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In patients with advanced HR-positive, HER2-negative breast cancer, the addition of the cyclin-dependent kinase inhibitor ribociclib to letrozole was associated with a significantly higher rate of progression-free survival than placebo. Up to 75% of breast cancers express the estrogen receptor or progesterone receptor (hormone-receptor [HR]–positive). 1 , 2 Endocrine therapy is the standard of care for postmenopausal women with advanced breast cancer that is HR-positive and human epidermal growth factor receptor 2 (HER2)–negative, with aromatase inhibitors being the preferred first-line treatment option. 3 , 4 However, in the majority of patients, resistance to currently available options eventually develops, which requires the administration of sequential therapy with alternative endocrine regimens. 4 – 8 Thus, the identification of effective treatment options that prolong or restore sensitivity to endocrine therapies is important. Cyclin-dependent kinases 4 and 6 (CDK4/6) in . . .

Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1–21·7) in the chemotherapy-alone group and 16·1 months (10·6–22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4–7·2] vs 4·2 months [3·9–4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61–0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. F Hoffmann-La Roche.

BackgroundThe EQ-5D-5L questionnaire is used in oncology to generate health-related quality of life (HRQoL) weights and corresponding health states. The purpose was to explore the relationship between demographic and clinical characteristics and HRQoL among advanced or metastatic colorectal cancer (CRC) patients by linking clinical data of a German CRC registry to self-reported HRQoL measures from the EQ-5D-5L.MethodsThe study sample included patients with advanced or metastatic CRC currently recruited in the German Tumor Registry Colorectal Cancer. The EQ-5D-5L was administered once to patients who were at the start or at later stages of palliative treatment. Data on comorbidities, disease-specific health states, symptoms, and treatment status were drawn from the registry. Multivariate regression analyses were performed to explore the impact of patient and disease characteristics on HRQoL.ResultsIn total, n = 433 questionnaires were included in the data analysis. Mean age of patients was 66.3 years and 61.2% were male. The mean EQ-5D-5L utility score was 0.82 and the mean EQ-5D-5L VAS score was 62.05. The regression analyses revealed that none of the demographic characteristics and few of the clinical characteristics, such as fatigue and pain, had a significant impact on the HRQoL.ConclusionsThe study demonstrated a reduced HRQoL of patients with advanced or metastatic CRC when compared to the general population. The symptoms fatigue and pain negatively affected the HRQoL, whereas other characteristics such as age, gender, and comorbidities did not have a significant impact on HRQoL.

The standard combination of intravenous fluorouracil plus leucovorin for adjuvant treatment of colon cancer was compared with the oral fluoropyrimidine capecitabine in almost 2000 patients with resected colon cancer. With disease-free survival as the primary end point, capecitabine was at least as effective as fluorouracil plus leucovorin. The oral drug had fewer side effects than the intravenous combination. With disease-free survival as the primary end point, capecitabine was at least as effective as fluorouracil plus leucovorin. The oral drug had fewer side effects than the intravenous combination. Almost 1 million patients receive a diagnosis of colorectal cancer yearly, and half a million deaths from this neoplasm occur annually worldwide. 1 Each year, approximately 230,000 patients with colon cancer are eligible for adjuvant chemotherapy. 1 – 3 The benefits of fluorouracil-based adjuvant chemotherapy in reducing the risk of relapse and prolonging survival in patients with resected colon cancer are well established, particularly in stage III disease. 4 – 6 Survival advantages were demonstrated with bolus intravenous fluorouracil plus leucovorin administered according to the Mayo Clinic regimen (five days, monthly, for six months) or the Roswell Park regimen (weekly bolus, six of every eight . . .

Background Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap. Methods INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome. Discussion INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications. Trial registration The study is registered at ClinicalTrials.gov, NCT04389541.

Background Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 −) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients’ satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician–patient interaction. Methods PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 − MBC. All patients ( n  = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). Discussion The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016–004191-22

The efficacy and safety of tivozanib for the treatment of advanced or metastatic renal cell carcinoma (mRCC) have been established in the first-line setting in the Phase III trial TIVO-1. The prospective T-Rex study conducted in German clinical practice evaluated the safety, effectiveness and impact on quality of life (QoL) of first-line treatment with tivozanib in 32 patients with mRCC recruited between May 2019 and April 2021. Recruited patients were predominantly elderly, with 53.1% aged over 75 years. Patients received a median of 6.5 tivozanib treatment cycles and the median time on treatment was 5.7 months. Overall, 78.1% of patients experienced treatment-related adverse events, including diarrhea, nausea and hypotension/hypertension. A clinical (i.e., complete or partial) response was observed in 46.9% of patients. Patients' QoL remained stable from baseline to the end of treatment and most symptomatic toxicities resolved by the final treatment cycle, with the exclusion of dry skin, itching, and hand-foot syndrome. These data demonstrate that first-line treatment with tivozanib was associated with clinical activity, favorable tolerability, and stable QoL in patients with mRCC treated in everyday clinical practice across Germany, including those with advanced age.

The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor‐positive (HR+), HER2‐negative advanced breast cancer patients after failure of prior endocrine therapy. In this open‐label, single‐arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100 mg) and tamoxifen (20 mg) once daily on a continuous schedule (28‐day cycle) until progression or unacceptable toxicity. Primary endpoint was overall 6‐month progression‐free survival (PFS) rate. Key secondary endpoints included the 6‐month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety. Overall, the 6‐month PFS rate was 33.3% (n/N = 7/21, one‐sided 95% CI 16.8‐100) and median PFS was 6.1 (CI 2.6‐10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA‐mutated subgroup consistently showed the highest 6‐month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk‐benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR+ breast cancer. Further biomarker‐stratified studies with isoform‐specific PI3K inhibitors are warranted. EudraCT No: 2014‐000599‐24. This phase II study evaluated the efficacy and safety of buparlisib plus tamoxifen in pretreated patients with advanced HR+/HER2− breast cancer, stratified for PIK3CA mutations and/or loss of PTEN expression in tumor tissue and circulating blood DNA. A signal for higher buparlisib/tamoxifen activity in patients with PIK3CA‐mutated tumors was obtained. Our findings support the value of somatic PIK3CA mutations as predictive biomarker for PI3K‐targeting therapies combined with antihormonal treatment in metastatic HR+ breast cancer.

Several randomized trials investigating the preferable first-line combination chemotherapy regimen for metastatic colorectal cancer have shown inconsistent findings. Because a substantial number of patients are still being treated with \"chemo-only\" first-line therapies without targeted agents, we compared overall survival (OS) of patients treated in routine practice with oxaliplatin-fluoropyrimidine and irinotecan-fluoropyrimidine. Using the database of the Tumor Registry Colorectal Cancer, we identified 605 patients with metastatic colorectal cancer who received first-line fluoropyrimidine combination chemotherapy with either oxaliplatin (n=430) or irinotecan (n=175). The Tumor Registry Colorectal Cancer is a cohort study that prospectively documents treatment of colorectal cancer by office-based medical oncologists in Germany and has recruited over 5,000 patients. OS was estimated using the Kaplan-Meier method, and a multivariate Cox proportional hazard model was used to adjust for potentially confounding variables. Median OS was 26.8 (95% confidence interval [CI] 22.4-31.9) months with an oxaliplatin-fluoropyrimidine combination and 18.3 (95% CI 15.1-23.2) months with irinotecan-fluoropyrimidine first-line \"chemo-only\" therapy. Median progression-free survival was 9.0 (8.1-10.2) and 7.9 (7.2-10.2) months, respectively. The difference in OS was confirmed if analysis was restricted to patients with synchronous metastases (no prior treatment). Among other variables, proportion of patients receiving any second-line therapy did not differ between groups. Oxaliplatin-based first-line therapy was associated with improved OS in multivariate analysis adjusted for potentially confounding variables (hazard ratio 0.678, 95% CI 0.510-0.901, P=0.007). In clinical routine practice, first-line treatment with oxaliplatin-fluoropyrimidine combination chemotherapy compared to irinotecan-fluoropyrimidine combination is associated with improved survival in patients with metastatic colorectal cancer, independent of all examined potentially confounding factors.

PurposeMany studies on cancer patients investigate the impact of treatment on health-related quality of life (QoL). Typically, QoL is measured longitudinally, at baseline and at predefined timepoints thereafter. The question is whether, at a given timepoint, patients who return their questionnaire (available cases, AC) have a different QoL than those who do not return their questionnaire (non-AC).MethodsWe employed augmented inverse probability weighting (AIPW) to estimate the average QoL of non-AC in two studies on advanced-stage cancer patients. The AIPW estimator assumed data to be missing at random (MAR) and used machine learning (ML)-based methods to estimate answering probabilities of individuals at given timepoints as well as their reported QoL, as a function of auxiliary variables. These auxiliary variables were selected by medical oncologists based on domain expertise. We aggregated results both by timepoint and by time until death and compared AIPW estimates to the AC averages. Additionally, we used a pattern mixture model (PMM) to check sensitivity of our AIPW estimates against violation of the MAR assumption.ResultsOur study included 1927 patients with advanced pancreatic and 797 patients with advanced breast cancer. The AIPW estimate for average QoL of non-AC was below the average QoL of AC when aggregated by timepoint. The difference vanished when aggregated by time until death. PMM estimates were below AIPW estimates.ConclusionsOur results indicate that non-AC have a lower average QoL than AC. However, estimates for QoL of non-AC are subject to unverifiable assumptions about the missingness mechanism.