibitors: a qualitative study with patients and medical oncologists.

PURPOSE: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of locally advanced and metastatic gastrointestinal stromal tumours (GISTs). Patients are experiencing prolonged survival but often at the expense of their health-related quality of life. It is not only the physical side effects that impact GIST patients' daily lives but also the psychological and social challenges they have to deal with. This qualitative study aimed to explore the psychological and social life challenges of GIST patients with locally advanced and metastatic disease on ≥ 5 years TKI treatment. METHODS: Semi-structured interviews with 15 locally advanced and/or metastatic GIST patients and 10 medical oncologists with experience of delivering care to this specific patient group were conducted. Thematic analysis was used to interpret the data. RESULTS: Psychological challenges expressed by participants concerned fears, scanxiety, negative change in emotion and mood, doubts about their treatment and follow-up, living with uncertainty, lack of understanding from others or healthcare professionals, and constantly being reminded of their illness. Challenges regarding social health included financial difficulties, challenges in relationships, concerns about fertility and parenting, work, and impact on social activities. CONCLUSION: The reported psychological and social challenges can significantly hamper the overall quality of life of GIST patients. Some challenges were clearly underreported and hardly recognized by medical oncologist, as they may tend to focus on the physical side effects and clinical outcomes of treatment. Therefore, it is essential to take the patient's perspective into account in research and clinical practice to ensure optimal care for this patient group.