open access (pdf) Underestimating Cardiac Toxicity in Cancer Trials: Lessons Learned?

Underestimating Cardiac Toxicity in Cancer Trials:Lessons Learned?

Sunitinib (Sutent; Pfizer, New York, NY) represents one of the
most successful cancer therapies, with US Food and Drug Administration (FDA) approval for three malignancies and ongoing trials in more than 30 tumor types.1,2 It also represents an instructive example revealing how adverse events can be vastly underestimated. The purpose of this article is to critically evaluate the history of the underrecognition of the cardiac toxicity of sunitinib and to propose solutions to improve adverse event monitoring for future therapies.......

"Cardiac toxicity from a wide variety of tyrosine kinase inhibitors
is now recognized to be of importance, with toxicity observed
from both on- and off-target effects. In the case of sunitinib, which
inhibits more than 50 kinases, mechanisms likely include inhibition
of angiogenesis and disturbances of mitochondrial structure
and energy metabolism—both potentially similarly important for
tumor proliferation.11,13"

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy:

Background:
.....This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting.

Material and methods:
The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously).

Results:
Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9–8.1] months; arm 2: 2.9 [2.9–5.1] months) and the median overall survival (arm 1: 13.6 [7.0–23.2] months; arm 2: 13.7 [8.4–25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups.

Conclusions:
Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

Expert Review - slides: Renal Cell Carcinoma Biology and the Rationale for VEGF (sorafenib, sunitinib, erlotinib, avastin, interleukins, etc)

Note: if you are unable to access this slide presentation it is because you need to register on the site (free); it may be of interest to those with clear cell ovarian cancer; the largest % of renal cancers are of the clear cell subtype (a known ~75%) ------------------------------------------------------------------------------------------------------- MODULE 1: Renal Cell Carcinoma Biology and Rationale for VEGF Expert review with Lee Lokey, MD, and Brian I. Rini, MD, focusing on renal cell carcinoma
Discussant:	Brian I. Rini, MD—Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, United States
Interviewed by:	Lee Lokey, MD—prIME Oncology, Atlanta, Georgia, United States

JCO: Lettter: Risk of Arterial Thrombosis Not Increased by Sorafenib or Sunitinib

Note: analyzing the research including a reference to Avastin

A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study

Results: Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand–foot syndrome and hypertension. No gastrointestinal perforation occurred.

Conclusions: Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.

Cardiovascular Safety of VEGF-Targeting Therapies: Current Evidence and Handling Strategies -- Girardi et al., 10.1634/theoncologist.2009-0235 -- The Oncologist

Abstract
Treatment with the angiogenesis inhibitors bevacizumab, sunitinib, and sorafenib as single agents or in combination with conventional chemotherapy is becoming a cornerstone of modern anticancer therapy. However, the potential toxicity of these drugs, mainly to the cardiovascular system, is still being investigated. Patient assessment at baseline, of crucial importance in candidates for treatment, involves the evaluation of risk factors and screening for past or present cardiovascular disease. Strict monitoring of treatment-related adverse effects must be conducted in order to allow the early detection of cardiovascular toxicities and their prompt medication. In the present paper, the most frequent cardiovascular toxicities and their underlying mechanisms are investigated, with a view to providing indications for effective patient management.

Translating Science Behind Cancer Cell Starvation into New Therapy (hydroxychloroquine and sunitinib-early stage trial)