Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas

INTRODUCTION: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity. MATERIALS AND METHODS: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment. RESULTS: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care. CONCLUSION: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin®▾) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care

Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast cancer.

BACKGROUND AND AIMS: Anthracyclines are highly effective chemotherapeutic agents which may cause long-term cardiac damage (chronic anthracycline cardiotoxicity) and heart failure. The pathogenesis of anthracycline cardiotoxicity remains incompletely understood and individual susceptibility difficult to predict. We sought clinical features which might contribute to improved risk assessment. METHODS: Subjects were women with early breast cancer, free of pre-existing cardiac disease. Left ventricular ejection fraction was measured using cardiovascular magnetic resonance before and >12 months after anthracycline-based chemotherapy (>3 months post-Trastuzumab). Variables associated with subclinical cardiotoxicity (defined as a fall in left ventricular ejection fraction of ≥5%) were identified by logistic regression. RESULTS: One hundred and sixty-five women (mean age 48.3 years at enrollment) completed the study 21.7 months [IQR 18.0-26.8] after starting chemotherapy. All received anthracyclines (98.8% epirubicin, cumulative dose 400 [300-450] mg/m2); 18% Trastuzumab. Baseline blood pressure was elevated (≥140/90mmHg, mean 147.3/86.1mmHg) in 18 subjects. Thirty-four subjects (20.7%) were identified with subclinical cardiotoxicity, independent predictors of which were the number of anthracycline cycles (odds ratio, OR 1.64 [1.17-2.30] per cycle), blood pressure ≥140/90mmHg (OR 5.36 [1.73-17.61]), body surface area (OR 2.08 [1.36-3.20] per standard deviation (0.16m2) increase), and Trastuzumab therapy (OR 3.35 [1.18-9.51]). The resultant predictive-model had an area under the receiver operating characteristics curve of 0.78 [0.70-0.86]. CONCLUSIONS: We found subclinical cardiotoxicity to be common even within this low risk cohort. Risk of cardiotoxicity was associated with modestly elevated baseline blood pressure-indicating that close attention should be paid to blood pressure in patients considered for anthracycline based chemotherapy. The association with higher body surface area suggests that indexing of anthracycline doses to surface area may not be appropriate for all, and points to the need for additional research in this area

Admission of advanced lung cancer patients to intensive care unit: A retrospective study of 76 patients

<p>Abstract</p> <p>Background</p> <p>Criteria for admitting patients with incurable diseases to the medical intensive care unit (MICU) remain unclear and have ethical implications.</p> <p>Methods</p> <p>We retrospectively evaluated MICU outcomes and identified risk factors for MICU mortality in consecutive patients with advanced lung cancer admitted to two university-hospital MICUs in France between 1996 and 2006.</p> <p>Results</p> <p>Of 76 included patients, 49 had non-small cell lung cancer (stage IIIB n = 20; stage IV n = 29). In 60 patients, MICU admission was directly related to the lung cancer (complication of cancer management, n = 30; cancer progression, n = 14; and lung-cancer-induced diseases, n = 17). Mechanical ventilation was required during the MICU stay in 57 patients. Thirty-six (47.4%) patients died in the MICU. Three factors were independently associated with MICU mortality: use of vasoactive agents (odds ratio [OR] 6.81 95% confidence interval [95%CI] [1.77-26.26], p = 0.005), mechanical ventilation (OR 6.61 95%CI [1.44-30.5], p = 0.015) and thrombocytopenia (OR 5.13; 95%CI [1.17-22.5], p = 0.030). In contrast, mortality was lower in patients admitted for a complication of cancer management (OR 0.206; 95%CI [0.058-0.738], p = 0.015). Of the 27 patients who returned home, four received specific lung cancer treatment after the MICU stay.</p> <p>Conclusions</p> <p>Patients with acute complications of treatment for advanced lung cancer may benefit from MCIU admission. Further studies are necessary to assess outcomes such as quality of life after MICU discharge.</p

Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography

Cancer therapy has shown terrific progress leading to important reduction of morbidity and mortality of several kinds of cancer. The therapeutic management of oncologic patients includes combinations of drugs, radiation therapy and surgery. Many of these therapies produce adverse cardiovascular complications which may negatively affect both the quality of life and the prognosis. For several years the most common noninvasive method of monitoring cardiotoxicity has been represented by radionuclide ventriculography while other tests as effort EKG and stress myocardial perfusion imaging may detect ischemic complications, and 24-hour Holter monitoring unmask suspected arrhythmias. Also biomarkers such as troponine I and T and B-type natriuretic peptide may be useful for early detection of cardiotoxicity. Today, the widely used non-invasive method of monitoring cardiotoxicity of cancer therapy is, however, represented by Doppler-echocardiography which allows to identify the main forms of cardiac complications of cancer therapy: left ventricular (systolic and diastolic) dysfunction, valve heart disease, pericarditis and pericardial effusion, carotid artery lesions. Advanced ultrasound tools, as Integrated Backscatter and Tissue Doppler, but also simple ultrasound detection of "lung comet" on the anterior and lateral chest can be helpful for early, subclinical diagnosis of cardiac involvement. Serial Doppler echocardiographic evaluation has to be encouraged in the oncologic patients, before, during and even late after therapy completion. This is crucial when using anthracyclines, which have early but, most importantly, late, cumulative cardiac toxicity. The echocardiographic monitoring appears even indispensable after radiation therapy, whose detrimental effects may appear several years after the end of irradiation

Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy

Gemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematological malignancies and has become the standard chemotherapy for the treatment of advanced pancreatic cancer. Combinational gemcitabine regimes (e.g. with doxorubicin) are being tested in clinical trials to treat a variety of cancers, including colon cancer. The limited success of these trials has prompted us to pursue a better understanding of gemcitabine's mechanism of cell killing, which could dramatically improve the therapeutic potential of this agent. For comparison, we included gamma irradiation that triggers robust cell cycle arrest and Cr(VI), which is a highly toxic chemical that induces a robust p53-dependent apoptotic response. Gemcitabine induced a potent p53-dependent apoptosis that correlated with the accumulation of pro-apoptotic proteins such as PUMA and Bax. This is accompanied by a drastic reduction in p2l and 14-3-3 sigma protein levels, thereby significantly sensitizing the cells to apoptosis. In vitro and in vivo studies demonstrated that gemcitabine required PUMA transcription to instigate an apoptotic programme. This was in contrast to Cr(VI)-induced apoptosis that required Bax and was independent of transcription. An examination of clinical colon and pancreatic cancer tissues shows higher p53, p21, 14-3-3 sigma and Bax expression compared with matched normal tissues, yet there is a near absence of PUMA protein. This may explain why gemcitabine shows only limited efficacy in the treatment of these cancers. Our results raise the possibility that targeting the Bax-dependent cell death pathway, rather than the PUMA pathway, could result in significantly improved patient outcome and prognosis for these cancers.Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BPD/84634/2012]; European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Canadian Institute of Health Researchinfo:eu-repo/semantics/publishedVersio

Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments