Difference In Progression-free Survival Research Articles

Survival outcomes of endometrial cancer patients with disease involving the lower uterine segment: A meta-analysis.

Lower uterine segment (LUS) involvement is encountered in a small proportion of endometrial cancer patients and is associated with aggressive histological features. Despite the available evidence, there seems to be a lack of consensus concerning its actual impact on disease related survival. The search strategy involved the Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases. Nine studies were included in the present systematic review that recruited 3300 patients. Pooled hazard ratios (HR) were retrieved from Cox-regression analyses to limit the confounding effect of other factors that influence the course of the disease. Nine articles were included in the present meta-analysis that involved 3300 endometrial cancer patients. The meta-analysis revealed a significant difference in progression free survival that was found increased in patients without LUS involvement (HR 1.59, 95% CI 1.22, 2.05, data from 9 studies). Similarly, a significantly smaller overall survival was observed among patients with LUS involvement (HR 1.69, 95% CI, 1.34, 2.13, data from 7 studies). Sensitivity analysis revealed that there were no outliers in either outcome, however, the possibility of data manipulation could not be ruled out entirely. The results of this meta-analysis indicate that lower uterine segment involvement is associated with decreased survival outcomes. It remains unclear if these patients can benefit from adjuvant treatment in the absence of other negative prognostic indicators and this needs to be examined by future studies.

Assessing the predictive role of platelet-lymphocyte ratio in EGFR-mutated non-small cell lung cancer patients treated with tyrosine kinase inhibitors: an analysis across TKI generations

IntroductionThe predictive utility of laboratory markers in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations treated with tyrosine kinase inhibitors (TKIs) is an ongoing area of research. The predictability of the platelet-lymphocyte ratio (PLR) on survival outcomes depending on the generation of EGFR TKI is undetermined.Methods151 patients treated with EGFR TKIs in Los Angeles were grouped according to generation of TKI. Differences in progression free survival (PFS) by stratification by PLR was determined using Kaplan–Meier analysis. Differences in median change in laboratory markers by generation of TKI was analyzed using Mann–Whitney tests. Cox Hazard Regression was used to perform multivariate analysis.ResultsMedian PFS of those managed with 1st or 2nd generation TKIs was significantly lower in patients with a PLR ≥ 180 (10.5 months) compared to those with PLR < 180 (16.6 months, p = 0.0163). Median PFS was comparable in those treated with osimertinib regardless of PLR. Patients managed with osimertinib had a significant decrease in absolute lymphocyte count (ALC) at 6 weeks and in platelets at 6 weeks and 3 months compared to those managed with 1st or 2nd generation TKIs.DiscussionThe predictive value of PLR was more apparent in patients treated with 1st or 2nd generation TKIs compared to those treated with osimertinib. Third generation EGFR TKIs may be more efficacious in treating patients with laboratory findings previously shown to predict poor survival. The significant changes in peripheral cell counts suggest variable tumor microenvironment changes dependent on the generation of TKI received.

Assessing platelet-lymphocyte ratio in EGFR-mutated non-small cell lung cancer patients treated with tyrosine kinase inhibitors: An analysis across TKI generations.

The prognostic utility of laboratory markers in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations treated with tyrosine kinase inhibitors (TKIs) is an ongoing area of research. The utility of the platelet-lymphocyte ratio (PLR) in patients treated with osimertinib is undetermined. 151 patients treated with EGFR TKIs in Los Angeles were grouped into one of two groups according to generation of TKI. Differences in progression free survival (PFS) by stratification by PLR was determined using Kaplan-Meier analysis. Differences in median change in laboratory markers by generation of TKI was analyzed using Mann-Whitney tests. Cox Hazard Regression was used to perform multivariate analysis. Median PFS of those managed with 1st or 2nd generation TKIs was significantly lower in patients with a PLR ≥ 180 (10.5 months) compared to those with PLR < 180 (16.6 months, p = 0.0163). Median PFS was comparable in those treated with osimertinib regardless of PLR. Patients managed with osimertinib had a significant decrease in absolute lymphocyte count (ALC) at 6 weeks and in platelets at 6 weeks and 3 months compared to those managed with 1st or 2nd generation TKIs. The prognostic value of PLR was more apparent in patients treated with 1st or 2nd generation TKIs compared to those treated with osimertinib. Third generation EGFR TKIs may be more efficacious in treating patients with laboratory findings previously shown to predict poor survival. The significant changes in peripheral cell counts suggest variability tumor microenvironment changes dependent on the generation of TKI received.

Impact of systemic steroids on the efficacy of first line imatinib treatment of patients with advanced gastrointestinal stromal tumors (GISTs).

Effective management of adverse events is required to maintain sufficient imatinib dosing when treating patients with gastrointestinal stromal tumors (GISTs). Skin rash is a common adverse event of imatinib, which can be effectively controlled by systemic steroid treatment without imatinib dose modification or interruption. However, the impact of the use of systemic steroids on the efficacy of imatinib treatment remains unclear. Between October 2014 and February 2022, 277 consecutive patients from a prospective registry of GIST patients were included as the study population. Patients who started systemic steroids due to grade ≥ 3 skin rash or grade 2 skin rash with grade 2 pruritis were classified as the steroid group, whereas patients who did not develop a skin rash or those who did not require steroids for a mild skin rash were classified as the control group. Efficacy outcomes were compared between the two groups. Among the 277 patients, 30 (10.8%) were treated with systemic steroids for skin rash. There was no significant difference in progression free survival (PFS) or overall survival (OS) between the steroid and control groups (3-year PFS, 67.7% vs. 65.1%, p = 0.53; 3-year OS, 91% vs. 89.9%, p = 0.67, respectively). The use of systemic steroids was not an independent factor associated with PFS (hazard ratio 0.73, 95% confidence interval 0.36-1.49, p = 0.39) and OS (hazard ratio 0.37, 95% confidence interval 0.12-1.18, p = 0.09). In the steroid group, patients who successfully maintained the imatinib dosage showed a trend toward more favorable survival outcomes than those who did not (3-year PFS, 73.3% vs. 44.4%, p = 0.34; 3-year OS, 95.8% vs. 75.0%, p = 0.15, respectively). The use of systemic steroids for the control of imatinib induced severe skin rash did not adversely affect the efficacy outcomes of imatinib in patients with advanced GIST.

Outcomes of patients with peritoneal carcinomatosis treated with HIPEC and chemotherapy or HIPEC alone: A single center community experience.

e15578 Background: Peritoneal carcinomatosis is a common presentation of intraperitoneal malignancies. The optimal management of peritoneal carcinomatosis is currently unknown but can contain a combination of HIPEC and chemotherapy. Optimal timing and order of these interventions is controversial. HIPEC surgery alone can provide a cure rate of approximately 16% with macroscopically complete resection. The PRODIGE 7 trial demonstrated no difference in overall survival between HIPEC plus cytoreduction versus cytoreduction alone with six months of systemic chemotherapy. Which patients should receive HIPEC, chemotherapy and HIPEC or chemotherapy alone remains unknown. Methods: This is a single center, retrospective chart review assessing all patients age 18 and above who received HIPEC surgery with and without the administration of chemotherapy at Ascension Saint John Hospital. Results: We found that there was no significant difference in overall survival and progression free survival between the HIPEC and HIPEC with chemotherapy group with a OS of 57.2 months and 52.5 months; and PFS of 33.6 and 34.4 months respectively. We found that patients with a PCI score between 0 and 13, overall survival favored the HIPEC alone group versus the HIPEC with chemotherapy with a p value of 0.043. There was no difference in progression free survival and overall survival in all other groups when stratified by PCI. When stratified by disease subtype, we no differences between PFS and OS for both appendiceal and colon cancer. Conclusions: The primary objective of this study was to investigate the difference in overall survival and progression free survival among patients with peritoneal carcinomatosis when treated with either HIPEC with systemic chemotherapy versus HIPEC alone. This analysis among 100 patients showed no statistically significant differences in OS or PFS for patients receiving a combination of HIPEC with systemic chemotherapy versus HIPEC alone. The only exception to this was with respect to OS in patients with a PCI score between 0-13. In this group, 0 patients in the HIPEC along group experienced disease progression where 5 progressed in the HIPEC and chemotherapy group. Our data suggests that HIPEC alone may be a reasonable treatment approach for patients with a low PCI score. Important conclusions can be drawn from the data when compared to historical trials. The PROTEGE 7 study found that the median overall survival was approximately 41.7 months for the HIPEC and cytoreductive surgery group and 41.2 months versus cytoreductive surgery alone. The overall survival for the HIPEC alone group was 57.2 months and 52.5 months for the HIPEC plus chemotherapy group. This data suggests that the combination of HIPEC and chemotherapy is a reasonable approach to patients with peritoneal carcinomatosis.

Abstract PO2-14-06: CIRCULATING TUMOR DNA DYNAMICS IN THE FIRST TREATMENT LINE OF THE SONIA TRIAL

Abstract Background and objective: CDK4/6 inhibitors (CDK4/6i) improve the outcome of patients with ER+/HER2- advanced breast cancer when added to endocrine therapy in the first line or second line of treatment. The recently reported SONIA trial shows no difference in progression free survival after two lines of treatment (PFS2), overall survival (OS) or quality of life benefit of CDK4/6i in first-line compared to second-line, while adverse events are substantially higher when CDK4/6i is added in the first-line. However, a subgroup of patients shows early progression on endocrine mono-treatment and not all patients respond equally well to CDK4/6i. This highlights the need for early response markers during the first weeks of treatment to reduce unnecessary toxicity while providing the most optimal care. In this SONIA side study, we aim to investigate whether we could identify patients who will progress rapidly during first line of therapy by using circulating tumor DNA (ctDNA) dynamics. Methods: Blood samples were obtained from patients included in the SONIA trial in both the first line CDK4/6i + aromatase inhibitor (AI) combination arm (arm A) and the first line AI monotherapy arm (arm B) at three time points: before start, after two weeks and after three months of first line treatment. Cell free DNA (cfDNA) was isolated from all samples and subsequently baseline cfDNA was sequenced with the Oncomine™ Breast cfDNA Assay v2 (Thermofisher), a focused NGS panel of 10 genes. Dedicated dPCR assays were used to track an identified driver mutation over time. Results: Blood samples of 332 patients (206 in arm A and 126 in arm B) before start of first line treatment and after two weeks of treatment were obtained. At baseline, in 142 of the 332 (42.7%) patients at least one somatic mutation was detected. In 30 patients two or more mutations were identified, in which case the mutation with the highest variant allele frequency (VAF) was followed over time. The most frequently mutated genes were PIK3CA (102 patients (30.7% of the total included cohort)), TP53 (32 patients (9.6%)), SF3B1 (8 patients (2.4%) and ESR1 (6 patients (1.8%)). The median observed VAF at baseline was 4.1% (IQR: 1.5%-13.1%). Of the 142 patients with detectable ctDNA at baseline, 141 patients and 100 patients, respectively, had blood samples taken after 2 weeks and after 3 months of treatment. After two weeks, the VAF of the tracked mutation was increased in 15.2% (14/92) of the patients in arm A and in 18.4% (9/49) of the patients in arm B. At the same time 40.2% (37/92) of the patients in arm A and 34.7% (17/49) of the patients in arm B had cleared ctDNA. No difference was observed between the arms for both an increase in VAF (P=0.63, Chi-square test) and ctDNA clearance (P=0.52, Chi-square test). After 3 months an increased VAF of the tracked mutation compared to baseline was observed in 6.3% (4/64) of the patients in arm A and 8.3% (3/36) of the patients in arm B. At this timepoint 59.4% (38/64) of the patients in arm A and 61.1% (22/36) of the patients in arm B had cleared ctDNA. No difference was observed between the arms for both ctDNA clearance (P=0.86, Chi-square test) and increase in VAF (P=0.70, Chi-square test) after three months. Conclusions: ctDNA was detected at baseline in almost half of the patients in the SONIA study. Compared to baseline, a decreasing number of patients had an elevation of the VAF of the tracked mutation and an increasing number of patients showed ctDNA clearance from 2 weeks to 3 months after start of treatment. There was no difference between the two arms observed regarding ctDNA dynamics. Interestingly, irrespective of treatment arm, about 1/3rd of patients remained ctDNA-positive even after 3 months of treatment. Associations of these ctDNA data with the clinical outcome data are currently being evaluated and will be presented at the meeting. Citation Format: Elisabeth M Jongbloed, Stefania Stella, Lotte van Bergen, Corine Beaufort, Jean Helmijr, Vanja de Weerd, Frans Erdkamp, Joan Heijns, Yvonne Kamm, Anne-Marie van Riel, Quirine van Rossum-Schornagel, Maurice Jansen, Inge RHM Konings, Gabe Sonke, John WM Martens, Agnes Jager, Saskia M Wilting. CIRCULATING TUMOR DNA DYNAMICS IN THE FIRST TREATMENT LINE OF THE SONIA TRIAL [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-14-06.

A randomized trial to evaluate the preventive effect of lafutidine on chemotherapy-induced peripheral neuropathy in patients treated with carboplatin and paclitaxel for lung cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) has a significant impact on the therapeutic efficacy of chemotherapy and patients' quality of life. The aim of this study was to assess the preventive effect of lafutidine on CIPN. Patients were randomly assigned (1:1) to carboplatin and paclitaxel chemotherapy with lafutidine 10 mg twice daily (lafutidine group) or without lafutidine (control group). Peripheral neuropathy in both groups was assessed with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and two patient-based questionnaires, the Patient Neurotoxicity Questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx). The primary outcome was the incidence of grade 2 or higher peripheral neuropathy in CTCAE version 5.0. The target number of cases was set at approximately 40. In total, 18 patients were screened, and 16 patients were assigned to the lafutidine group (n=9) or control group (n=7) between January 2021 and January 2023. Due to poor recruitment, the target number of cases was not reached. Grade 2 or higher neuralgia was 22.2% in the lafutidine group and 14.3% in the control group. Grade 2 or higher peripheral sensory neuropathy was 100% in the lafutidine group and 71.4% in the control group (P=0.175). Grade 3 or higher peripheral neuropathy was not detected in either group. There was no significant difference in PNQ scores between the two groups. Median FACT/GOGNtx scores after the fourth cycle tended to be lower in the lafutidine group than in the control group. There was no statistically significant difference in progression free survival (PFS) between the two groups. There were no adverse events due to lafutidine administration. Although the preventive effect of lafutidine on CIPN could not be demonstrated statistically, lafutidine FACT/GOG-Ntx scores showed a trend toward decreased neurotoxicity as chemotherapy proceeded. More reliable studies using lafutidine on the prevention of CIPN should be conducted. Japan Registry of Clinical Trials identifier: jRCTs021200031.

Evaluating disparities in pancreatic cancer outcomes in African Americans.

e18657 Background: Pancreatic Adenocarcinoma (PA) is a leading cause of cancer-related death across the world, with poorer outcomes observed in minority populations. The observed variation in outcomes has been attributed to delayed diagnosis, barriers to optimal treatment and health care related disparities. We sought to evaluate the impact of race on clinical presentation and outcomes in pancreatic cancer at a large academic teaching center. Methods: We performed a retrospective review of patients with pancreatic adenocarcinoma diagnosed between January 2016 to December 2021. The demographic characteristics (age, tobacco use, alcohol use, BMI); comorbidities (diabetes, acute/chronic pancreatitis); pathology, treatment (chemotherapy regimen, radiation, surgery) and progression free survival (PFS) based on race were analyzed. Results: The cohort (N = 983) consisted of 154 (16%) African Americans (AA) and 803 (82%) Non-Hispanic Whites (NHW). The median age at diagnosis was 65 years (60, 70) among AA and 71 years (64, 78) in NHW. Thirty-seven (26%) of AA and 104 (14%) of NHW were current smokers; 46 (33%) of AA and 323 (45%) of NHW consumed alcohol regularly. Among AA, 32 (22%) were obese (BMI &gt; 30), compared to 194 (25%) in NHW. Other comorbidities included diabetes (35% in AA vs. 32% in NHW) and acute/chronic pancreatitis (11% among AA vs. 9% among NHW). The treatment modality consisted of chemotherapy (57% in AA vs. 61% in NHW), surgery (26% in AA vs. 27% in NHW) and radiation (10% in AA vs. 12% in NHW). The median time to treatment initiation was 24 (16, 41) months for AA and 34 (20, 56) months for NHW. On univariate analysis, AA race was associated with younger age at diagnosis (p 0.043), higher current tobacco use (p 0.001), lower alcohol use (p 0.012), lower rates of obesity (p 0.024) and higher rate of acute pancreatitis (p 0.037) in pancreatic cancer. On multivariate analysis, race was not associated with difference in progression free survival (12 months in AA vs. 14 months in NHW; p 0.96) when adjusted for age, sex, alcohol use, tobacco use, cancer stage and chemotherapy. Conclusions: Our study revealed that pancreatic cancer in AA was diagnosed at a younger age, associated with active smoking and pancreatitis. Although there was a shorter time to treatment initiation among AA, there was no significant difference in progression free survival compared to NHW when adjusted for other variables. Future studies incorporating novel biomarkers are needed to determine impact of racial health disparities on outcomes in pancreatic cancer.

An evaluation of cisplatin, doxorubicin, and cyclophosphamide (PAC) compared to other regimens for patients with unresectable or metastatic thymic carcinoma: A single-institution retrospective analysis.

e20650 Background: Thymic Epithelial Tumors (TETs) are uncommon tumors of the anterior mediastinum comprised of thymomas and Thymic Carcinomas (TC). Given the rarity of these tumors, little data exists regarding the comparative effectiveness of various combination therapies. Platinum-based treatment regimens in combination with anthracyclines (e.g., PAC), taxanes (e.g., carboplatin plus paclitaxel (CT)) or etoposide (PE) have demonstrated efficacy in TETs in the front-line setting (although current NCCN guidelines recommend only CT for the treatment previously untreated advanced TC). We sought to characterize the efficacy of these regimens for TCs in a real-world setting. Methods: We conducted a single-institution, retrospective database analysis of 164 TC patients seen at the IUSCCC from 1996 - 2020. Of those patients, 42 met the study criteria as having a de novo diagnosis of TC treated with front-line systemic chemotherapy and available outcome data. Chemotherapeutic intervention and demographic/clinical variables were evaluated in this study. Data was compiled and collected using descriptive statistics and the Kaplan Meier method for survival analysis via GraphPad Prism software. Results: Of the 42 patients identified to have sufficient data, the median age was 55.6 years (range, 21 - 82). The median follow-up for patients was 23 months. Metastatic sites of disease included the pleura (11%), lymph nodes (11%), bone (10%) and lungs (5%). Multi-site involvement accounted for 36% of cases. Squamous cell carcinoma (SCC) was found in 52.3% (n = 22) of the patients, while 26.2% (n = 11) had rare TC subtypes, including, SCC with basaloid features, SCC with neuroendocrine features, and neuroendocrine (21.4% of cases were classified as TC only). Most patients received first line treatment with PAC (n = 16), CT (n = 13) or PE (n = 9). There was no difference in progression free survival (PFS) for TC patients treated with PAC or CT (10.5 v. 7.5 months, respectively, NS). PE was associated with inferior outcomes compared to PAC (4.5 vs. 10.5 months, ***p = 0.0005) and CT (4.5 vs. 7.5 months, *p = 0.0158), respectively. A subgroup analysis of rarer histologic subtypes revealed a trend towards improved PFS for patients who received PAC compared to CT (9.5 v. 4.5 months, NS). Conclusions: The results of our study support PAC combination chemotherapy as a reasonable alternative for patients with previously untreated advanced TC. Further studies to correlate the genomic differences of common and uncommon TC subtypes will be crucial to optimize the role of conventional and targeted systemic therapies in this rare malignancy.

Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).

4107 Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG &lt; 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]

Abstract 4384: Does progressive disease justify pembrolizumab discontinuation: a simulation analysis

Abstract Background: With checkpoint inhibition becoming first line therapy in several cancer indications, there is a growing number of patients that are refractory to PD1 therapy. It is unclear if these patients should remain on PD1 inhibitors while new therapies are added on top or if PD1 should be discontinued when new therapies are initiated. Here we simulate a randomized controlled study comparing pembrolizumab + a checkpoint inhibitor (P+C) to a checkpoint inhibitor (C) in virtual patients that are refractory to PD1 therapy. Methods: An IO QSP model was developed that includes intra-patient heterogeneity in tumor dynamics (target, non-target, and new metastatic lesions). The model was calibrated to individual lesion data from a large multicentre, open-label phase III study (Keynote-001) in patients with metastatic melanoma. A two year phase III study comparing P+C to C was simulated with 310 virtual patients in each group. Virtual patients were removed from the trial at the time of RECISTv1.1 progression or dropout due to AE or loss to follow-up. Results: Virtual patients in the P+C arm displayed deeper (-11.5% vs 24.5%) and longer response (186.4 days vs 96.5 days) than virtual patients in the CPI arm. The percent of virtual patients displaying low prevalence progression (&amp;lt; 50% of the target lesions with PD) was 86% vs 52% for P+C vs. C. Median progression free survival was also longer in the P+C arm (3.8 vs 2.1 months). Difference in progression free survival were driven mainly by virtual patients that displayed oligoprogression during the pembrolizumab monotherapy run-in period. Conclusions: Simulations presented here show that virtual patients that continued pembrolizumab treatment beyond RECISTv1.1 progression (as part of a combination) did better than virtual patients that discontinue pembrolizumab (and switch to a new therapy). Citation Format: Kannan Thiagarajan, Madhav Channavazzala, Brian Gregory Topp. Does progressive disease justify pembrolizumab discontinuation: a simulation analysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4384.

MRI-based long-term follow-up of indolent orbital lymphomas after curative radiotherapy: imaging remission criteria and volumetric regression kinetics

We systematically analyzed the kinetics of tumor regression, the impact of residual lesions on disease control and the applicability of the Lugano classification in follow-up MRI of orbital non-Hodgkin lymphomas that were irradiated with photons. We retrospectively analyzed a total of 154 pre- and post-irradiation MRI datasets of 36 patients with low-grade, Ann-Arbor stage I, orbital non-Hodgkin lymphomas. Patients with restricted conjunctival involvement were excluded. Lymphoma lesions were delineated and volumetrically analyzed on T1-weighted sequences. Tumor residues were present in 91.2% of all cases during the first six months after treatment. Volumetric partial response rates (> 50% volume reduction) were 75%, 69.2%, and 50% at 12–24 months, 36–48 months and > 48 months after the end of treatment. The corresponding complete response (CR) rates according to the Lugano classification were 20%, 23.1% and 50%. During a median clinical follow-up of 37 months no significant differences in progression free survival (PFS) rates were observed between the CR and non-CR group (p = 0.915). A residual tumor volume below 20% of the pretreatment volume should be expected at long-term follow-up beyond one year after radiotherapy.

Predictors of ibrutinib-associated atrial fibrillation: 5-year follow-up of a prospective study.

Ibrutinib-associated atrial fibrillation (IRAF) emerged among the adverse events of major interests in ibrutinib-treated patients as real-world studies showed a higher incidence compared to clinical trials. We prospectively analyzed predictors of IRAF in 43 single-center consecutive patients affected by chronic lymphocytic leukemia that started therapy with ibrutinib between 2015 and 2017. Key secondary endpoints were to describe the management of IRAF and survival outcomes. During a median follow-up period of 52months, we registered 45 CV events, with a total of 23 AF events in 13 patients (CI 30.0% (95% CI: 16.5-43.9)). Pre-existent cardiovascular risk factors, in particular hypertension, a previous history of AF and a high Shanafelt risk score emerged as predictors of IRAF. Baseline echocardiographic evaluation of left atrial (LA) dimensions confirmed to predict IRAF occurrence and cut-off values were identified in our cohort: 32mm for LA diameter and 18cm2 for LA area. No difference in progression free survival and overall survival emerged in patients experiencing IRAF. Following AF, anticoagulation was started in all eligible patients, and cardioactive therapy was accordingly modified. Echocardiography represents a highly reproducible and widespread tool to be included in the work-up of ibrutinib candidates; the identification of IRAF predictors represents a useful guide to clinical practice.

Ki67 as a Predictor of Response to PARP Inhibitors in Platinum Sensitive BRCA Wild Type Ovarian Cancer: The MITO 37 Retrospective Study.

There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC). MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010-2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off. A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0-99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5% PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials. Ki67 at diagnosis did not discriminate responders to PARPi.

Neoadjuvant chemoradiation in elderly Irish patients with esophageal cancer: A review of the clinical outcomes and toxicity.

335 Background: In locally advanced esophageal cancer, neoadjuvant chemo-radiotherapy improves survival compared with surgery alone. In the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), the median age was 60. However, 1/3 of patients diagnosed with esophageal cancer are over 70 years. The CROSS outcomes are therefore limited in its application to older patients. The objective of this study is to report and compare the outcomes and tolerability in elderly patients (≥70 years), who underwent neoadjuvant chemo-radiation for esophageal cancer with younger patients &lt; 70 years. Methods: A retrospective analysis of patients treated with neoadjuvant chemo-radiation for esophageal cancer between 1st January 2015 and 1st January 2021 was completed. Baseline characteristics and haematological toxicities were reported. Pathological response was reported. Survival was estimated using the Kaplan-Meier method. Results: In total 105 patients were included; 35 (33%) were ≥ 70 years and 70 (67%) patients were &lt; 70 years. In the elderly cohort, the median age was 75 (70-86) and the younger cohort median age was 60 (29-69). 73% of patients in each cohort were male. 31 (89%) of older adults experienced any grade of anaemia compared with 45 (64%) of the younger cohort. Only one patient experienced ≥ grade 3 anaemia in each cohort. 18(51%) and 33(47%) of older and younger patients respectively experienced any grade of neutropenia. 5(14%) older and 7(10%) younger patients experienced ≥ grade 3 neutropenia. 15(43%) and 43(61%) of older and younger patients experienced any grade of thrombocytopenia. No patients experienced ≥ grade 3 thrombocytopenia. 80% of the older and 86% of the younger cohort proceeded to surgery. 3(11%) and 17(29%) of the older and younger cohorts respectively who underwent surgery achieved a complete pathological response. There was no difference in overall survival (OS) between the cohorts (p=0.48). There was also no difference in progression free survival (PFS) between the cohorts. Conclusions: In conclusion, we confirm that neoadjuvant chemo-radiation is tolerable in patients ≥ 70 when compared with patients &lt; 70 years. Both OS and PFS is similar in both cohorts. We recommend the use of neoadjuvant therapy in appropriately selected patients ≥ 70 years.

Upfront surgery in patients with epithelial ovarian cancer and enlarged supradiaphragmatic lymph nodes associated with comparable to neoadjuvant chemotherapy

BackgroundThere is little data regarding the optimal approach to advanced epithelial ovarian cancer (EOC) with isolated extra-peritoneal disease in the cardiophrenic lymph nodes. This study assessed whether the prognosis and surgical outcomes are affected by the treatment approach among these patients.Material and methodsThis retrospective cohort study included patients with advanced EOC, who were treated 2012–2020. Computed tomography scans were reviewed for disease extent and the presence of enlarged supradiaphragmatic nodes (SDLN). Demographic, clinical and oncologic data were recorded. Characteristics and outcomes of patients with and without enlarged SDLN were evaluated, and outcomes of patients with enlarged SDLN who underwent upfront surgery and neoadjuvant chemotherapy were compared.ResultsAmong 71 women, 47 (66%) had enlarged supradiaphragmatic lymph nodes. Groups had similar baseline characteristics. Among 47 women who had enlarged SDLN. There was no significant difference in progression free survival among patients who had upfront cytoreduction compared to those who received neoadjuvant chemotherapy. Only one asymptomatic chest recurrence was observed.ConclusionPatients with enlarged SDLN have comparable outcomes with either upfront surgery or neoadjuvant chemotherapy. Moreover, the frequency of chest recurrences in patients presenting with enlarged SDLN is exceedingly low.

The effect of concomitant use of proton pump inhibitors with CDK 4/6 inhibitors on survival in metastatic breast cancer

To evaluate the difference of progression free survival between the patients using concomitant proton pump inhibitors and non-users in the patients using CDK 4/6 inhibitors with HR + and HER2 negative mBC. We included 86 patients with HR + and HER 2 negative mBC treated with CDK 4/6 inhibitors in this study. Patients were divided into two categories according to their status of PPI use. The primary end points was progression free survival (PFS). We compared PPI users and non-users. Forty-five (52.3%) patients used a PPI concomitantly with a CDK 4/6 inhibitor, and 41 (47.7%) did not. The median duration of follow-up was 10.68 (1.94-27.56) months. Of the patients, 50 (58.1%) palbociclib and 36 (41.9%) received ribociclib. The median progression free survival (mPFS) was 10.9months (95% CI: 7.5-14.27) in the group with concomitant PPI use with a CDK 4/6 inhibitor, whereas the median progression free survival could not be reached in the group without concomitant PPI use (p = 0.04). In addition, concomitant PPI use with palbociclib was associated with a shorter PFS; there was no significant difference between the concomitant PPI users and non-users in terms of PFS in the patients using ribociclib. Palbociclib and ribociclib are weak base drugs so their bioavailability is pH-dependent. PPIs can affect their solubility and their concentration in the plasma. Therefore, we must avoid concomitant use of PPIs and CDK 4/6 inhibitors. If we need to use concomitant PPI and CDK 4/6 inhibitors, we should prefer ribociclib than palbociclib.

Cytokine Release Syndrome (CRS) Is Not Required for CAR-T Cell Efficacy in Aggressive Large B-NHL

BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy for treatment of aggressive large B-cell non-Hodgkin lymphoma (B-NHL) has changed management and outcomes for this disease. Treatment with CAR T-cells is accompanied by a unique set of adverse effects, including development of cytokine release syndrome (CRS). Though rates of CRS varied in trials, the development of severe (Grade 3 or 4) CRS was rare and similar incidences have been noted in real world studies. Here, we addressed whether the development of CRS is associated with outcomes in patients with aggressive large B-NHL undergoing treatment with CAR T cells. METHODS Patients aged ≥18 years with aggressive large B-NHL who underwent apheresis between May 2018 and January 2021 for commercial CAR T-cell therapy at eight academic US medical centers were identified from the Cell Therapy Consortium (CTC) registry. Providers could prescribe either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). CRS was graded using ASTCT consensus criteria. Tumor response 90 days after CAR T-cell infusion was assessed per Lugano criteria by the treating clinician. Persistent cytopenias were defined as ANC<1000 and/or Plt<50 and evaluated at the following intervals post infusion: day 30, 3 months, 6 months, 9 months, and one year. Cox regression analysis and the Kaplan Meier method were used for survival outcomes. Logistic regression analysis was used to assess association with tumor response and persistent cytopenias. RESULTS This study included 351 patients who underwent apheresis for commercial CAR T cell therapy for aggressive large B-NHL (Table 1A). Of these, 262 (74.4%) developed CRS while 90 (25.5%) did not. The median age at apheresis was 61 (range 18-88) among patients who developed CRS and 65 (range 37-85) among those who did not (p=0.005). Of the patients included, 202 (57.6%) received axi-cel and 149 (42.5%) received tisa-cel. With median follow up of 21.6 months, there were no differences in progression free survival (PFS) or overall survival (OS) between patients who developed CRS and those who did not. Median PFS in patients who did not develop CRS was 5.99 months compared to 5.89 months (p=0.99) in those who did. Median OS in patients who did not develop CRS was 26.6 months compared to 17.5 months in patients who did (p=0.16). Exploratory analysis showed that CRS grade did not influence PFS or OS (Figure 1). Results of the multivariate analysis are summarized in Table 1. The development of CRS did not have a significant impact on PFS or OS. A peak ferritin level of greater than 5000 within 28-days following CAR T-cell infusion was associated with worse PFS (HR 2.61; CI: 1.71-3.98, p<0.001) and OS (HR 2.38; CI: 1.50-3.76, p<0.001). LDH greater than the upper limit of normal was associated with worse progression-free (HR 2.11; CI: 1.49-2.98, p<0.001) and OS (HR 2.34; CI: 1.55-3.53, p<0.001). The administration of steroids for treatment of CAR T-cell associated toxicities had no significant impact on PFS or OS. Presence of bulky disease (≥10 cm) had no impact on PFS but was associated with worse OS (HR 1.81; CI: 1.29-2.75, p=0.005). Receipt of bridging therapy was associated with worse PFS (HR 1.58; CI: 1.11-2.24, p=0.011), though not OS. At 30 days post-infusion, there was no difference in ORR (66% vs 52%, p=0.081) or CR rate (39% vs 27%, p=0.155) between patients who developed CRS and those who did not. The occurrence of CRS within 28 days of treatment was significantly associated with cytopenias at day 30 (p=0.001), but not at any other time point. Amongst patients with Grade ≥3, 63% had cytopenias at day 30, compared to 47% among patients who did not have CRS (p=0.142). Grade ≥3 CRS was not significantly associated with cytopenias beyond day 30. CONCLUSION Survival outcomes were similar in patients with aggressive large B-NHL treated with CAR T-cell therapy who did or did not develop CRS. Furthermore, the occurrence of CRS had no impact on ORRs or CR rates. Having CRS was associated with cytopenias at day 30 post infusion, though not at subsequent time points. These findings lend further support to the finding that development of CRS does not impact efficacy of CAR T-cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunoparesis Recovery in Transplant-Ineligible Newly Diagnosis Multiple Myeloma Patients: An Independent Prognosis Factor That Could Complement Prognostic Value of Minimal Residual Disease

Introduction: Immunoparesis (IP) or the suppression of polyclonal uninvolved immunoglobulins (Ig) is one of the immune system alterations present in patients with multiple myeloma (MM) at diagnosis. Several studies have shown that the lack of IP recovery after treatment is associated with worse prognosis. However, these are observational retrospective studies and patients were not homogeneously treated. On the other hand, the depth of response, specially reaching minimal residual disease (MRD) negative, is one of the most important prognostic factors in patients with MM. We decided to study, in a prospective way, the prognostic value of IP recovery in a group of elderly patients not suitable for transplantation and treated in a similar way and compare it with the depth of response to treatment, especially with MRD status. Methods: We analyze patients included and treated in the PETHEMA/GEM2010MAS65 study (registered at www.clinicaltrial.gov as #NCT01237249) who reached CR or VGPR. All patients included in this trial were older than 65 years old and transplant-ineligible and were planned to receive 9 cycles of bortezomib plus melphalan and prednisone (VMP) and 9 cycles of lenalidomide plus dexamethasone (LD). Polyclonal Ig were analyzed by nephelometry or turbidimetry at diagnosis, at the end of the treatment (after 18 cycles) and during subsequent follow up. Minimal residual disease (MRD) was analyzed at the end of the treatment by multidimensional flow cytometry (MFC) with a sensitivity level of 10-5. Results: Of the 233 patients included in the study, 161 reached CR or VGPR, but the protocol design did not included determination of uninvolved Igs at diagnosis and for this reason they were only available in 120 patients. Only 9 cases (7,5%) had normal Ig at diagnosis while 111 patients (92,5%) had IP. There were no differences in progression free survival (PFS) and overall survival (OS) between patients with or without IP. We had Ig determination of 117 cases at the end of the treatment and during follow up. Those patients who had IP at diagnosis and recover it after treatment had better PFS (p<0,001; HR 0,33) and better OS (p=0,001; HR 0,35) than those who do not recover it (Figure 1A). We found no differences between those patients who had recovery of IP at cycle 18 than those who recover IP during follow up. When we focused the analysis in CR patients and VGPR patients separately, in both groups recovery of IP was associated with a better PFS and OS. In fact, when we compared both groups, we found that those patients with VGPR and complete recovery of IP had better PFS (p=0,001; HR 0,12) and OS (p=0,015; HR 0,22) than those with CR and no recovery of IP. These data suggest that IP recovery could be a prognostic factor equal or more important than conventional response. MRD information by MFC was available in 112 cases. As previously reported, in this trial those patients with MRD negative (-ve) had longer PFS and OS than MRD positive (+ve). When we analyzed IP recovery in MRD -ve patients we found that patients with MRD -ve and IP recovery (33 cases) had better PFS (p=0,004; HR 0,30) and better OS (p=0,010; HR 0,21) than patients with MRD -ve without IP recovery (11 cases), although it should be recognized that the number of patients within this latter subgroup was rather small (Figure 1B). We performed a multivariate analysis including other prognostic factors, and we found that both MRD and IP recovery have independent prognostic value for PFS, but only MRD and no IP recovery, is an independent prognosis factor for OS. Conclusions: Recovery of IP after non-continuous treatment in elderly patients with CR or VGPR confers better prognosis (PFS and OS). Prognostic value of IP recovery could be equal or more important than conventional response to treatment. Prognostic value of MRD could be complemented when combined with IP recovery, but these data must be confirmed in other series. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Quality of Life in Patients Undergoing Double Umbilical Cord Blood Vs. Haploidentical Marrow Transplantation: A QOL Analysis Report of BMT CTN 1101

Introduction BMT CTN 1101 was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QOL) of patients with hematological malignancies receiving double umbilical cord blood transplants (dUCBT) or haploidentical bone marrow transplants (haplo) with post-transplant cyclophosphamide after reduced intensity conditioning. Extended follow-up at 5 years showed that there were no significant differences in progression free survival (PFS) or overall survival (OS) between the two cohorts. However, the hazard ratio for NRM was 2.69 in favor of haplo transplants with all of the difference seen in the first 18 months post-transplant. The impact of donor source on QOL, however, is unknown. Thus, the objectives of this analysis are to compare longitudinal QOL between dUCBT and haplo and to investigate the association of QOL and clinical outcomes. Methods Enrollment occurred from 6/2012-6/2018, and included 368 patients (n=186 dUCBT, n=182 haplo), age 18-70 with 2 year follow up. QOL assessments included the FACT-BMT measure; the MOS Short Form 36 Physical Component Score (PCS) and Mental Component Score (MCS); the EQ-5D; and the Global QOL Scale. These were completed pre-transplant and at 12 and 24 months post-transplant. To account for missing assessments, scores were compared between arms using an inverse probability weighted-independent estimating equations (IPW-IEE) method that models scores in surviving patients while accounting for baseline variables (age, race/ethnicity, primary disease, disease risk, performance status, and HCT-CI) and follow-up outcomes that impact the likelihood of missingness. Cox models evaluated potential associations of pre-transplant QOL scores with OS and PFS while adjusting for these baseline variables. Analyses were performed using intention-to-treat (ITT) patient assignment from the time of randomization. A threshold of 1% was used to determine statistical significance for all analyses. Results No significant differences were observed between treatment arms in baseline patient, disease, and transplant characteristics (previously described) among patients who participated in at least one QOL assessment. In the UCB arm, PRO response rates were 145/186 (78%) pre-transplant, 67/105 (64%) at 12 months, and 47/85 (55%) at 24 months. In the haplo arm, PRO response rates were 134/182 (74%) pre-transplant, 79/115 (69%) at 12 months, and 50/102 (49%) at 24 months. HCT-CI >3 pre-transplant and relapse at 12 and 24 months were the most consistent factors significantly associated with lower completion of QOL questionnaires at respective time points. We found no significant difference in any of the QOL scores at pre-transplant, 12, and 24 months between the treatment arms (Figure 1). In multivariable IPW-IEE models, pre-transplant FACT-BMT total score, SF-36 PCS, and EQ-5D scores were the only significant predictors of post-transplant QOL scores. There was no significant association of treatment arm or baseline clinical variables with FACT-BMT or SF-36 PCS scores post-transplant. Age >60 was associated with higher mean EQ-5D (0.08, 99% CI 0.025-0.131, p=0.0002) and SF-36 MCS scores (4.45, 99% CI 0.288-8.622, p=0.0059) on post-transplant assessments. There was no significant impact of treatment arm on Global QOL score or subscale scores post-transplant. We evaluated the association of post-transplant clinical events with primary QOL endpoints (Table 1). Relapse and Grade III-IV aGVHD were associated with significant declines in mean FACT-BMT and SF-36 PCS scores. cGVHD was associated with a decline in mean EQ-5D utility scores. We found no significant association between pre-transplant QOL scores and OS or PFS (p>0.10 for all models). There were no significant interactions between treatment groups and baseline characteristics on QOL measures. Conclusions This longitudinal QOL analysis of BMT CTN 1101 showed that donor type did not impact post-transplant QOL. Pre-transplant QOL scores were the only predictor of post-transplant 12 and 24 month scores which, however, were not associated with OS or PFS in either treatment arm. Clinical events of GVHD and relapse were associated with declines in QOL scores. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal