Pancreatic cancer is a highly lethal malignancy. Developments in recent years have broadened our therapeutic armamentarium. Novel drugs such as nab‐paclitaxel, liposomal irinotecan and chemotherapy ...regimens such as FOLFIRINOX have been successfully tested in clinical trials. Data on patients outside of clinical trials are scarce but necessary to assess and improve the standard of care. We present data on treatment and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. Between February 2014 and June 2017, patients were recruited by 104 sites at start of first‐line therapy into the ongoing, prospective clinical cohort study TPK (Tumour Registry Pancreatic Cancer). As first‐line therapy, 89% of patients received one of the three treatment regimens: gemcitabine monotherapy (23%), nab‐paclitaxel plus gemcitabine (42%), or FOLFIRINOX (24%). The corresponding subgroups differed: Patients receiving gemcitabine monotherapy were older and more comorbid (median age 78 years, 73% ECOG ≥ 1) than patients receiving nab‐paclitaxel plus gemcitabine (median age 71, 64% ECOG ≥ 1) or patients receiving FOLFIRINOX (median age 60, 52% ECOG ≥ 1). At least 40% of patients died before receiving second‐line treatment. First‐line progression‐free survival was 4.6 months (95% CI: 3.7–5.2) for gemcitabine, 5.6 months (95% CI: 5.0–6.2) for nab‐paclitaxel plus gemcitabine, and 6.3 months (95% CI: 5.5–6.9) for FOLFIRINOX. Our data represent the treatment reality in a German community setting. Although there are no stringent inclusion criteria for our cohort study, overall survival is comparable to that reported by randomised clinical trials.
What's new?
More than four‐fifths of patients with pancreatic cancer present with locally advanced, inoperable (LAPC) or metastatic (MPC) disease at diagnosis. Beyond clinical trials, relatively little data is available on survival outcomes for these patients. Here, real‐world data, derived from an unselected cohort of 1,174 patients enrolled between 2014 and 2017 in a prospective study in Germany, show that the vast majority of first‐line therapies given to LAPC/MPC patients consisted of either gemcitabine monotherapy, nab‐paclitaxel plus gemcitabine, or FOLFIRINOX. About 40 percent of the patients received second‐line therapy. Overall cohort survival was comparable to that reported for randomized clinical trials.
According to the seminal theory by Sternling and Scriven 1, solutal Marangoni convection during mass transfer of surface-active solutes may occur as either oscillatory or stationary instability. With ...strong support of Manuel G. Velarde, a combined initiative of experimental works, in particular to mention those of Linde, Wierschem and coworkers, and theory has enabled a classification of dominant wave types of the oscillatory mode and their interactions. In this way a rather comprehensive understanding of the nonlinear evolution of the oscillatory instability could be achieved. A comparably advanced state-of-the-art with respect to the stationary counterpart seemed to be out of reach a short time ago. Recent developments on both the numerical and experimental side, in combination with assessing an extensive number of older experiments, now allow one to draw a more unified picture. By reviewing these works, we show that three main building blocks exist during the nonlinear evolution: roll cells, relaxation oscillations and relaxation oscillations waves. What is frequently called interfacial turbulence results from the interaction between these partly coexisting basic patterns which may additionally occur in different hierarchy levels. The second focus of this review lies on the practical importance of such convection patterns concerning their influence on mass transfer characteristics. Particular attention is paid here to the interaction between Marangoni and buoyancy effects which frequently complicates the pattern formation even more. To shed more light on these dependencies, new simulations regarding the limiting case of stabilizing density stratification and vanishing buoyancy are incorporated.
Hierarchical Marangoni cell pattern showing simulated interfacial butanol concentration during mass transfer from cyclohexanol to water Display omitted
•New unified picture for pattern evolution in solutal Marangoni instability•Three basic patterns: cells, relaxation oscillations, relaxation oscillation waves•Different hierarchy levels and periodic decay and re-amplification of patterns•Computation of mass transfer characteristics in terms of transient Sherwood numbers Sh•Prediction of Sh via scaling relations due to self-similarity of Marangoni patterns
Abstract There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head‐to‐head phase III randomised trials are missing. We assess real‐world ...effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX ( n = 613) or gemcitabine/nab‐paclitaxel (GEMNAB; n = 938) as palliative first‐line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health‐related quality of life (HRQoL) between three common first‐ to second‐line treatment sequences, adjusting for time‐varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5‐fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 8.9, 11.9 and 6.4 4.8, 7.7 months for FOLFIRINOX→GEMNAB, 8.4 7.4, 9.7 and 5.8 4.6, 7.1 months for GEMNAB→FOLFOX/OFF and 8.9 7.8, 10.4 and 4.6 4.1, 6.1 months for GEMNAB→NALIRI+5‐fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor‐risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 1.47, 2.98; TTD: HR 1.97 1.19, 3.27) and those with GEMNAB→NALIRI+5‐fluorouracil (OS: HR 1.35, 0.76, 2.39; TTD: HR 2.62 1.56, 4.42). Brackets denote 95%‐confidence intervals. The estimated real‐world effectiveness of the three treatment sequences evaluated were largely comparable. Poor‐risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient‐reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.
Introduction: Targeted agents, in particular BCL2-inhibitors (BCL2i) and BTK-inhibitors (BTKi), have profoundly improved the outcome of patients (pts) with chronic lymphocytic leukemia (CLL) and are ...considered standard treatment. However, the transition from treatments evaluated within clinical trials into routine clinical practice can be complex. We here present real-world data from the German CLL Study Group (GCLLSG) registry and report outcomes and treatment sequences of pts treated with either BCL2i (venetoclax) or BTKi (acalabrutinib, ibrutinib, spebrutinib, tirabrutinib, or zanubrutinib) as first administered targeted agent. Methods: Pts from multiple German sites with confirmed diagnosis of CLL and with at least one documented first-line CLL treatment between July 1 st 2014 and January 30 th 2023 were included in this analysis. Pts participating in an active clinical trial were excluded. Treatments were categorized according to the backbone of therapy and pts were allocated to either the venetoclax (Ven) or the BTKi cohort depending on their first treatment with one of these substances. Time to next treatment (TTNT), event-free survival (EFS) and overall survival (OS) were analyzed using Kaplan-Meier methods. Results: A total of 274 pts were treated with a Ven-based regimen while 915 pts were treated with a BTKi as first therapy. Median observation time from the first documented treatment (irrespective if given as first-line or in a later therapy line) was 26 months (range 0 - 296) in the Ven cohort and 78 months (range 0-266) in the BTKi cohort. For the Ven cohort, median age at the time of first Ven treatment was 71 years (range 32 - 87) with 172 pts (62.8%) being male. Median CIRS score was 2 (range 0-13) and 12 pts (7.5%) had an ECOG performance status > 1. Among 57 pts with known molecular genetics, 32 pts (56.1%) had an unmutated IGHV status and 9 out of 51 evaluable pts (17.6%) had a deletion and/or mutation TP53. Applying the CLL-IPI, 11 out of 58 evaluable pts (19.0%) were in the very high-risk group. In the BTKi cohort, median age at time of first BTKi treatment was 72 (range 32 - 92), with 628 pts (68.6%) being male. Median CIRS score was 3 (range 0-17) and 45 pts (9.5%) had an ECOG performance status > 1. Among 162 pts with available data, 108 pts (66.7%) had an unmutated IGHV status and 59 out of 130 evaluable pts (45.4%) had a deletion and/or mutation TP53. Using the CLL-IPI, 46 out of 145 evaluable pts (31.7%) were in the very high-risk group. A total of 152 of 274 pts (55.5%) in the Ven cohort received Ven as first-line treatment (median number of prior treatments: 0, range 0-9) and 352 of 915 pts (38.5%) in the BTKi cohort received a BTKi as first-line treatment (median number of prior treatments: 1, range 0-12). Among all 222 administered treatments prior to first Ven and 1090 treatments administered prior to first BTKi, chemoimmunotherapy (70.3% and 68.3%, respectively) and chemotherapy (10.4% and 17.8%, respectively) were the most frequent. For subsequent therapy following the first documented Ven or BTKi treatment, most pts were treated with targeted agent regimens. In the Ven cohort, 37 subsequent treatments were documented in 26 pts, of which 10 (27.0%) were a Ven-containing regimen and 13 (35.1%) a BTKi-containing regimen. Within the BTKi cohort, 393 subsequent treatments were administered in 264 pts, of which 146 (37.2%) included Ven and 106 (27.0%) a BTKi Treatment sequences were visualized with a sankey-diagram ( Figure 1). Median EFS from the start of the first documented Ven treatment was 31.8 months, with an estimated 2-year EFS rate of 66.6%. Median TTNT was 63.7 months and median OS was 96.5 months with an estimated 2-year OS rate of 89.5%. When Ven was given as first-line treatment, the estimated 2-year OS rate was 93.6% versus 86.5% when given in a later therapy line for the first time. For the BTKi cohort, median EFS from start of first documented BTKi treatment was 23.2 months, with an estimated 2-year EFS rate of 48.6%. Median TTNT was 68.4 months and median OS was 85.9 months with an estimated 2-year OS rate of 84.9%. When BTKi were given as first-line treatment, the estimated 2-year OS rate was 92.3% versus 81.3% when given in a later therapy line for the first time. Conclusion: EFS, TTNT and OS were comparable following Ven versus BTKi-based therapy in pts documented in the GCLLSG registry between 2014 and 2023.
Clinical trials in chronic myeloid leukemia (CML) are usually carried out in specialized centers whereas primary care for patients (pts) with CML is mainly provided by local oncology practices. The ...aim of this study was to assess treatment practices in pts with CML in the setting of private oncology practices in Germany. We collected data of 819 pts with a confirmed diagnosis (dx) of CML in 2013 or later from 43 practices. At dx, 84.2% (
n
=690) and 9.4% (
n
=77) of pts were in chronic or accelerated phase, 0.7% (
n
=6) had a blast crisis. Molecular monitoring was provided by EUTOS certified laboratories in 87.7% of pts. Typical
BCR::ABL1
transcripts were detected in 86.6% (
n
=709). Molecular response was assessed after 2.8, 6.0, 9.4 and 12.9 m (mean) after start of treatment. Of the pts with available data, 11.1% did not achieve early molecular response and at 18 m, 83.7% had at least a major molecular response. 288 (35.2%) of pts switched to 2
nd
line (2L) treatment after a mean of 21.0 months. Reasons for 2L treatment were side effects in 43.4% and suboptimal response or failure in 31.4% of pts. 106 pts went on to third line (3L) treatment. 36.8 % of pts switched to and 92.8 % of pts still on 3L treatment achieved
BCR::ABL1
IS
≤1% at 12 m. In conclusion, in Germany pts with CML are routinely monitored by qPCR and good responses are achieved in the majority. Treatment changes are mainly due to adverse events rather than suboptimal responses.
Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit ...after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at
www.clinicaltrials.gov
as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0–11). Median treatment duration with idelalisib was 5.1 months (range 0–55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included.
Treatment recommendations in chronic lymphocytic leukemia (CLL) are based upon selected, otherwise healthy study populations mostly under 72 years of age. The Project group Internistic Oncology (PIO) ...embarked on an analysis of the 'real-world' safety and efficacy of bendamustine with and without rituximab in unselected outpatients.
A multicenter, open-label, prospectively stratified, retrospective study was conducted to determine routine feasibility, toxicity, and response rates obtained by bendamustine with and without rituximab in a random population of mostly elderly patients with CLL. Records were obtained from 775 patients with CLL from 60 private medical oncology practices. Informed consent was obtained prior to study participation. The median observation time was 28 months. Patients were stratified according to age, and treatment. Response criteria and statistics followed international guidelines adopted by the "German Chronic Lymphocytic Leukemia Study Group".
Overall, 57.5% of patients were over 70 (range=36-95) years old. Eastern Cooperative Oncology Group performance status and age influenced the total dose given, decreasing by 20% between ECOG 0 and 3, and by 15% above 80 years old. Response rates did not differ between the ages of 60 to 80 years, with an overall remission rate for bendamustine of 83%, and for the combination therapy of 89%, decreasing above the age of 80 years. Febrile neutropenia occurred in 25% of 775 patients, and grade 3 or 4 non-hematological adverse events in 9.55% (n=74), not interfering with the treatment.
Bendamustine with and without rituximab was associated with high activity and tolerability, irrespective of age and risk factors. The median overall survival was 64 months with a 3-year survival rate of 72%; progression-free survival was 30.6 months, and the 3 year PFS was 43%. The good tolerability and feasibility of bendamustine with and without rituximab, in particular for the elderly population with CLL argues for it being a safe outpatient treatment.
Long‐term data of chronic lymphocytic leukemia (CLL) patients with favorable risk who were treated with fludarabine, cyclophosphamide, and rituximab (FCR) within clinical trials show good efficacy. ...We here report long‐term data collected within the GCLLSG registry. Altogether, 417 CLL patients who received first‐line treatment with FCR were analyzed, of which 293 (70.3%) were treated outside of clinical trials. The median observation time from first‐line was 95.8 (interquartile range 58.7–126.8) months. Focusing on data of 194 (46.5%) patients who received FCR first‐line treatment after 2013 (start of data collection within GCLLSG registry), responses were documented in 85% of the patients, non‐responses in 15%, and for 3.6% the assessment was missing. Median event‐free survival (EFS, time until disease progression, subsequent treatment, or death) was 60.2 months with a 5‐year EFS‐rate of 50.6%. Patients with higher‐risk disease, characterized by unmutated IGHV (N = 78), had a median EFS of 45.4 months with a 5‐year EFS rate of 36.3%, while the median EFS was 77.5 months with a 5‐year EFS rate of 60.3% in patients with mutated IGHV (N = 40). Median overall survival was not reached with a 5‐year survival rate of 92.7%. In summary, first‐line FCR was associated with long EFS, especially in patients exhibiting a mutated IGHV status.
PDF
