Exploring long-term cancer survivors' care experiences and unmet needs: protocol for a qualitative study.

BACKGROUND: The number of cancer survivors has increased in recent decades, and the majority of them suffer from sequelae of their disease and treatment. This study, which is part of the larger research project OPTILATER, aims to explore different aspects of care services for long-term survivors (≥ 5 years after initial cancer diagnosis) in Germany. The study places an emphasis on the situation of people from different age groups, with different socio-demographic and cultural backgrounds, and sexually and gender diverse individuals. METHODS: To investigate experiences related to follow-up care, focus groups (n = 2) will be conducted with members of patient advisory councils and advocacy groups, representatives of communities, healthcare workers and networks, as well as members of Associations of Statutory Health Insurance Physicians. Guided interviews will be carried out with patients and relatives (n = 40) to investigate needs, barriers and obstacles in terms of follow-up care. On this basis, additional focus groups (n = 2) will be carried out to derive possible scenarios for improving the consideration of needs. Focus groups and interviews will follow a semi-structured format and will be analysed content-analytically. Focus groups and interviews will be conducted online, recorded, transcribed, and analysed independently by two persons. DISCUSSION: The qualitative approach is considered suitable because of the exploratory research aims. The identification of experiences and barriers can reveal disparities and optimization potential in the care of long-term cancer survivors.

Streamlining clinical research: an ESMO awareness call to improve sponsoring and monitoring of clinical trials.

BACKGROUND: During recent years, the burden of bureaucracy in clinical research has increased dramatically, adversely impacting the activity of investigators and clinical research teams. Although compliance with the Declaration of Helsinki, the guidelines for Good Clinical Practice (GCP), and other applicable regulations remains unquestionable, their overinterpretation and substitution by the internal operating procedures of sponsors and Contract Research Organizations (CROs) have increased the administrative burden. A survey conducted by the European Society for Medical Oncology (ESMO) Clinical Research Observatory (ECRO) among 940 investigators confirmed that they considered that the administrative burden in clinical research is excessive; that administrative procedures could be reduced without affecting the safety and the rights of the patients and the quality of the data; and that bureaucracy represents an obstacle for clinical research. METHODS: A panel of physicians with extensive experience in clinical research, composed by members of the ECRO and the ESMO Scientific Medical and Public Policy divisions, analyzed clinical trial procedures related to administrative workflow, pharmacovigilance, and medical care. RESULTS: The panel identified situations that generate debate between investigators and sponsors/CROs and selected real clinical scenarios that exemplify such situations. The panel discussed and proposed specific recommendations for those situations, based on GCP. CONCLUSIONS: This initiative aspires to streamline clinical research procedures and to become a platform for discussion among all clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients.

Systemic therapy in metastatic renal cell carcinoma (mRCC): an evidence-based recommendation of the German interdisciplinary RCC guidelines group.

PURPOSE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. CONCLUSION: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

[Predictive biomarkers in oncologic uropathology]. / Prädiktive Biomarker in der onkologischen Uropathologie.

BACKGROUND: Tumors of the genitourinary system are common. In recent years, our understanding of their molecular background and therefore the number of potential predictive biomarkers has massively increased. OBJECTIVES: The aim of the current work is to give an overview of recent (molecular) developments and predictive biomarkers in urologic oncology and to give a perspective of what might become relevant in the future of the field. MATERIAL AND METHODS: We considered the recent literature and study data and combined it with our own expertise in tumors of the urinary system, kidneys, and prostate. RESULTS AND CONCLUSIONS: The molecular subtypes of muscle-invasive urothelial bladder cancer (MIBC) hold a predictive and prognostic significance and correlate with clinicopathological features. Immune therapy with checkpoint inhibitors (CPI) has a major role in urothelial carcinoma (UC), but also in renal cell carcinoma and a subgroup of prostate cancers. The first-line use in UC is restricted to PD-L1-"positive" cases (≥IC2/3, CPS ≥ 10). Further predictive markers are currently under evaluation, while the predictive significance of tumor mutational burden (TMB) is under debate. In addition to a subgroup of renal cell carcinomas, a subgroup of prostate carcinomas with alterations in the DNA repair system might benefit from a customized therapy approach (PARP inhibitors, platin-containing chemotherapy). The multitude of potentially therapy-relevant molecular alterations and related predictive biomarkers calls for the implementation of sophisticated molecular analyses in daily routine. This will lead to an even more rapid dynamic in the field of genitourinary pathology.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms.

BACKGROUND: Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making. MATERIALS AND METHODS: Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach. RESULTS: The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria. CONCLUSION: In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred.

Does the onset of bone metastasis in sunitinib-treated renal cell carcinoma patients impact the overall survival?

PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4-26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.

Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.

BACKGROUND: In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. PATIENTS AND METHODS: Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. RESULTS: Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. CONCLUSIONS: Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.

TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO).

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN. PATIENTS AND METHODS: The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after ≥1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence. RESULTS: A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0-54.6). The median PFS and OS were 56 days (95% CI 36-113 days) and 152 days (76-256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF. CONCLUSION: Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies. CLINICAL TRIALS NUMBER: NCT01172769.

Topotecan plus cyclophosphamide in adults with relapsed or refractory pediatric-type sarcoma: a retrospective analysis from the German Sarcoma Medical Oncology Group (AIO).

BACKGROUND: To assess the efficacy and safety of topotecan and cyclophosphamide (TC) in adult patients with pediatric-type sarcoma subtypes who failed induction chemotherapy. PATIENTS AND METHODS: Patients with pediatric sarcoma subtypes, refractory to or relapsed after at least one prior induction chemotherapy, inoperable, ECOG PS 0-2, with measurable, progressive disease (PD), adequate organ functions, who have been treated with TC combination were retrospectively analysed within the AIO and SAREZ/BMBF network. RESULTS: Thirty-nine patients, median age 28 years (18-58), 14 females, 25 males, have been identified. All patients had received induction treatment according to (inter)national study protocols. Second-line TC was applied in 33 patients (≥3rd-line in 6 patients). Twenty-three patients had refractory disease (evidence of PD during induction chemotherapy); 8 patients experienced an early relapse within 6 months as well as 8 patients after more than 24 months (late relapse). A median of 3 cycles (range, 1-6) had been applied and antitumor activity was: CR 2.6 %, PR 7.9 %, and disease stabilisation (SD) 26.3 %. PR lasted 32.8 months and median duration in patients with SD was 5 months (range, 2.0-14.7). The 3/6-months progression-free rates were 43.2 and 18.9 %. CONCLUSIONS: Limited activity was seen in adult pts with refractory or relapsed pediatric-type sarcomas with the regimen which has proven activity in pediatric patients. Adults with refractory small cell sarcoma appear to have a similar dismal outcome as seen in pts with common adult-type histologies; however, a subset of patients has achieved long-lasting remissions on TC resulting in long-term survival.

Sunitinib re-challenge in advanced renal-cell carcinoma.

Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal sequences of therapy is therefore the focus of much current research. There is also evidence that treatment 're-challenge' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior targeted therapy with sunitinib and/or an alternative tyrosine kinase inhibitor or mammalian target of rapamycin inhibitor. Re-challenge with sunitinib appears to be of clinical benefit, thus representing a feasible therapeutic option for patients with advanced RCC who are refractory to other treatments and are able to receive further therapy. These observations support hypotheses that resistance to targeted agents is transient and can be at least partially reversed by re-introduction of the same agent after a treatment break. Median progression-free survival durations appear to be shorter and response rates lower on re-challenge than following initial treatment, although a wider interval between treatments appears to increase response to sunitinib re-challenge.

[Pharmacotherapy of solid tumors. New hopes and frustrations]. / Arzneitherapie solider Tumoren. Hoffnung und Frustration.

Recent years have seen dramatic changes in the biological understanding and treatment of solid tumors. Based on the tumor biology, targeting agents have been developed which directly affect the underlying genetic or immunological changes found in specific tumor entities. Significant increases in survival have delivered the functional proof of the concept of targeted and immunological tumor therapy. The management and adherence of the patient as well as optimized cooperation with clinicians are decisive for the results of therapy and disease control.Several solid tumors are currently under investigation in clinical studies evaluating the (sequential) therapy with targeting and immunologically active agents, e.g. tyrosine kinase and mTOR inhibitors, targeting antibodies, such as bevacizumab, specific antagonists, such as enzalutamide and immunological checkpoint inhibitors via PD(L)1 and/or CTLA 4 antibodies.Currently approved agents have dramatically changed the landscape of treatment options especially for prostate cancer. Such agents include hormone therapy with enzalutamide and abiraterone, radiotherapy with cabazitaxel and xofigo (radium 223), metastatic breast cancer (eribulin and everolimus), renal cell carcinoma (sunitinib, sorafenib, axitinib, everolimus and temsirolimus), non-small cell lung cancer (crizotinib and afatinib), colorectal cancer and gastrointestinal stromal tumor (regorafenib) and melanoma (ipilimumab and vemurafenib). The treatment of rarer tumors, such as pancreatic and hepatocellular cancer and soft tissue sarcoma has entered the stage of targeted therapy with the approval of nanoparticle albumin-bound (nab)-paclitaxel, sorafenib, and eribulin/pazopanib. Current clinical trials are focusing on the best time point and sequence of therapy and also improvement in the management of these promising agents.

[Update of the German S3 guideline on renal cell carcinoma]. / Aktualisierte S3-Leitlinie Nierenzellkarzinom.

BACKGROUND: Renal cell carcinoma is the third most common tumor among urological tumors. In Germany more than 14,000 people are affected every year. The sex ratio is 2/3 men and 1/3 women. OBJECTIVES: The S3 guideline is intended to provide all disciplines dealing with renal cell carcinoma with the current status of diagnostics, therapy and follow-up care of the patients with this tumor. MATERIALS AND METHODS: The first version of the German guideline on renal cell carcinoma was published in 2015. The development was carried out at S3 level, which means that a structured, evidence-based literature search was carried out, recommendations and statements were developed in topic-related working groups and were approved by an interdisciplinary group of officials elected by the different medical societies. The chapters were gradually revised in 2017, 2020 and 2021 to reflect new aspects. This article provides information about the most important innovations of the most recent update from 2023. RESULTS: In the epidemiology subsection, the substance trichlorethene has been added as a risk factor for the development of renal cell carcinoma. While there were no new data on neoadjuvant therapy, the checkpoint inhibitor pembrolizumab was the first substance to demonstrate improved disease-specific and overall survival in the adjuvant situation. The combination nivolumab plus cabozantinib and lenvatinib plus pembrolizumab were included in the chapter on systemic therapy for metastatic clear cell renal cell carcinoma. New are the chapters on non-clear cell renal cell carcinoma and hereditary tumors. CONCLUSIONS: The S3 guideline provides a structured, evidence-based overview of all aspects of renal cell carcinoma.

Tumour shrinkage measured with first treatment evaluation under VEGF-targeted therapy as prognostic marker in metastatic renal cell carcinoma (mRCC).

BACKGROUND: The aim of our analysis is to further characterise the prognostic relevance of early tumour shrinkage (TS) during VEGF-targeted therapy in mRCC, in order to explore whether this could define a group of patients with long-term survivorship. METHODS: A hundred patients were stratified into five subgroups according to their change of tumour size with first treatment evaluation: -100% to -60%; -59% to -30% and -29% to 0% TS or gain of tumour size from 1% to 19% and ≤20% or occurrence of new lesions (i.e., progressive disease). RESULTS: The median PFS and OS were 10.4 months and 28.2 months, respectively. The median OS stratified according to the subgroups as described above was 77.4, 33.5, 26.9, 30.0 and 14.3 months, respectively. Multivariate analysis revealed early TS as a prognostic marker (P=0.021; HR 1.624). CONCLUSION: The extent of TS defines a small proportion of patients with an excellent prognosis. Larger studies are warranted to define the relationship of long-term survivorship and extent of TS with targeted therapies.