Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database

Introduction: As both anti-tumour effects and toxicity are thought to be dose-dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored. Methods: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0–2 vs. 3–4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression. Results: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender. Conclusion: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under-treatment

Adherence to Guidelines for Adult (Non-GIST) Soft Tissue Sarcoma in the Netherlands: A Plea for Dedicated Sarcoma Centers

Introduction: Optimal management of soft tissue sarcoma (STS) remains a challenge. A nationwide survey assessed the quality of STS care in the Netherlands, thereby aiming to identify potentialities for improvement through more centralized disease management. Methods: From the Netherlands Cancer Registry (NCR), data were obtained on 3317 adult STS patients (excluding gastrointestinal stromal tumor, GIST) diagnosed in 2006–2011. Logistic regression models were employed to compare outcomes on selected clinical indicators reflecting prevailing STS guidelines between high-volume (≥10 resections annually) and low-volume (<10 resections) hospitals, between academic and general hospitals, and between sarcoma research centers and other hospitals, adjusted for case mix. Analyses were performed on imputed datasets (m = 50), generated through multiple imputations by chained equations. Results: Overall, 89% of patients underwent surgical resection. Resection status remained unknown in 24% (excluding those with metastasized disease), and grade was not documented for one-third of tumors. Microscopic residual disease was detected in 20% with an increased risk for older patients, larger and deeply located tumors, and those located in the (retro)peritoneum or upper extremity. Almost half of patients with an R1 resection re

Surgery after treatment with imatinib and/or sunitinib in patients with metastasized gastrointestinal stromal tumors: Is it worthwhile?

Background: Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy with imatinib. Surgery is performed to remove metastatic lesions to induce long-term remission or even curation. In other patients, surgery is performed to remove (focal) progressive or symptomatic lesions. The impact and long-term results of surgery after systemic therapy have not been clearly defined.Methods: Between September 2001 and May 2010, all patients with metastatic GIST who underwent surgery for metastatic GIST after systemic therapy (that is, imatinib and sunitinib) at four Dutch specialized institutions were included. Primary end-points were progression-free survival (PFS) and overall survival (OS).Results: All 55 patients underwent surgery after treatment with systemic therapy. At the last follow-up, tumor recurrence or progression was noted after surgery in 48% of the patients who responded on systemic therapy, and in 85% of the patients who were treated while having progressive disease. Median PFS and OS were not reached in the group of responders. In the non-responders group PFS and OS were median 4 and 25 months, respectively. Response on systemic therapy and a surgical complete resection were significantly correlated to PFS and OS.Conclusions: Surgery may play a role in responding patients. In patients with progressive disease, the role of surgery is more difficult to distinguish in this retrospective analysis since PFS is short. Which patients benefit and whether this improves long-term outcome should be established in a multicentric randomized trial

Pazopanib exposure decreases as a result of an ifosfamide-dependent drug-drug interaction: Results of a phase I study

Background:The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.Methods:In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m -2 per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.Results:Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.Conclusion:Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m -2 per cycle, every 3 weeks) is 800 mg daily

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

Diagnosed with a rare cancer: Experiences of adult sarcoma survivors with the healthcare system—results from the survsarc study

The aim of this study was to explore the experience of rare cancer patients with the healthcare system and examine differences between age groups (adolescents and young adults (AYA, 18–39 years), older adults (OA, 40–69 years) and elderly (≥70 years)). Dutch sarcoma patients, 2–10 years after diagnosis, completed a questionnaire on their experience with the healthcare sys-tem, satisfaction with care, information needs, patient and diagnostic intervals (first symptom to first doctor’s visit and first doctor’s visit to diagnosis, respectively) and received supportive care. In total, 1099 patients completed the questionnaire (response rate 58%): 186 AYAs, 748 OAs and 165 elderly. Many survivors experienced insufficient medical and non-medical guidance (32% and 38%), although satisfaction with care was rated good to excellent by 94%. Both patient and diagnostic intervals were >1 month for over half of the participants and information needs were largely met (97%). AYAs had the longest patient and diagnostic intervals, experienced the greatest lack of (non-)medical guidance, had more desire for patient support groups and used supportive care most often. This nationwide study among sarcoma survivors showed that healthcare experiences differ per age group and identified needs related to the rarity of these tumors, such as improvements concerning (non-)medical guidance and diagnostic intervals

Psychological aspects in patients with advanced cancer receiving lifelong systemic treatment: Protocol for a scoping review

Introduction A better understanding of the molecular, genetic and immunological characteristics of cancer and the introduction of new systemic treatment regimens in the last decades, has led to better treatment outcomes and increased survival rates for patients with previously short lived cancers. However, there is no uniform description to refer to this growing group of patients with advanced cancer who now respond to new systemic treatments for longer periods. Furthermore, little is known about the unique psychological challenges these patients face, living with ongoing uncertainty about the course of their disease and life expectancy. The objective of this scoping review is to identify the psychological aspects experienced by, and the definitions used to refer to patients with advanced cancer receiving lifelong systemic treatment. Methods and analysis This review will be among the first to summarise literature on the psychological issues in the growing group of advanced cancer patients undergoing long-Term systemic treatment. Articles will be retrieved from six databases (MEDLINE, Embase, Web of Science, PsycINFO, CINAHL and the Cochrane Database of Systematic Reviews) and reviewed for eligibility by two investigators independently. Definitions and psychological challenges will be extracted and narratively summarised following a descriptive approach. Furthermore, results will contribute in providing a uniform definition for this patient group, and help to identify knowledge gaps to give direction to further research in this field. Ethics and dissemination No ethical approval is required. The results of the scoping review will be submitted for publication to a scientific journal and presented at relevant conferences

A single digital droplet PCR assay to detect multiple KIT exon 11 mutations in tumor and plasma from patients with gastrointestinal stromal tumors

__Background:__ Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic KIT mutations that cluster in two exon 11 hotspots. The aim of this study was to develop a single, sensitive, quantitative digital droplet PCR (ddPCR) assay for the detection of common exon 11 mutations in both GIST tumor tissue and in circulating tumor DNA (ctDNA) isolated from GIST patients' plasma. __Methods:__ A ddPCR assay was designed using two probes that cover both hotspots. Available archival FFPE tumor tissue from 27 consecutive patients with known KIT exon 11 mutations and 9 randomly selected patients without exon 11 mutations were tested. Plasma samples were prospectively collected in a multicenter bio-databank from December 2014. ctDNA was analyzed of 22 patients with an exon 11 mutation and a baseline plasma sample. __Results:__ The ddPCR assay detected the exon 11 mutation in 21 of 22 tumors with exon 11 mutations covered by the assay. Mutations in ctDNA were detected at baseline in 13 of 14 metastasized patien

Prognostic factors for soft tissue sarcoma patients with lung metastases only who are receiving first-line chemotherapy: An exploratory, retrospective analysis of the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG)

The prognosis of adult soft tissue sarcoma (STS) patients with metastases is generally poor. As little is known about the impact of the involvement of different metastatic sites and the extent of pulmonary lesions on the outcome for patients receiving first-line chemotherapy, we aimed to establish prognostic factors for STS patients with lung metastases only. A retrospective, exploratory analysis was performed on 2,913 metastatic STS patients who received first-line chemotherapy. Detailed information from 580 patients who had lung metastases only