Limited tools exist to predict the risk of chemotherapy toxicity in older adults with early-stage breast cancer.
Patients of age ≥ 65 years with stage I-III breast cancer from 16 institutions treated ...with neoadjuvant or adjuvant chemotherapy were prospectively evaluated for geriatric and clinical features predictive of grade 3-5 chemotherapy toxicity. Logistic regression with best-subsets selection was used to identify and incorporate independent predictors of toxicity into a model with weighted variable scoring. Model performance was evaluated using area under the ROC curve (AUC) and goodness-of-fit statistics. The model was internally and externally validated.
In 473 patients (283 in development and 190 in validation cohort), 46% developed grade 3-5 chemotherapy toxicities. Eight independent predictors were identified (each assigned weighted points): anthracycline use (1 point), stage II or III (3 points), planned treatment duration > 3 months (4 points), abnormal liver function (3 points), low hemoglobin (3 points), falls (4 points), limited walking (3 points), and lack of social support (3 points). We calculated risk scores for each patient and defined three risk groups: low (0-5 points), intermediate (6-11 points), or high (≥ 12 points). In the development cohort, the rates of grade 3-5 chemotherapy toxicity for these three groups were 19%, 54%, and 87%, respectively (
< .01). In the validation cohort, the corresponding toxicity rates were 27%, 45%, and 76%. The AUC was 0.75 (95% CI, 0.70 to 0.81) in the development cohort and 0.69 (95% CI, 0.62 to 0.77) in the validation cohort. Risk groups were also associated with hospitalizations and reduced dose intensity (
< .01).
The Cancer and Aging Research Group-Breast Cancer (CARG-BC) score was developed and validated to predict grade 3-5 chemotherapy toxicity in older adults with early-stage breast cancer.
Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality as most patients present with advanced disease. The development of ascites has been associated with poor ...outcomes and further characterization and contemporary management strategies are needed. 437 patients enrolled in the Gastrointestinal Biobank at Cedars-Sinai Medical Center who had epithelial pancreatic malignancy were included in the prospective cohort group. 41.7% of patients included in the study developed ascites. The majority (>80%) of ascites patients had high serum-ascites albumin gradient (SAAG) ascites. In both univariate and multivariate analysis, history of >=1 form of chemotherapy was significantly associated with ascites. Estimated median OS in patients with ascites was significantly lower than in patients without ascites, 473 days vs. 573 days, and ascites had a HR of 1.37. Patients with ascites who received diuretics and indwelling peritoneal catheter had an estimated median survival of 133 days from diagnosis of ascites, and those that received only the indwelling peritoneal catheter without diuretics had an estimated median survival of only 54 days. The estimated median survival from the diagnosis of ascites was 92 days and median time to puncture was 7 days. Median time from first tap to death was 45 days. The use of diuretics is lower than would be expected for PDAC patients with elevated SAAG. Other therapies such as beta blockers should be investigated in this subset of patients. The etiology of ascites in these patients is poorly understood and further research is needed to establish treatment guidelines and improve outcomes.
Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, ...elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (
= 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.
Chemotherapy decreases the risk of relapse and mortality in early-stage breast cancer (BC), but it comes with the risk of toxicity. Chemotherapy efficacy depends on relative dose intensity (RDI), and ...an RDI < 85% is associated with worse overall survival. The pro-inflammatory (interleukin (IL)-6, C-reactive protein (CRP)) and coagulation factors (D-dimer) serve as biomarkers of aging. The purpose of this study is to determine if these biomarkers are associated with reduced RDI in women with stage I-III BC.
This study enrolled women with stage I-III BC. Prior to adjuvant or neoadjuvant chemotherapy, peripheral blood was collected for biomarker measurement. Dose reductions and delays were captured and utilized to calculate the RDI delivered. Univariate and multivariate analyses were performed to describe the association between pre-chemotherapy IL-6, CRP, and D-dimer levels and an RDI < 85%, controlling for relevant tumor and patient factors (age, stage, receptor status, chemotherapy regimen, and pre-chemotherapy physical function and comorbidity).
A total of 159 patients (mean age 58 years, range 30-81, SD 11.3) with stage I-III BC were enrolled. An RDI < 85% occurred in 22.6% (N = 36) of patients and was associated with higher pre-chemotherapy IL-6 (OR 1.14, 95% CI 1.04-1.25; p = 0.006) and D-dimer (OR 2.32, 95% CI 1.27-4.24; p = 0.006) levels, increased age (p = 0.001), increased number of comorbidities (p = 0.01), and decreased physical function by the Medical Outcomes Survey Activities of Daily Living (ADL) Scale (p = 0.009) in univariate analysis. A multivariate model, including two biomarkers (IL-6 and D-dimer), age, ADL, BC stage, and chemotherapy regimen, demonstrated a significant association between the increased biomarkers and reduced RDI < 85% (OR 2.54; p = 0.04).
Increased pre-chemotherapy biomarkers of aging (IL-6 and D-dimer) are associated with reduced RDI (<85%). Future studies are underway to validate these findings.
ClinicalTrials.gov, NCT01030250 . Registered on 3 November 2016.
Older adults are at increased risk for chemotherapy toxicity, and standard oncology assessment measures cannot identify those at risk. A predictive model for chemotherapy toxicity was developed (N = ...500) that consisted of geriatric assessment questions and other clinical variables. This study aims to externally validate this model in an independent cohort (N = 250).
Patients age ≥ 65 years with a solid tumor, fluent in English, and who were scheduled to receive a new chemotherapy regimen were recruited from eight institutions. Risk of chemotherapy toxicity was calculated (low, medium, or high risk) on the basis of the prediction model before the start of chemotherapy. Chemotherapy-related toxicity was captured (grade 3 hospitalization indicated, grade 4 life threatening, and grade 5 treatment-related death). Validation of the prediction model was performed by calculating the area under the receiver-operating characteristic curve.
The study sample (N = 250) had a mean age of 73 years (range, 65 to 94 standard deviation, 5.8). More than one half of patients (58%) experienced grade ≥ 3 toxicity. Risk of toxicity increased with increasing risk score (36.7% low, 62.4% medium, 70.2% high risk; P < .001). The area under the curve of the receiver-operating characteristic curve was 0.65 (95% CI, 0.58 to 0.71), which was not statistically different from the development cohort (0.72; 95% CI, 0.68 to 0.77; P = .09). There was no association between Karnofsky Performance Status and chemotherapy toxicity (P = .25).
This study externally validated a chemotherapy toxicity predictive model for older adults with cancer. This predictive model should be considered when discussing the risks and benefits of chemotherapy with older adults.
10029
Background: Immune checkpoint inhibitors targeting PDL-1 have shown clinical benefit in adults with cancer. We conducted a first in pediatrics, phase 1 clinical trial to assess safety, ...pharmacokinetics (PK), and pharmacodynamics of durvalumab in children with solid and central nervous system malignancies. Methods: This single center investigator-initiated trial enrolled eligible patients considered incurable with measurable/evaluable disease (exception: osteosarcoma in 3
rd
remission), no prior exposure to checkpoint inhibitors and adequate organ function on 2 dose levels: 10 mg/kg (DL1) and 15 mg/kg (DL2), utilizing a standard 3+3 design. The primary objectives were to assess safety and PK of durvalumab. Durvalumab was administered intravenously (IV) Q2 weeks for a maximum of 24 doses (12 cycles) on study or until disease progression/unacceptable toxicity. Patients were assessed for dose-limiting toxicity (DLT) in the first 28 days. The tolerable dose level was expanded to obtain PK on at most 6 patients age ≥12 years (yrs) and 6 patients < 12 yrs weighing < 35 kg). Soluble PDL-1 (sPDL1) and anti-drug antibody (ADA) levels were also assessed. Results: Fifteen patients (8M/7F) were enrolled (3 DL1, 12 DL2) with median age of 12.7 (2.9-16.6) yrs. Diagnoses included 5 osteosarcoma, 4 ependymoma and 1 each of glioblastoma, astrocytoma, rhabdomyosarcoma, synovial sarcoma, hepatoblastoma and adrenocortical carcinoma. Of the 14 patients evaluable for DLT, 3 were on DL1 and 11 on DL2. Only 1 DLT was observed, Grade (Gr) 3 intracranial hemorrhage (ICH). Median number of cycles administered was 3 (1-12). There were no treatment related deaths. There were 72 treatment-related adverse events (TRAEs) observed in 11 patients in a total of 73 cycles administered on the trial. The most common TRAE was AST elevation (7 instances in 4 patients). All TRAEs were < Gr 3 except for 1 instance each of Gr 3 AST elevation, anemia, and ICH. All 15 patients had PK, sPDL1 and ADA samples analyzed. PK for DL2 in patients ≥35 Kg and < 35 Kg were comparable to PK in adults dosed with durvalumab 10 mg/kg IV Q2W. Mean (SD) DL2 Cmax 292 (102) mg/mL, Ctrough 85.1 (27.7) mg/mL, AUC 2220 (986) day*mg/mL in pts ≥35 Kg and Cmax 442 (338), Ctrough 120 (123), AUC 2470 (1870) in pts < 12 yrs weighing < 35 kg. sPDL1 was completely suppressed in all patients 2 weeks after a single dose of durvalumab. No ADA were detected in any patients. Five patients (2 osteosarcoma, 3 ependymoma) completed > 6 cycles and 3 (1 osteosarcoma, 2 ependymoma) completed all 12 cycles of treatment. One objective response (PR) was seen in a patient with anaplastic ependymoma by RECIST1.1. Four patients were alive at the time of data cut-off with a median follow up of 30.5 (8.8-58.1) months. Conclusions: Durvalumab at 15 mg/kg IV Q2W was well tolerated in children with drug exposures comparable to adults receiving10 mg/kg IV Q2W. A signal for activity was noted in ependymoma where 3 of 5 children benefitted clinically. Clinical trial information: NCT02793466.
4024
Background: PDAC is an aggressive cancer and refractory to immunotherapy due to its immunosuppressive tumor microenvironment (TME). Focal adhesion kinase (FAK) is a master regulator of the TME ...and associated with TME immune suppression. Our current randomized phase II trial evaluates the use of pembrolizumab, a programmed cell death 1 (PD-1) immune checkpoint inhibitor, with or without defactinib, a FAK inhibitor (FAKi), as sequential neoadjuvant and adjuvant therapy in patients with high risk resectable PDAC. We hypothesize that the patients receiving pembrolizumab and defactinib treatment will exhibit a decrease in immunosuppressive fibroblasts and myeloid subtype populations, leading to increased CD8+ T-cell infiltration into the TME compared to patients receiving pembrolizumab alone. Methods: We performed quantitative analysis of multiplex immunohistochemistry (mIHC) using 40 biomarkers, evaluating immune and stromal cell types on 14 pre-treatment biopsies and post-treatment resections of PDAC patients enrolled in our platform neoadjuvant clinical trial (NCT03727880). All patients received 2 cycles of gemcitabine+nab-paclitaxel neoadjuvant chemotherapy and underwent a biopsy after completion of chemotherapy. Patients randomized to Arm A received 2 cycles of pembrolizumab 200 mg IV every 3 weeks and defactinib 400 mg PO BID, and those randomized to Arm B received pembrolizumab alone, followed by surgical resection. Image cytometry was used to quantify immune cell populations and colocalize biomarker expression in distinct cell types. Cell populations were compared using unpaired T-tests. Results: Lower FAP+ fibroblast density was significantly associated with higher CD8+ T-Cell infiltration in Arm A (p=0.002), but not in Arm B. Patients in Arm A demonstrated a 5.44-fold average increase in CD8+ T-cell percentage between pre-immunotherapy treatment and post-immunotherapy treatment specimens compared to a 2.01-fold increase in patients in Arm B (p=0.02, p=0.09, respectively). Only patients in Arm A showed a significant increase in M1 macrophage cell density (p=0.02) after treatment. Both arms increased in CXCR4+ cell percentage (p=0.011, p=0.06) following neoadjuvant immunotherapy; however, the increase in Arm A was less than in Arm B (0.72 and 0.84-fold, respectively). Conclusions: In this analysis, pembrolizumab combined with defactinib was associated with lower fibroblast infiltration, higher anti-tumor M1 macrophage expression and increased CD8+ T-cell infiltration into the TME, versus pembrolizumab alone. The increased expression of CXCR4 across both treatment arms may represent a resistance mechanism and supports CXCR4 as an additional TME target. These preliminary findings warrant continued research into FAK inhibition and immune checkpoint combinatorial strategies. Clinical trial information: NCT03727880 .
11561
Background: Antibodies against the insulin-like growth factor type 1 receptor (IGF1-R) have shown transient objective partial responses (PR) in patients with RMS followed by rapid development ...of resistance. Preclinical data demonstrate that activation of the SRC family kinase YES acts as a bypass resistance mechanism to IGF-1R targeting. Co-targeting IGF-1R and YES results in sustained responses in murine RMS models. We developed a phase I/II trial of the anti-IGF-1R antibody ganitumab combined with the multi-kinase inhibitor dasatinib in patients with RMS (NCT03041701). During the phase II part of the study, ganitumab became unavailable, and the trial was terminated early. We report here the results of the completed phase I study. Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. A 3+3 dose escalation design was used to determine the maximum tolerated dose (MTD), and evaluable patients were assessed for response using RECISTv1.1 criteria. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib was administered orally on a continuous schedule. Dose level (DL)1 was 60 mg/m
2
/dose (max 100 mg) once daily; DL2 was 60 mg/m
2
/dose (max 70 mg) twice daily. MTD was determined based on cycle 1 dose-limiting toxicities (DLTs) and responses were assessed every 2 cycles. Results: Thirteen eligible patients (5M, 8F), median age 18 years (range 8-29 years) with embryonal (n = 6) and alveolar (n = 7) RMS were enrolled at DL1 (n = 7) and DL2 (n = 6). Median number of prior systemic therapies was 3 (range 1-6), all had received prior radiation, 5 prior surgery, and 2 prior high dose chemotherapy with stem cell rescue. Of 11 patients evaluable for toxicity, 1/6 had a DLT at DL1 (grade 3 diarrhea) and 2/5 had DLTs at DL2 (grade 3 pneumonitis and grade 3 hematuria) confirming DL1 as MTD. Common non-DLTs at least possibly attributed to dasatinib, ganitumab, or both included thrombocytopenia (n = 12), anemia (n = 10), lymphopenia (n = 8), hypophosphatemia (n = 7), hypocalcemia (n = 6), elevated transaminases (n = 5), fatigue (n = 5), nausea (n = 5), and vomiting (n = 5). The most common grade 3-4 adverse events were cytopenias and electrolyte abnormalities. Of 9 patients evaluable for response, 1 had a confirmed PR at DL2 sustained for 5 cycles, and 1 had prolonged stable disease (SD) for 6 cycles at DL1. Patients received a median of 1.5 cycles (range 0-6). Analysis of correlative biology studies of ctDNA and target expression are ongoing. Conclusions: The combination of dasatinib and ganitumab was safe and tolerable at DL1 in patients with relapsed and refractory RMS. Once daily dasatinib at 60 mg/m
2
/dose (max 100 mg) combined with 18 mg/kg ganitumab every 2 weeks was determined to be the MTD. PR and SD for > 4 months were observed in this phase I trial suggesting that the addition of a YES-targeting agent may delay the development of acquired resistance to IGF-1R antibody therapy in RMS. Clinical trial information: NCT03041701.
Purpose
The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer.
Methods
We ...recruited 16 women aged ≥ 60 years with stage I–III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry.
Results
The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (
p
FWE(family-wise error)-corrected
< 0.05). The baseline GMD in left insula was positively correlated with the baseline list-sorting working memory score in the HC group (
p
FWE-corrected
< 0.05). No correlation was observed for the changes in GMD with the changes in cognitive testing scores from TP1 to TP2 (
p
FWE-corrected
< 0.05).
Conclusions
Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432).
Full text
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Older adults (≥65 years) with gastrointestinal (GI) cancers who receive chemotherapy are at increased risk of hospitalization caused by treatment-related toxicity. Geriatric assessment (GA) has been ...previously shown to predict risk of toxicity in older adults undergoing chemotherapy. However, studies incorporating the GA specifically in older adults with GI cancers have been limited. This study sought to identify GA-based risk factors for chemotherapy toxicity-related hospitalization among older adults with GI cancers.
We performed a secondary post hoc subgroup analysis of two prospective studies used to develop and validate a GA-based chemotherapy toxicity score. The incidence of unplanned hospitalizations during the course of chemotherapy treatment was determined.
This analysis included 199 patients aged ≥65 years with a diagnosis of GI cancer (85 colorectal, 51 gastric/esophageal, and 63 pancreatic/hepatobiliary). Sixty-five (32.7%) patients had ≥1 hospitalization. Univariate analysis identified sex (female), cardiac comorbidity, stage IV disease, low serum albumin, cancer type (gastric/esophageal), hearing deficits, and polypharmacy as risk factors for hospitalization. Multivariable analyses found that patients who had cardiac comorbidity (OR 2.48, 95% CI 1.13-5.42) were significantly more likely to be hospitalized.
Cardiac comorbidity may be a risk factor for hospitalization in older adults with GI cancers receiving chemotherapy. Further studies with larger sample sizes are warranted to examine the relationship between GA measures and hospitalization in this vulnerable population.
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