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HER2-positive (HER2+) breast cancer (BC) affects older women nearly as frequently as younger ones. Many older patients have cardiovascular comorbidity and risk greater toxicity from therapy. Treatment therefore requires careful consideration, especially since trials include few patients over 65 and so provide limited guidance. A multidisciplinary task force of the International Society of Geriatric Oncology conducted a literature review to make specific recommendations. In the absence of impaired left ventricular ejection fraction, older patients with HER2+ advanced or metastatic BC (MBC) should receive HER2-targeted therapy adjusted to their general condition. Although trastuzumab combined with pertuzumab and docetaxel or paclitaxel is recommended first-line in fit patients, taxanes are difficult in vulnerable ones, making a better-tolerated chemotherapy partner highly desirable. Hormonal therapy with anti-HER2 treatment is an alternative with hormone sensitive tumours. T-DM1 is the standard for fit trastuzumab- and taxane-exposed patients. Lapatinib activity differs from trastuzumab and causes more side effects and drug interactions that are at higher risk in older patients. For fit HER2+ early BC (EBC) patients, chemotherapy plus one year trastuzumab is standard, dual blockade being restricted to high risk and fit patients. Although there is a low level of evidence, using trastuzumab alone (omitting chemotherapy) or enhancing its action through multiple blockade of HER2 and/or the oestrogen receptor pathway may suit vulnerable and frail MBC and EBC patients. Introducing adjuvant therapy lasting less than one year or harnessing neoadjuvant exposure to assess tumour sensitivity and adjust potential rescue treatment accordingly are other key approaches for older patients. These would be particularly helpful for less robust patients or in health systems with limited resources but need further evaluation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Napabucasin is a novel oral first-in-class cancer stemness inhibitor. Preclinical and early phase clinical trials showed promising antitumor efficacy signals for napabucasin in a variety of malignancies. In this article, we describe the design and rationale for the now completed BRIGHTER trial, a multicenter, randomized, placebo-controlled, Phase III study designed to determine the efficacy and safety of combining napabucasin with paclitaxel in previously treated patients with advanced gastric and gastroesophageal junction adenocarcinoma (NCT02178956). Patients were randomized in a 1:1 fashion to receive weekly paclitaxel with either napabucasin or placebo. The study failed to achieve its primary end point of overall survival in the intention to treat population. Ongoing analysis of the secondary end points includes progression-free survival, objective response rate, disease control rate, the safety of the combination therapy and evaluation of efficacy in the biomarker-positive subpopulation.

This study evaluates the effects of previously synthesized hydrazinyldiene-chroman-2,4-diones on cell proliferation and apoptosis, cell cycle distribution and migration capacity of MCF-7 breast cancer cells in synergy with doxorubicin. Physicochemical properties of the synthesized compounds were correlated with their structure and activity. Significant cell viability decrease in comparison with the effect of doxorubicin alone and the reference 4-hydroxycoumarin was observed when combination treatment comprising doxorubicin and the title compounds was applied. Synergistic effect with doxorubicin was also observed in down-regulation of phospho-Thr308Akt levels, confirming reduced proliferation and increased apoptosis. Combined treatment increased the percentage of cells arrested at the G2/M stage. Additive inhibition of cell migration was also observed, pointing to the possibility of reducing the risk of metastases. With their solubility profile and log D7.4, all the synthesized compounds follow Lipinski's rule of five for good permeability (absorption) potential.

Background: The use of surgery in patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy is increasing. However, most series do not report on the total cohort of patients undergoing surgical exploration; therefore, this single-center study investigates outcomes among all consecutive patients with LAPC who underwent surgical exploration., Methods: We conducted a retrospective, single-center analysis including all consecutive patients with LAPC (Dutch Pancreatic Cancer Group criteria) who underwent surgical exploration with curative intent (January 2014-June 2023) after induction therapy. Primary outcomes were resection rate and overall survival (OS) from the time of diagnosis., Results: Overall, 127 patients underwent surgical exploration for LAPC, whereby 100 patients (78.7%) underwent resection and 27 patients (21.3%) underwent a non-therapeutic laparotomy due to the extent of vascular involvement (n = 11, 8.7%) or occult metastases (n = 16, 12.6%). The overall in-hospital/30-day mortality rate was 0.8% and major morbidity was 31.3% (in patients after resection: 1.0% and 33.3%, respectively). The overall 90-day mortality rate was 5.5%, which included 3.1% mortality due to disease progression. Resection was associated with longer median OS {29 months (95% confidence interval [CI] 26-43) vs. 17 months (95% CI 11-26); p < 0.001} compared with patients undergoing non-therapeutic laparotomy, with corresponding 5-year OS rates of 28.4% and 7.7%. In Cox proportional hazard regression analysis, only pancreatic body/tail tumors independently predicted OS (hazard ratio 1.788 [95% CI 1.042-3.068])., Conclusion: This single-center series found a resection rate of 78.7% in patients with LAPC selected for surgical exploration, with a low risk of mortality and morbidity in all explored patients and a 5-year OS rate after resection of 28.4%., (© 2024. The Author(s).)

Background: Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy., Methods: Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned., Discussion: We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials., Trial Registration: This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm).

The available data on rituximab in combination with chemotherapy confirm that the addition of an independently active biological agent to full-dose standard chemotherapy results in higher rates of complete response, lower rates of relapse, prolonged survival, little additional toxicity and no compromise of the dose intensity of standard chemotherapy regardless of age and risk group. Given the strength of these data, the British Committee for Standards in Haematology believes that rituximab should be available for prescription by UK haematologists and oncologists according to its licensed indication in patients with diffuse large B-cell lymphoma until further data are available to confirm or refute these results. We consider that the use of rituximab with chemotherapy in aggressive lymphoma is cost-effective and that failure to support its introduction will be strongly in conflict with professional and patient opinion.

Objective: This retrospective analysis aimed to evaluate the efficacy and adverse reactions of metronomic oral vinorelbine and its combination therapy as second- and later-line regimens for advanced non-small-cell lung cancer (NSCLC)., Methods: NSCLC patients undergoing metronomic oral vinorelbine as second- and later-line regimens in Fujian Cancer Hospital from October 2018 to October 2022 were enrolled, and patients' demographic and clinical characteristics were collected. The efficacy and safety of metronomic oral vinorelbine monotherapy and its combination therapy regimens were compared., Results: Of 57 study subjects, 63.2% received third- and later-line therapy, with median progression-free survival (mPFS) of 4 months, overall response rate (ORR) of 10.5%, and disease control rate (DCR) of 80.7%. The incidence of therapy-related adverse events was 42.1%, and there was only one case presenting grades 3 and 4 adverse events (1.8%). Among driver gene-negative participants, vinorelbine combination therapy regimens achieved longer mPFS (4.6 vs. 1.2 months, hazards ratio = 0.11, P < 0.0001) and comparable toxicity in relative to metronomic oral vinorelbine, and metronomic oral vinorelbine combined with immune checkpoint inhibitors showed the highest response, with mPFS of 5.6 months (95% CI 4.8 to 6.4 months), ORR of 25%, and DCR of 81.3%. Among participants with gradual resistance to osimertinib, continuing osimertinib in combination with metronomic oral vinorelbine achieved mPFS of 6.3 months (95% CI 0.1 to 12.5 months) and DCR of 86.7%., Conclusion: Metronomic oral vinorelbine and its combination therapy regimens are favorable options as second- and later-line therapy for advanced NSCLC patients, with acceptable efficacy and tolerable toxicity. Vinorelbine combination therapy regimens show higher efficacy and comparable toxicity in relative to metronomic oral vinorelbine, and metronomic oral vinorelbine may have a synergistic effect with immunotherapy and EGFR-TKI targeted therapy., Competing Interests: Declarations Conflict of interests The authors have no conflict of interests., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Isolated limb infusion (ILI) treats unresectable extremity malignancies with high-dose regional chemotherapy limited to the limb. This study assessed long-term outcomes after ILI for limb-threatening sarcomas., Methods: A retrospective review analyzed patients with an extremity sarcoma who underwent ILI with melphalan and dactinomycin from 2008 to 2023 at a single institution., Results: The study identified 61 patients (52.5% female; median age, 73 years; range, 20-94 years). Of these patients, 68.9% had lower-extremity disease. The median follow-up period was 6.9 years. The overall response rate was 48.3% (complete response [CR], 21.7%; partial response [PR], 26.7%), and the disease control rate (DCR: CR + PR + stable disease [SD]) was 65%. The median progression-free survival (PFS) for the patients with CR/PR/SD/progressive disease (PD) was respectively 16.8/9.6/4.8/2.4 months (P < 0.0001). The responders (CR + PR) had significantly longer PFS than the non-responders (SD + PD) (hazard ratio [HR], 6.3; 95% confidence interval [CI], 3.1-12.9; P < 0.001). The median in-field PFS times for CR/PR/SD/PD were respectively 16.8/12/4.8/2.4 months (P < 0.001). The responders had a significantly longer risk of in-field PFS than the non-responders (HR, 5.9; 95% CI 2.9-12.0; P < 0.001). The median distant relapse PFS for CR/PR/SD/PD was not reached (NR)/NR/44.4/40.8 months (P = 0.02). The responders had a significantly longer distant relapse PFS than the non-responders (HR, 2.7; range, 1.1-6.8; P = 0.04). The median overall survival (OS) was 8.6 years for the responders and 4.1 years for the non-responders (P = 0.02). The disease-specific survival (DSS) rates were 87% at 1 year, 71% at 3 years, and 64% at 5 years. The median DSS was not reached for the responders and was 4.1 years for the non-responders (P = 0.003). The limb salvage rates at 6 months were 85% at 1 year, 80% at 3 years, and 70% at 5 years. The patients with PD had a higher risk of requiring amputation than the patients with CR + PR + SD (HR, 3.0; 95% CI 1.0-8.7; P = 0.04)., Conclusions: The 5-year limb salvage rates after ILI are notably high, reaching 70%. After ILI, the responders had significantly better in-field and distant relapse PFS, OS, and DSS., (© 2024. Society of Surgical Oncology.)

While there are many proposed clinical prediction models for diffuse large B-cell lymphoma, like the International Prognostic Index (IPI), revised IPI and the National Comprehensive Cancer Network IPI, there is no widely used model for older patients. A recent study proposed a Geriatric Prognostic Index (GPI) validated in a Norwegian cohort, using independent predictors involving demographic, biochemical and functional parameters. This study aims to validate the GPI in an Asian cohort and simplify the GPI for ease of clinical application. Older patients (age ≥ 70) treated with R-CHOP-like regimens were identified through the Singapore Lymphoma Study. In a retrospective Asian cohort comprising 268 patients, a simplified GPI (sGPI) was created using variables of predictive significance advanced age > 80 years, Eastern Cooperative Oncology Group performance score ≥ 2, serum lactate dehydrogenase level > 3-times upper limit of normal, and stage 3-4, stratifying patients into Low (0), Intermediate (1-2) and High risk (3-4). Cox regression analysis demonstrated a statistically significant difference between risk groups in terms of overall survival (p < 0.00010), with hazard ratios of 1.50 (95% CI: 0.93-2.42), and 4.86 (95% CI: 1.63-14.48), for intermediate and high-risk groups respectively, when compared to the low-risk group. Similar findings were noted for progression free survival (p = 0.00010), with hazard ratios of 1.49 (95% CI: 0.93-2.39) and 4.92 (95% CI: 1.64-14.77) for intermediate and high-risk groups respectively. The sGPI was found to have a C-index of 0.65 (95% CI: 0.60-0.70), which was superior to existing models. In conclusion, we have validated the GPI in an Asian cohort. The sGPI demonstrates good predictive value in an Asian cohort as compared to existing prognostic models., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment 1-7 . Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting 8 . All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74-1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients., Competing Interests: Competing interests: G.S.S. reports institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen; and consultancy for Biovica, Novartis and Seagen. H.M.B. received grants from CADTH, ZIN and Medical Delta; and participated in a data safety monitoring board or advisory board for Pfizer. A.H.H. received consulting fees from Gilead and Lilly; and received payment or honoraria from Lilly. Q.C.v.R.-S. has participated in a data safety monitoring board or advisory board for Roche. I.R.K. reports institutional research grant support from Novartis and Gilead. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma., Methods: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology., Results: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function., Conclusions: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient., Clinical Trial Registration: NCT00047138., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m 2 , non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC., Methods: Retrospective analysis of single-institution data., Results: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease., Conclusions: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained., (© 2024. The Author(s).)

Purpose: Atezolizumab/bevacizumab (atezo-bev) is the first-line chemotherapy for patients with unresectable hepatocellular carcinoma (HCC). However, hepatic artery infusion chemotherapy (HAIC) can be used as an alternative. Our aim was to compare the prognosis of HAIC treatment between newly diagnosed patients and patients treated after failure of atezo-bev., Methods: We retrospectively assessed 73 patients with HCC treated with HAIC between January 2022 and September 2023. Fifty-seven patients were treated with HAIC at initial diagnosis, while 16 were treated with HAIC after first-line atezo-bev combination chemotherapy. We evaluated tumor responses, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR)., Results: No significant difference was observed in either OS or PFS between patients with HCC treated with HAIC at the initial diagnosis and those treated after atezo-bev treatment failure. However, the ORR of the initial HAIC group was 19.6% and that of the HAIC group after atezo-bev therapy failure was 43.6%, which was a statistically significantly difference., Conclusion: Although no significant difference was observed for OS and PFS, the ORR of patients in the HAIC group after the failure of atezo-bev therapy was superior to that of newly diagnosed patients. HAIC may prolong survival in patients with HCC after atezo-bev treatment failure., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Health-related quality of life (HRQoL) data are important indicators of health status in patients with lymphoma. The objective of this analysis was to assess the impact of treatment with Sandoz rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on HRQoL in treatment-naïve adult patients with diffuse large B-cell lymphoma (DLBCL) included in the prospective, real-world REFLECT study. REFLECT is the first prospective study to assess HRQoL in patients with DLBCL treated with a rituximab biosimilar. HRQoL was assessed via the patient-reported European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire at baseline, mid-treatment (month 3), end of treatment (month 6), and follow-up (months 9 and 12). Subgroup analyses were performed to evaluate the influence of baseline characteristics on HRQoL, and associations between baseline HRQoL and treatment response. HRQoL was assessed in 169 patients. Mean global health status score remained stable from baseline (54.8) to mid-treatment (month 3; 54.7), before steadily improving through to end of treatment (month 6; 61.4), and follow-up month 9 (64.9) and month 12 (68.8). Similar trends were observed across most functional and symptom subscales. Higher cognitive, physical, or role functioning, and less appetite loss, diarrhea, fatigue, or pain at baseline, were all associated with an improved likelihood of reaching a complete versus partial response at the end of treatment. Overall, these findings confirm the HRQoL benefits of R-CHOP therapy in treatment-naïve adult patients with DLBCL, and suggest that baseline HRQoL may be predictive of treatment response., (© 2024. The Author(s).)

Background: The improved outcome of childhood acute lymphoblastic leukemia (ALL) over the last decades has increased the importance of assessing late effects and health-related quality of life (HRQoL), particularly when evaluating and comparing outcomes in clinical trials. This study aimed to assess HRQoL in children treated for ALL according to the NOPHO ALL2008 protocol., Procedure: Children, aged 1 to less than 18 years at diagnosis, alive in first remission, and their parents, were asked to complete PedsQL 4.0 Generic Core Scales (self- and proxy-report) at ≥6 months after end of therapy. Data on socioeconomic factors and parent-reported toxicity were collected through a study-specific questionnaire, and the NOPHO ALL2008 database was used to identify eligible families and add additional disease- and treatment-related data. HRQoL data were collected during 2013-2019 in Sweden, Finland, and Denmark., Results: A total of 299 children were included. The older children (8 years and older) reported similar HRQoL scores compared to Finnish reference data, except lower scores for School Functioning in high-risk patients. Scores from the parent-proxy and self-reports from 5-7-year olds were notably lower than reference. Parent-reported toxicity was associated with lower total and physical HRQoL scores in adjusted models for younger as well as older children in the self-report and parent-proxy versions, and also with lower psychosocial score in the parent-proxy., Conclusions: Self-reported HRQoL was similar to reference population. The most important determinant for HRQoL after end of ALL treatment was parent-reported toxicity during treatment. Thus, minimizing complications is an obvious focus for future treatment protocols., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Thrombosis represents a frequent and potentially severe complication in individuals diagnosed with multiple myeloma (MM). These events can be driven by both the disease as well as the therapies themselves. Overall, available evidence is inconclusive about the differential thrombogenicity of carfilzomib/lenalidomide/dexamethasone (KRd) and bortezomib/lenalidomide/dexamethasone (VRd). This meta-analysis compares the risk for venous thromboembolism (VTE; including deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE; including myocardial infarction and ischemic stroke) with KRd versus VRd as primary therapy for newly diagnosed MM (NDMM). Out of 510 studies identified after deduplication, one randomized controlled trial and five retrospective cohort studies were included. We analyzed 2304 patients (VRd: 1380; KRd: 924) for VTE events and 2179 patients (VRd: 1316; KRd: 863) for ATE events. Lower rates of VTE were observed in the VRd group when compared with the KRd group (6.16% vs. 8.87%; odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.88; p = .01). Both treatment groups exhibited minimal ATE incidence, with no significant difference between them (0.91% vs. 1.16%; OR, 1.01; 95% CI, 0.24-4.20; p = .99). In view of potential biases from retrospective studies, heterogeneity of baseline population characteristics, and limited access to patient-level data (e.g., VTE risk stratification and type of thromboprophylaxis regimen used) inherent to this meta-analysis, additional research is warranted to further validate our findings and refine strategies for thrombosis prevention in MM., (© 2024 Wiley Periodicals LLC.)

Objective: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months of induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC)., Background: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking., Methods: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy (±radiotherapy) with CA19-9 ≥5 U/mL at baseline were analyzed (2015-2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed using COX regression analysis., Results: Overall, 212 patients were included, of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant median OS difference (12.7 vs. 19.6 months) was seen at ≥40% CA19-9 decrease. The optimal cutoff for CA19-9 response was ≥60% decrease (21.7 vs. 14.0 mo, P =0.021). Only for patients with elevated CA19-9 levels at baseline (n=184), CA19-9 decrease ≥60% [hazard ratio (HR)=0.59, 95% CI, 0.36-0.98, P =0.042] was independently associated with prolonged OS, as were SBRT (HR=0.42, 95% CI, 0.25-0.70; P =0.001), and resection (HR=0.25, 95% CI, 0.14-0.46, P <0.001), and duration of chemotherapy (HR=0.75, 95% CI, 0.69-0.82, P <0.001)., Conclusions: CA19-9 decrease of ≥60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, ≥40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Survival for patients following relapse remains poor, and achieving complete remission (CR) after relapse is the first critical step to cure. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been assessed in children. The primary objective of this phase 1b study was to assess the safety and tolerability of carfilzomib combined with vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) in children with relapsed and/or refractory ALL., Methods: Patients aged 1-21 years (n = 24) received 4-week induction therapy with carfilzomib at dose levels of 27 mg/m 2 (n = 3), 36 mg/m 2 (n = 7), 45 mg/m 2 (n = 4), and 56 mg/m 2 (n = 10) in combination with VXLD. Patients achieving stable disease were offered further consolidation chemotherapy. Analyses were based on the safety evaluable population., Results: Following dose escalation of carfilzomib, the recommended phase 2 carfilzomib dose was identified as 56 mg/m 2 . Grade ≥3 hematological adverse events were common (83%, 20/24 patients), and serious treatment-emergent adverse events occurred in 58% (14/24) of patients. At the end of induction, CR/CR with incomplete platelet recovery (CRp)/CR with incomplete blood count recovery (CRi) was identified in 50% of patients (n = 12/24). By the end of consolidation, cumulative CR/CRp/CRi was identified in 58% of patients (n = 14/24)., Conclusion: These data support the use of carfilzomib in pediatric patients with relapsed and/or refractory ALL., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Purpose: Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600 mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients., Methods: BRAFV600 mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC 0-τ and C trough ) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed., Results: Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib C trough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE., Conclusion: In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600 mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The clinical management of older adult patients with Hodgkin lymphoma (HL) remains a major challenge. The aim of this study was to evaluate the impact of comorbidity assessment according to a standardized approach, the Cumulative Illness Rating Scale (CIRS), on prognosis in patients with classical HL aged 60 years and older. We studied 76 consecutive older adult patients with HL (median age 69 y, range 60-84) who had been treated in our institution between 1999 and 2018. Comorbidity was assessed at diagnosis according to CIRS. Anthracycline-containing chemotherapy with curative intent was administered in 59 (78%) patients. We identified 41 (54%) patients with at least one severe comorbidity rated on CIRS grade ≥ 3. Patients with severe comorbidity were more likely to have advanced-stage disease (P = .003), to have an International Prognostic Score (IPS) > 3 (P = .03), and to not receive anthracycline-containing chemotherapy (P = .008). The probability of overall survival (OS) at 3 years was 88% (95% CI, 71%-95%) in patients without severe comorbidities, while it was only 46% (95% CI, 29%-62%) in patients with a comorbidity CIRS grade ≥ 3 (P = .0001). The impact of comorbidity on prognosis was also evident when restricting the analysis to patients treated with anthracycline-containing therapy. The 3-year OS was 93% (95% CI, 76%-98%) (P = .004) in patients without severe comorbidity and 72% (95% CI, 47%-87%) in patients with severe comorbidity (P = .004). In a multivariate analysis, presence of comorbidity, but not age, was a significant factor for OS. Therefore, we conclude that a significant proportion of older adult patients with HL has severe comorbidity on the CIRS scale, which impacts more importantly than age on prognosis., (© 2020 John Wiley & Sons Ltd.)

Aim: The aims of this study were to assess survival outcome of pediatric patients with localized osteosarcoma of the extremities in Upper Egypt, identify factors of prognostic significance for survival, and to determine factors predictive of surgical methods used in these patients, as well as developing a clinical model for risk prediction., Patients and Methods: A retrospective analysis of data assembled from medical records of 30 pediatric patients with a histologically verified nonmetastatic osteosarcoma of the extremities treated at South Egypt Cancer Institute with a unified chemotherapy protocol between January 2001 and December 2015 was carried out. Prognostic factors were determined using univariable and multivariable methods. A model for surgical outcomes in these patients based on the baseline clinical factors, and the parameters predictive of their tumor response to chemotherapy, was developed., Results: With a median follow-up of 63 months for the study population, the estimates for event-free survival and overall survival (OS) at 3 and 5 years were 69.5% and 79% and 65.2% and 65.3%, respectively. Age 16 years or above was independently associated with both worse metastasis-free survival (hazard ratio [HR]=6.05, 95% confidence interval [CI]: 1.43-25.6, P=0.015) and OS (HR=7.9, 95% CI: 1.71-36.2, P=0.008). In the multivariable analysis, a proximal location within the limb gained a statistical significance to be independently associated with worse OS (HR=2.4, 95% CI: 1.13-22.1, P=0.003). Poor response to chemotherapy was marginally associated with worse metastasis-free survival (HR=4.9, 95% CI: 1.02-23.8, P=0.047) only in the univariable analysis. The patients found to be more likely to undergo an amputation surgery (odds ratio=14.1, 95% CI: 1.34-149.4, P=0.028) were those in whom a tumor was poorly responding to chemotherapy., Conclusion: In Upper Egypt, despite the reasonable survival outcomes in nonmetastatic osteosarcoma, a relatively high limb amputation rate has been encountered. The development of a clinical prediction model for future planning of possible outcome improvement in these patients, however, is still feasible.

Aims and Objectives: To examine and compare the differences in symptoms and symptom clusters between postmenopausal women with early-stage breast cancer who did and did not receive chemotherapy prior to aromatase inhibitor (AI) therapy., Background: Women with breast cancer often experience multiple concurrent symptoms during AI therapy. The burden of symptoms prior to AI is associated with nonadherence to cancer treatment. To date, few studies have comprehensively explored the symptoms and symptom clusters occurring prior to AI therapy., Design: Secondary analysis of a prospective repeated-measures study., Methods: The sample comprised postmenopausal women (N = 339) with breast cancer who would receive AI therapy with or without chemotherapy. We collected information on 48 symptoms after surgery or chemotherapy but before AI therapy using different symptom assessment tools. Mann-Whitney U tests were used to compare the differences in the severity of symptoms between groups. Exploratory factor analysis (EFA) was conducted to determine symptom clusters. This study followed STROBE guidelines., Results: The most severe symptoms among women with breast cancer prior to AI therapy were breast sensitivity, unhappy with the appearance of my body, general aches and pain, joint pain and muscle stiffness. Women who received chemotherapy prior to AI therapy experienced significantly higher severity of 22 symptoms than women who did not receive chemotherapy. Through EFA seven distinct symptom clusters were revealed in both groups: cognitive, musculoskeletal, psychological, vasomotor, weight, sexual and urinary, with additional gastrointestinal symptom cluster been identified in women who received chemotherapy., Conclusions: This study indicates the presence of symptoms among women with breast cancer prior to AI therapy, with higher severity of symptoms and greater number of symptom clusters for women who received chemotherapy., Relevance to Clinical Practice: Nurses should assess and be aware of symptoms and symptom clusters existed prior to AI therapy and manage them in advance., (© 2019 John Wiley & Sons Ltd.)

Objective: To examine risk of emergency hospital admission and survival following adjuvant chemotherapy for early breast cancer., Methods: Linked data from New South Wales population-based and clinical cancer registries (2008-2012), hospital admissions, official death records and pharmaceutical benefit claims. Women aged ≥18 years receiving adjuvant chemotherapy for early-stage operable breast cancer in NSW public hospitals were included. Odds ratios (OR) for emergency hospitalisation within 6 months following chemotherapy initiation were estimated using logistic regression and survival using Kaplan-Meier and Cox proportional hazards methods., Results: A total of 3,950 women were included and 30.6% were hospitalised. The most common principal diagnosis at admission was neutropenia (30.8%). Women receiving docetaxel/carboplatin/trastuzumab (TCH) and docetaxel/cyclophosphamide (TC) were the most frequently hospitalised. After adjustment for demographic and clinical factors, the increased risk of hospitalisation for TCH and TC remained compared with doxorubicin/cyclophosphamide 3-weekly (OR 1.71, 95% confidence interval [CI] 1.24-2.37 and OR 1.47, 95% CI 1.17-1.85 respectively). Five-year overall survival was similar for women who were (92.2%, 95% CI 90.7-93.8) and were not hospitalised (93.1%, 95% CI 92.1-94.1)., Conclusion: Emergency hospitalisations following chemotherapy for early breast cancer were relatively common, especially following docetaxel-containing protocols. Further examination of reasons for admission is needed to inform actions to improve patient safety., (© 2019 John Wiley & Sons Ltd.)

The incidence of systemic diffuse large B cell lymphoma (DLBCL) concurrently involving the central nervous system (CNS) at diagnosis, is very low and data regarding the clinical course of these patients are scarce. We investigated characteristics, efficacy of treatment regimens including consolidative autologous stem cell transplantation and outcome of patients presenting with concomitant systemic and CNS DLBCL. The records of 44 patients, diagnosed between 2004 and 2017, who fulfilled the inclusion criteria, were retrospectively reviewed. CNS involvement was diagnosed as solely parenchymal in 41%, solely leptomeningeal in 43%, and paranchymal with leptomeningeal in 11% of the patients. Induction regimens were anthracycline-based combined with high-dose methotrexate (HD-MTX) in 80% (n = 35) of patients, anthracycline-based combined with intrathecal MTX in 3, cytarabine-based (without antracyclines) in 2, HD-MTX in 1 and palliative in three. Five of 41 patients treated with chemotherapy died of treatment-related toxicity, all due to infections. Nineteen patients had consolidative autologous transplantation. Overall response rate following induction was 80% (complete responses 66% and partial responses 15%). All relapses (n = 11) occurred within less than 2 years. Within a median follow-up of 26.8 months, 3-years projected overall survival (OS) and progression free survival rates for the entire cohort were 56% ± 8.3 and 42% ± 8.9, respectively. In multivariate analysis, RCHOP-HD MTX-based induction [HR = 0.228, (0.054-0.964)], administration of 3.5 g/m 2 MTX [HR = 0.735 (0.620-0.871)], and attaining CR following induction [HR = 0.185, (0.051-0.667)] predicted longer OS. RCHOP-HD MTX can provide prolonged remissions in DLBCL patients presenting with concomitant systemic and CNS involvement whereas role of autograft remains uncertain., (© 2019 Wiley Periodicals, Inc.)

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFR i s) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFR i afatinib (Giotrif®) is being evaluated in a multicentric Phase II trial. As tyrosine kinase inhibitor (TKI) monotherapies are invariably followed by resistance, we aimed to evaluate potential therapeutic combinations with EGFR i s., Methods: We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFR i s (afatinib and erlotinib) in the clival chordoma cell line UM-Chor1. Synergistic combinations were analysed in a 7 × 7 matrix format. The most promising combination was further explored in clival (UM-Chor1, MUG-CC1) and sacral (MUG-Chor1, U-CH1) chordoma cell lines. Secretomes were analysed for receptor tyrosine kinase ligands (EGF, TGF-α, FGF-2 and VEGF-A) upon drug treatment., Results: Drugs that were active as single agents (n = 45) included TKIs, HDAC and proteasome inhibitors, and cytostatic drugs. Six combinations were analysed in a matrix format: n = 4 resulted in a significantly increased cell killing (crizotinib, dabrafenib, panobinostat and doxorubicin), and n = 2 exhibited no or negligible effects (regorafenib, venetoclax). Clival chordoma cell lines were more responsive to combined EGFR-MET inhibition. EGFR-MET cross-talk (e.g. via TGF-α secretion) likely accounts for the synergistic effects of EGFR-MET inhibition., Conclusion: Our screen revealed promising combinations with EGFR i s, such as the ALK/MET-inhibitor crizotinib, the HDAC-inhibitor panobinostat or the topoisomerase-II-inhibitor doxorubicin, which are part of standard chemotherapy regimens for various bone and soft-tissue sarcomas., (© 2021. The Author(s).)

Purpose: Febrile neutropenia (FN) incidence during docetaxel and cyclophosphamide (TC) chemotherapy, known as a high-risk regimen, differs among countries. The role of prophylactic granulocyte colony-stimulating factor (G-CSF) in FN is unclear. This study aimed to investigate FN frequency and relative dose intensity (RDI) of TC chemotherapy in patients with breast cancer and identify the correct population requiring prophylactic G-CSF., Methods: In total, 205 patients with breast cancer were scheduled for TC chemotherapy (docetaxel/cyclophosphamide 75/600 mg/m 2 , every 3 weeks, 4 cycles) as adjuvant chemotherapy. Trastuzumab (8 mg/kg; continued with 6 mg/kg) was administrated intravenously for human epidermal growth factor receptor 2 (HER2)-positive cancer. Fifty-five patients received primary prophylactic measures (G-CSF: 20 and antibiotics: 35). We investigated the frequency of FN and hospitalization, RDI, and the factors related to FN, adverse events, hospitalization, and RDI., Results: FN occurred in 70 patients (35.7%). FN incidence was noted in 41.1% without any prophylactic measures and in 5.0% with prophylactic G-CSF. In multivariate analysis, the independent risk factors of FN were older age (≥ 60 years, P = 0.017) and without primary prophylactic G-CSF (P = 0.011). Eleven patients (5.6%) were hospitalized of which 8 (72.7%) were elderly. The median RDIs of docetaxel and cyclophosphamide were 96.7% and 99.7%, respectively., Conclusion: FN frequency during TC chemotherapy was high, and primary prophylactic G-CSF reduced FN incidence. Primary prophylactic G-CSF is an effective therapy for preventing FN during TC chemotherapy. However, prophylactic G-CSF should be considered for elderly patients based on the low hospitalization rate and the high RDI.

Over the past decade, several drugs have been approved for the treatment of relapsed or refractory multiple myeloma (RRMM). This retrospective study, using the French National Healthcare database (SNDS), describes the treatment patterns and outcomes of patients with RRMM treated in real-world clinical practice in France. Patients were adults, with a diagnosis of multiple myeloma, who initiated second-line (2L) treatment approved for use in France between 2014 and 2018; this included bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide, or pomalidomide. Data were analyzed overall, by first-line (1L) autologous stem cell transplant (ASCT) status and by lenalidomide treatment status at 2L. In total, 12987 patients with RRMM were included in the study (mean age 69.5 years); 27% received an ASCT at 1L, and 30% received a lenalidomide-sparing regimen at 2L. Overall, and among the ASCT and non-ASCT subgroups, most patients received a bortezomib-based regimen at 1L, whereas lenalidomide-based regimens were most common at 2L. Among patients who received a lenalidomide-sparing regimen at 2L, this was most often a proteasome inhibitor-based regimen. Mortality rate was 26.1/100 person-years, and median (95% confidence interval) survival from 2L initiation was 32.4 (31.2-33.6) months. Survival differed by various factors, shorter survival was reported in the non-ASCT group, those receiving a lenalidomide-sparing regimen at 2L, older patients (≥ 70 years), and those with multiple comorbidities. This analysis provides insight into the real-world use of approved novel MM treatments and highlights an ongoing unmet need to improve outcomes, particularly for selected patient groups.