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Despite having been long regarded as too toxic for adult patients, pediatric-like regimens containing L-asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated-asparaginase (PEG-asp) in adults, we reviewed all doses (2000 IU/m(2) ) administered as part of a pediatric-inspired regimen in adult ALL at our center. Subjects aged 18-60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3-4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3-4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG-asp was always discontinued after grades 3-4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG-asp dosing is safe in adults aged 18-60 yr, even after occurrence of a drug-related toxicity., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Conventional stroke risks are thought responsible for most cerebral ischemic events (CIE) in adult cancer patients. Also suspected as a risk is cisplatin chemotherapy, alone or in combination with tumor angiogenesis inhibitor. We investigated whether treatment or tumor characteristics, independently of conventional stroke risks, are associated with CIE in a retrospective cohort study of 1,559 patients with advanced non-small cell lung cancer or hormone-refractory prostate cancer followed during 3 clinical trials of matrix metalloprotease inhibitor (prinomastat) versus placebo, with chemotherapy (gemcitabine/cisplatin, paclitaxel/carboplatin or mitoxantrone/prednisone). During 11,907 patient-months, 28 CIE (17 cerebral infarction, 11 transient ischemic attack) were diagnosed in 24 patients, all but 1 over 55 years. Neither prinomastat, platinum-based chemotherapy nor their combination was associated with CIE after age 55. However, such events were predicted by the presence of distant metastases in the liver or lungs and not in distant lymph nodes (hazard estimate 4.6, 95% CI 2.0-10.5, adjusted for conventional stroke risks). Further studies are needed to verify this preliminary finding and determine its generalizability to advanced tumors other than lung or prostate cancer.

Background Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. Patients and Methods We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method. Results The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28). Conclusion While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib. [ABSTRACT FROM AUTHOR]

Background: Objective, treatment-independent markers of cancer-related fatigue are needed to advance clinical trials. In the current study, the authors evaluated physical, neurocognitive, and serologic markers for correlation with self-reported fatigue before and after (neo)adjuvant chemotherapy for patients with early-stage breast cancer.Methods: Women with AJCC TNM Stage I-III breast cancer consented to assessment before and after the completion of 4 cycles of dose-dense doxorubicin and cyclophosphamide. Assessment included self-reported fatigue (using the Brief Fatigue Inventory), depression (using the Center for Epidemiologic Studies-Depression Scale [CES-D]), Pittsburgh Sleep Quality Index, and 28 objective measures (grip strength in dominant and nondominant hands, 6-minute walk, daily total energy expenditure, 14 neurocognitive tests, and 10 serologic markers). Generalized linear regression models of fatigue were constructed (1 model per marker), and adjusted for depression, timing before/after chemotherapy, menopausal status, obesity, and educational level. P values were adjusted to control the False Discovery Rate.Results: Of 28 subjects, 3 withdrew without completing baseline assessments. Prechemotherapy and postchemotherapy data were available for the evaluation of physical measures (25 subjects aged 50.6 ± 9.5 years), neurocognitive tests (22 subjects), and serologic markers (10 subjects). On covariate-adjusted analysis, interleukin (IL)-12 was found to be associated with fatigue at both assessments (P<.01). Serum eotaxin (P < .01), IL-1RA (P < .01), monocyte chemoattractant protein 1 (MCP-1) (P<.01), and performance on 2 neurocognitive (Trail Making) tests (P<.01 and P = .02, respectively) were found to be inversely associated with fatigue before chemotherapy but not afterward, whereas daily energy expenditure, serum MCP-1, and serum macrophage inflammatory protein 1a (MIP-1a) were found to be associated with fatigue after receipt of chemotherapy but not before (P<.01 for each). The association between energy expenditure and fatigue was detectable only if an actively athletic subject with outlier values of energy expenditure was excluded.Conclusions: Serum IL-12 merits confirmatory testing as an objective, treatment-independent measure of fatigue in patients with early-stage breast cancer. Cancer 2017;123:1810-1816. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. [ABSTRACT FROM AUTHOR]

Abstract: Phase II trial designs that ignore between-patient heterogeneity and do not allow for treatment–subgroup interactions may produce very large false positive and false negative error rates if efficacy varies by subgroup. Recent discussions of this problem were illustrated with scenarios and computer simulations. In this short communication, we reanalyzed a published phase II trial to highlight the need to consider between-patient heterogeneity and the possibility of treatment–subgroup interaction when designing and analyzing phase II studies. The single-arm trial evaluated amsacrine plus cytosine arabinoside, vincristine, and prednisone (a combination abbreviated as OAP) for adult acute leukemia, when standard treatment was adriamycin plus OAP. We carried out an analysis of covariance (ANCOVA) incorporating data from historical control patients who met eligibility criteria for the trial and received standard treatment at the study center in the years immediately preceding the trial. Patients administered experimental treatment and control patients were classified as having favorable or unfavorable prognosis according to their predicted probability of response to standard treatment. When the prognostic subgroup of patients was ignored, the response rates for experimental and standard treatment appeared similar. However, fitting an ANCOVA model determined that the effects of subgroup, treatment, and their interaction were statistically significant: experimental treatment was superior to standard treatment in patients with unfavorable prognosis and inferior to standard treatment in patients with favorable prognosis. This real-world example of treatment–subgroup interaction highlights the need to employ phase II designs that consider between-patient heterogeneity and the possibility that efficacy differs by subgroup. [Copyright &y& Elsevier]