Quality of life of GIST patients with and without current tyrosine kinase inhibitor treatment: Cross-sectional results of a German multicentre observational study (PROSa).

OBJECTIVE: We investigated the health-related quality of life (HRQoL) of patients with gastrointestinal stromal tumours (GIST). METHODS: In the multicentre PROSa study, the HRQoL of adult GIST patients was assessed between 2017 and 2019 using the European Organisation for Research and Treatment of Cancer HRQoL questionnaire (EORTC QLQ-C30). We performed group comparisons and multivariate linear regressions. RESULTS: Among 130 patients from 13 centres, the mean global HRQoL was 63.3 out of 100 points. Higher sores indicate better HRQoL. The highest restrictions were in emotional, social, role functioning, insomnia, fatigue, and pain. In multivariate linear regression, we found no significant differences between patients receiving tyrosine kinase inhibitor (TKI) treatment and those without TKI treatment as well as between patients treated with curative or with palliative intent. Patients who received multiple lines of TKI treatment had the most restrictions, notably in physical (unstandardized regression coefficient [B] = -15.7), role (B = -25.7), social (B = -18.4), and cognitive functioning (B = -19.7); fatigue (B = 15.93); general health (B = -14.23); and EORTC-sum score (B = -13.82) compared to all other patients. CONCLUSION: The highest HRQoL restrictions were in GIST patients receiving multiple lines of TKI therapy. Underlying causes need further investigation.

Initial Clinical Experience with 90Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid Tumors: A Case Series of 9 Patients.

Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (68Ga-FAPI-46) for PET imaging. Here, we report our initial experience of the feasibility and safety of 90Y-FAPI-46 for radioligand therapy of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90Y-FAPI-46 therapy if they showed both an exhaustion of all approved therapies based on multidisciplinary tumor board decision, and high FAP expression, defined as SUVmax greater than or equal to 10 in more than 50% of all lesions. If tolerated, 90Y-FAPI-46 bremsstrahlung scintigraphy was performed after therapy to confirm systemic distribution and focal tumor uptake, and 90Y-FAPI-46 PET scans were performed at multiple time points to determine absorbed dose. Blood-based dosimetry was used to determine bone marrow absorbed dose. Adverse events were graded using Common Terminology Criteria for Adverse Events (version 5.0). Results: Nine patients either with metastatic soft-tissue or bone sarcoma (n = 6) or with pancreatic cancer (n = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 GBq (interquartile range [IQR], 3.25-5.40 GBq) for the first cycle, and 3 patients received subsequent cycles with a median of 7.4 GBq (IQR, 7.3-7.5 GBq). Posttreatment 90Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR, 0.41-0.65 Gy/GBq) in the kidney, 0.04 Gy/GBq (IQR, 0.03-0.06 Gy/GBq) in bone marrow, and less than 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median, 1.28 Gy/GBq). New laboratory G3 or G4 toxicities were noted in 4 patients (44%, n = 2 patients with thrombocytopenia only, n = 2 patients with new onset of thrombocytopenia and anemia). Other G3 or G4 laboratory-based adverse events occurred in 2 patients or fewer. No acute toxicities attributed to 90Y-FAPI-46 were noted. Radiographic disease control was noted in 4 patients (50%). Conclusion: FAP-targeted radioligand therapy with 90Y-FAPI-46 was well tolerated, with a low rate of attributable adverse events. Low radiation doses to at-risk organs suggest feasibility of repeat cycles of 90Y-FAPI-46. We observed signs of tumor response, but further studies are warranted to determine efficacy and the toxicity profile in a larger cohort.

Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities.

PURPOSE: We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities. EXPERIMENTAL DESIGN: Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT. RESULTS: Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and <0.14 Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients with thrombocytopenia (n = 6) and anemia (n = 6) being most prevalent. CONCLUSIONS: 90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.

Gene expression-based prediction of pazopanib efficacy in sarcoma.

BACKGROUND: The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug. PATIENTS AND METHODS: We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers. RESULTS: Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib. CONCLUSION: A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Pathology and systemic therapy of non-clear cell renal cell carcinoma: an overview.

Introduction: Non-clear cell renal cell carcinoma (nccRCC) represents a highly heterogenous group of kidney cancer entities. As most clinical trials predominantly include patients with clear cell RCC (ccRCC), nccRCC treatment guidelines are mainly extrapolated from recommendations in ccRCC. Here, we review and elucidate current data on the pathologic classification and treatment of nccRCC.Areas covered: This article gives an overview of the WHO classification of RCC, showing the histological diversity of nccRCC and focusing particularly on entities first characterized since 2016, their specific molecular behavior and their role as indicators for hereditary cancer syndromes. In this context, we discuss the available data on nccRCC treatment oprtions such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, cytotoxic chemotherapy, and immune checkpoint inhibitors.Expert opinion: Although nccRCCs are relatively uncommon, entities of this type account for a subgroup of up to 20-25% of all RCCs. Advances in histopathology and molecular genetics, together with evidence gained from retrospective and prospective clinical data, have improved understanding of these tumors in recent years. Nevertheless, selective trials of current and novel therapies including new targeted agents in patients with nccRCC are urgently needed to further improve treatment guidelines.

Impact of Time to Castration Resistance on Survival in Metastatic Hormone Sensitive Prostate Cancer Patients in the Era of Combination Therapies.

BACKGROUND: To evaluate the impact of time to castration resistance (TTCR) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies for mHSPC. MATERIAL AND METHODS: Of 213 mHSPC patients diagnosed between 01/2013-12/2020 who subsequently developed metastatic castration resistant prostate cancer (mCRPC), 204 eligible patients were analyzed after having applied exclusion criteria. mHSPC patients were classified into TTCR <12, 12-18, 18-24, and >24 months and analyzed regarding OS. Moreover, further OS analyses were performed after having developed mCRPC status according to TTCR. Logistic regression models predicted the value of TTCR on OS. RESULTS: Median follow-up was 34 months. Among 204 mHSPC patients, 41.2% harbored TTCR <12 months, 18.1% for 12-18 months, 15.2% for 18-24 months, and 25.5% for >24 months. Median age was 67 years and median PSA at prostate cancer diagnosis was 61 ng/ml. No differences in patient characteristics were observed (all p>0.05). According to OS, TTCR <12 months patients had the worst OS, followed by TTCR 12-18 months, 18-24 months, and >24 months, in that order (p<0.001). After multivariable adjustment, a 4.07-, 3.31-, and 6.40-fold higher mortality was observed for TTCR 18-24 months, 12-18 months, and <12 months patients, relative to TTCR >24 months (all p<0.05). Conversely, OS after development of mCRPC was not influenced by TTCR stratification (all p>0.05). CONCLUSION: Patients with TTCR <12 months are at the highest OS disadvantage in mHSPC. This OS disadvantage persisted even after multivariable adjustment. Interestingly, TTCR stratified analyses did not influence OS in mCRPC patients.

Localized Angiosarcoma, Not One Disease: A Retrospective Single-Center Study on Prognosis Depending on the Primary Site and Etiology.

BACKGROUND: Angiosarcomas are rare and heterogeneous tumors with poor prognosis. The clinical subtypes are classified depending on the primary site and etiology. METHODS: We conducted a retrospective, monocentric study of 136 patients with localized AS between May 1985 and November 2018. Overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) were estimated using the Kaplan-Meier method. To identify prognostic factors, univariate and multivariate analyses were performed based on Cox regressions. RESULTS: The median age was 67 years (19-72.8 years). Primary sites were cutaneous (27.2%), breast (38.2%), and deep soft tissue (34.6%). The majority was primary angiosarcomas (55.9%) followed by postradiation (40.4%) and chronic lymphedema angiosarcomas (2.9%). Prognosis significantly differed depending on the primary site and etiology. Shortest median OS and MFS were observed in deep soft tissue angiosarcomas, whereas cutaneous angiosarcomas, angiosarcomas of the breast, and radiation-associated angiosarcomas displayed worse median LRFS. Univariate analyses showed better OS for tumor size <10 cm (p = 0.009), negative surgical margins (p = 0.021), and negative lymph node status (p = 0.007). LRFS and MFS were longer for tumor size <10 cm (p = 0.012 and p = 0.013). In multivariate analyses, age <70 years was the only independent positive prognostic factor for OS in all subgroups. For LRFS, secondary AS of the breast was a negative prognostic factor (HR: 2.35; p = 0.035). CONCLUSIONS: Different behaviors and prognoses depending on the primary site and etiology should be considered for the treatment of this heterogeneous disease. In cutaneous angiosarcomas of the head/neck and postradiation angiosarcomas of the breast, local recurrence seems to have a crucial impact on OS. Therefore, improved local therapies and local tumor staging may have to be implemented. However, in deep soft tissue angiosarcomas, distant recurrence seems to have a major influence on prognosis, which indicates a benefit of additional perioperative chemotherapy.

[What is new in the diagnosis and therapy of renal cell carcinoma?] / Was ist neu bei der Diagnostik und Therapie des Nierenzellkarzinoms?

Renal cell carcinomas (RCC) include different tumor entities, of which clear cell RCC is the most common tumor with approx. 75 % followed by the papillary RCC with 10-15 %. RCC are increasingly being diagnosed incidental in the context of abdominal diagnostics from other indications using sonography or cross-sectional imaging.The prognosis of metastatic RCC has improved significantly due to new therapy options, especially through the use of immune checkpoint inhibitors (IO). In the first line, combination therapies of the tyrosine kinase inhibitor (TKI) axitinib with the PD-1 antibody pembrolizumab or the PDL-1 antibody avelumab apply regardless of the risk profile and histological entity, as well as the combination of the CTLA4 antibody ipilimumab with the PD-1 antibody nivolumab in patients with intermediate and high risk as new standards in therapy. The combinations lead to a higher response rate and longer survival. In the second line and subsequent lines, there is no evidence-based data after combination therapies, but drugs can be used that were not yet part of the first-line therapy.

The Health-Related Quality of Life of Sarcoma Patients and Survivors in Germany-Cross-Sectional Results of a Nationwide Observational Study (PROSa).

Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September 2017 and February 2019 in 39 study centers in Germany using standardized, validated questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Associated factors were analyzed exploratively using multivariable linear regressions. Among 1113 patients, clinically important limitations and symptoms were most pronounced in emotional (63%, 95% CI 60-66%), physical (60%, 95% CI 57-62%), role functioning (51%, 95% CI 48-54%), and pain (56%, 95% CI 53-59%) and fatigue (51%, 95% CI 48-54%). HRQoL differed between tumor locations with lower extremities performing the worst and sarcoma types with bone sarcoma types being most affected. Additionally, female gender, higher age, lower socioeconomic status, recurrent disease, not being in retirement, comorbidities, and being in treatment were associated with lower HRQoL. Sarcoma patients are severely restricted in their HRQoL, especially in functioning scales. The heterogeneity of sarcomas with regard to type and location is reflected in HRQoL outcomes. During treatment and follow-up, close attention has to be paid to the reintegration of the patients into daily life as well as to their physical abilities and emotional distress.

Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options.

Non-clear cell renal cell carcinomas (nccRCC) are rare diseases with heterogeneous histopathologically and genetically defined entities. The clinical data on optimal systemic treatments of nccRCC is rather limited. In this review, the current World Health Organization (WHO) classification of nccRCC based on histopathologic and genetic findings is reported. Regarding systemic treatment options, the most commonly used agents are mTOR inhibitors like everolimus or temsirolimus, or tyrosine kinase inhibitors like sunitinib. 2 small randomized clinical trials with nccRCC comparing sunitinib with everolimus revealed a trend towards a better progression-free survival (PFS) and overall survival (OS) in favor of sunitinib. In RCC with predominant sarcomatoid features, both chemotherapy and targeted agents are reported without any preference for outcome. For subsequent lines of therapy, some case reports describe promising effects of PD-1 or PD-L1 inhibitors in nccRCC including sarcomatoid subtype and Bellini duct carcinoma. Currently, nccRCCs are treated similarly to clear cell RCC or, whenever possible, within clinical trials. Clinical trials with immune checkpoint inhibitors are ongoing.

Limb-Salvage Surgery of Soft Tissue Sarcoma with Sciatic Nerve Involvement.

BACKGROUND: The surgical resection of soft tissue sarcomas (STS) with sciatic nerve involvement presents a significant surgical and oncological challenge. Current treatment strategies pursue a multimodal approach with the aim of limb preservation. We aim to evaluate the outcomes of limb-sparing surgery of STS in a patient cohort and to propose a classification for STS with sciatic nerve involvement. METHODS: Patients receiving limb-preserving resections for STS with sciatic nerve involvement between 01/2010 and 01/2017 were included. Clinical and oncological data were prospectively collected in a computerized database and retrospectively analyzed. Sciatic nerve involvement in STS was classified preoperatively as follows: type A for nerve encasement; type B for nerve contact; and type C for no nerve involvement. RESULTS: A total of 364 patients with STS were treated, of which 27 patients had STS with sciatic nerve involvement. Eight patients with type A tumors (29.6%) underwent sciatic nerve resection, and 19 patients with type B tumors (70.4%) received epineural dissections. Disease progression was observed in 8 patients (29.6%) with a local recurrence of 11.1% and distant metastasis in 29.6%. The type of nerve resection significantly influenced leg function but had no impact on disease recurrence or overall survival. CONCLUSION: In a cohort of carefully selected patients with STS and sciatic nerve involvement, the extent of sciatic nerve resection had no significant impact on disease recurrence or survival. Precise classification of neural involvement may therefore be useful in selecting the appropriate degree of nerve resection, without compromising oncological outcome or unnecessarily sacrificing leg function.

Trabectedin in metastatic soft tissue sarcomas: Role of pretreatment and age.

Trabectedin has mostly been studied in metastatic leiomyosarcoma and liposarcomas. Only limited data are available in other sarcoma subtypes, heavily pretreated and elderly patients. We retrospectively analyzed 101 consecutive sarcoma patients treated with trabectedin at our center. We recorded progression-free survival (PFS), clinical benefit rate (CBR, defined as complete or partial response or stable disease for at least 6 weeks) and toxicity. Covariates were sarcoma subtype, age and pretreatment. On average, trabectedin was administered for 2nd relapse/progression (range 1st to 12th line). A median of 2 cycles and a dose of 1.5 mg/m2 (range 1-21 cycles; 1.3-1.5 mg/m2) was administered. The median PFS under treatment with trabectedin was 2.1 months in the overall population. Different clinical outcomes were observed with respect to sarcoma subtypes: in patients with L-sarcoma [defined as leiosarcoma and liposarcoma (n=25)] the CBR was 55%. Notably, long lasting remissions were even observed in 7th-line treatment. In contrast, the majority of patients with non-L-sarcomas quickly progressed (median PFS 1.6 months). Nevertheless, a CBR of 34% was achieved, including long-lasting disease stabilization in subtypes such as rhabdomyosarcoma. Patients treated with trabectedin at 1st or 2nd line (n=16) achieved an improved PFS (median 5.7 months, range) and a CBR of 59%. No differences in terms of toxicity or efficacy were observed between patients older than 65 years (n=23) and younger patients (n=78). In this non-trial setting, port-associated complications were more frequent (14%) with trabectedin compared to other continuous infusion protocols administered at our outpatient therapy center. The majority of patients with relapsing L-sarcomas and a substantial fraction of patients with non-L-sarcomas derive a clinically meaningful benefit from trabectedin. Outpatient treatment is well tolerated also in elderly and heavily pretreated patients. Port-associated complications were observed at an unusually high rate. This suggests a drug-specific local toxicity that merits further investigation.

Effects of mitochondrial inhibitors and uncouplers on hypoxic vasoconstriction in rabbit lungs.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange; however, the underlying mechanism has not yet been fully elucidated. Lung nitric oxide (NO) generation appears to be involved in this process. Recently, mitochondria have been proposed as oxygen sensors, with HPV signaling via a hypoxia-induced increase in the generation of reactive oxygen species derived from mitochondrial complex III and escaping through an anion channel into the cytoplasm. In addition, complex II has been suggested to be specifically involved in hypoxia-dependent generation of reactive oxygen species in the lung. We investigated the effects of several mitochondrial inhibitors and uncouplers on the strength of HPV, and asked for their capacity to mimic HPV during normoxia in isolated buffer-perfused rabbit lungs. Specificity of the agents for HPV was tested by comparison of their effects on non-hypoxia-induced vasoconstriction, elicited by the thromboxane mimetic U46619. Interference with NO metabolism was determined by performing parallel studies with blocked lung NO generation and by measurement of exhaled NO. Rotenone, 3-nitroproprionic acid, and myxothiazol dose-dependently inhibited HPV without being mimics of HPV during normoxia. The inhibitory effect of these agents was only partly specific for HPV by comparison with U46619-induced vasoconstriction. During pre-blocked lung NO synthesis, the selectivity for HPV inhibition was increased for rotenone, but largely lost for myxothiazol. 2-tenoyltrifluoroacetone resulted in an unspecific inhibition of HPV as compared with U46619-induced vasoconstriction. 1-methyl-4-phenylpyridinium iodide and 2-heptyl-4-hydroxyquinoline-N-oxide specifically suppressed HPV and increased normoxic vascular tone. Antimycin A suppressed HPV, an effect being specific in lungs with intact NO synthesis and only partly specific while blocking NO. However, this agent did not mimic HPV during normoxia, as may be expected for interference with the mitochondrial electron transport downstream in complex III. The uncouplers 2,4-dinitrophenol (DNP, 10-200 microM) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP, 1-3 microM) induced sustained vasoconstriction during normoxia, with enhancement of HPV by DNP at low and suppression of HPV for both agents at high concentrations. The anion channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid inhibited HPV and U46619-induced vasoconstriction with identical dose-response curves. These findings suggest that mitochondria are in some manner involved in the regulation of HPV in intact rabbit lungs. The hypothesis that enhanced superoxide leak at complex III of mitochondria represents the underlying mechanism of acute HPV is supported by the rotenone and 2-heptyl-4-hydroxyquinoline-N-oxide data, but partly contradicted by the findings with 1-methyl-4-phenylpyridinium iodide, antimycin A, DNP, and FCCP. Further studies are mandatory to clarify the link between mitochondrial respiratory chain and hypoxic pulmonary vasoconstriction.