Background: This study sought to estimate the severity, etiology, and clinical importance of treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Methods: Serial ...lymphocyte counts and survival were analyzed retrospectively in 47 patients accounting for known prognostic factors. Results: Total lymphocyte counts (TLCs) were normal before therapy and did not change following neoadjuvant chemotherapy. Following radiation, TLC fell by 67% (median 500 cells/mm3, p <.00001). Multivariate analysis revealed an association between severe TLC and survival (HR 1.70, 95% CI: 0.8-3.6). Conclusions: Rapid and severe lymphopenia occurred in 50% of patients following radiation which was associated with reduced survival.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced ...survival.
Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non-small cell lung cancer (N=47).
Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate HR, 1.8; 95% CI, 1.13-2.87; resected pancreas: HR, 2.2; 95% CI, 1.17-4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53-5.42; and lung: HR, 1.7; 95% CI, 0.8-3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54-2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression.
Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors.
OBJECTIVE:To evaluate the efficacy of rituximab (R) when added to high-dose methotrexate (HD-MTX) in patients with newly diagnosed immunocompetent primary CNS lymphomas (PCNSLs).
...METHODS:Immunocompetent adults with newly diagnosed PCNSL treated at The Johns Hopkins Hospital between 1995 and 2012 were investigated. From 1995 to 2008, patients received HD-MTX monotherapy (8 g/m initially every 2 weeks and after complete response CR monthly to complete 12 months of therapy). From 2008 to 2012, patients received the same HD-MTX with rituximab (375 mg/m) with each HD-MTX treatment. CR rates and median overall and progression-free survival were analyzed for each patient cohort in this single-institution, retrospective study.
RESULTS:A total of 81 patients were identified54 received HD-MTX (median age 66 years) while 27 received HD-MTX/R (median age 65 years). CR rates were 36% in the HD-MTX cohort and 73% in the HD-MTX/R cohort (p = 0.0145). Median progression-free survival was 4.5 months in the HD-MTX cohort and 26.7 months in the HD-MTX/R cohort (p = 0.003). Median overall survival was 16.3 months in the HD-MTX cohort and has not yet been reached in the HD-MTX/R cohort (p = 0.01).
CONCLUSIONS:The addition of rituximab to HD-MTX appears to improve CR rates as well as overall and progression-free survival in patients with newly diagnosed PCNSL. Comparisons of long-term survival in the 2 cohorts await further maturation of the data.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that in immunocompetent patients with PCNSL, HD-MTX plus rituximab compared with HD-MTX alone improves CR and overall survival rates.
Fifty-three patients with resected pancreatic adenocarcinoma were studied to determine if adjuvant chemo-radiation causes severe lymphopenia and if this is associated with adverse outcomes. Total ...lymphocyte counts (TLC) were normal in 91% before adjuvant chemo-radiation. Two months later, TLC fell by 63% (p < .0001) with 45% of patients having TLC < 500 cells/mm3. Median survival in patients with low TLC was 14 versus 20 months (p = .048). Multivariate analysis revealed a significant association between treatment related lymphopenia and survival (HR 2.2, p = .014). Adjuvant chemo-radiation induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following ...promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
The blood–brain-barrier (BBB) limits the penetration of many systemic antineoplastic therapies. Consequently, many agents may be used in clinical studies and clinical practice though they may not ...achieve therapeutic levels within the tumor. We sought to compile the currently available human data on antineoplastic drug concentrations in brain and tumor tissue according to BBB status. A review of the literature was conducted for human studies providing concentrations of antineoplastic agents in blood and metastatic brain tumors or high-grade gliomas. Studies were considered optimal if they reported simultaneous tissue and blood concentration, multiple sampling times and locations, MRI localization, BBB status at sampling site, tumor histology, and individual subject data. Twenty-Four studies of 19 compounds were included. These examined 18 agents in contrast-enhancing regions of high-grade gliomas, with optimal data for 2. For metastatic brain tumors, adequate data was found for 9 agents. Considerable heterogeneity was found in the measurement value, tumor type, measurement timing, and sampling location within and among studies, limiting the applicability of the results. Tissue to blood ratios ranged from 0.054 for carboplatin to 34 for mitoxantrone in high-grade gliomas, and were lowest for temozolomide (0.118) and etoposide (0.116), and highest for mitoxantrone (32.02) in metastatic tumors. The available data examining the concentration of antineoplastic agents in brain and tumor tissue is sparse and limited by considerable heterogeneity. More studies with careful quantification of antineoplastic agents in brain and tumor tissue is required for the rational development of therapeutic regimens.
Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum ...tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.
Hyperglycemia has been associated with poor outcomes in many disease states. This retrospective study assessed the association between hyperglycemia and survival in patients with newly diagnosed ...glioblastoma multiforme (GBM). PATIENTS AND METHODS; Between 1999 and 2004, before the standard use of temozolomide, 191 patients were accrued onto New Approaches to Brain Tumor Therapy CNS Consortium trials with similar eligibility criteria. Time-weighted mean glucose and mean glucocorticoid dose were calculated for each patient using all values collected regularly in follow-up. The primary outcome was survival.
Mean glucose levels ranged between 65 and 459 mg/dL. These were divided into quartiles: quartile one (< 94 mg/dL), quartile two (94 to 109 mg/dL), quartile three (110 to 137 mg/dL), and quartile four (> 137 mg/dL). Median survival times for patients in quartiles one, two, three, and four were 14.5, 11.6, 11.6, and 9.1 months, respectively. The association between higher mean glucose and shorter survival persisted after adjustment for mean daily glucocorticoid dose, age, and baseline Karnofsky performance score (KPS). Compared with patients in the lowest mean glucose quartile, those in quartile two (adjusted hazard ratio HR, 1.29; 95% CI, 0.85 to 1.96), quartile three (adjusted HR, 1.35; 95% CI, 0.89 to 2.06), and quartile four (adjusted HR, 1.57; 95% CI, 1.02 to 2.40) were at progressively higher risk of dying (P = .041 for trend).
In these patients with newly diagnosed GBM and good baseline KPS, hyperglycemia was associated with shorter survival, after controlling for glucocorticoid dose and other confounders. The effect of intensive management of glucocorticoid-related hyperglycemia on survival deserves additional study in patients with GBM.
Radiation-induced lymphopenia (RIL) is associated with worse survival in patients with solid tumors, as well as lower response rates to checkpoint inhibitors. While single-fraction total-body ...irradiation is known to result in exponential decreases in the absolute lymphocyte count (ALC), the kinetics of lymphocyte loss after focal fractionated exposures have not previously been characterized. In the current study, lymphocyte loss kinetics was analyzed among patients undergoing focal fractionated radiotherapy for clinical indications. This registry-based study included 419 patients who received either total-body irradiation (TBI; n = 30), stereotactic body radiation therapy (SBRT; n = 73) or conventionally fractionated chemoradiation therapy (CFRT; n = 316). For each patient, serial ALCs were plotted against radiotherapy fraction number. The initial three weeks of treatment for CFRT patients and the entirety of treatment for SBRT and TBI patients were fit to exponential decay in the form
(
) =
, where
(
) is the ALC after
fractions. From those fits, fractional lymphocyte loss (FLL) was calculated as FLL = (1 -
) * 100, and multivariable regression was performed to identify significant correlates of FLL. Median linearized R
when fitting the initial fractions was 0.98, 0.93 and 0.97 for patients receiving TBI, SBRT and CFRT, respectively. In CFRT patients, apparent ALC loss rate slowed after week 3. Fitting ALC loss over the entire CFRT course therefore required the addition of a constant term, "
". For TBI and SBRT patients, treatment ended during the pure exponential decay phase. Initial FLL varied significantly with treatment technique. Mean FLL was 35.5%, 24.3% and 10.77% for patients receiving TBI, SBRT and CFRT, respectively (
< 0.001). Significant correlates of FLL varied by site and included field size, dose per fraction, mean spleen dose, chemotherapy backbone and age. Finally, total percentage ALC loss during radiotherapy was highly correlated with FLL (
< 0.001). Lymphocyte depletion kinetics during the initial phase of fractionated radiotherapy are characterized by pure exponential decay. Initial FLL is strongly correlated with radiotherapy planning parameters and total percentage ALC loss. The two groups with the highest FLL received no concurrent chemotherapy, suggesting that ALC loss can be a consequence of radiotherapy alone. This work may assist in selecting patients for adaptive radiotherapy approaches to mitigate RIL risk.
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