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"

abstract: Extraperitoneal metastases from recurrent ovarian cancer. (study n=233 women) eg. lung, CNS, pulmonary, skin (cutaneous)

Blogger's note: requires subscription ($$$) for full text

OBJECTIVES:

To identify patterns of metastasis in patients with recurrent ovarian cancer. The influence of the route of chemotherapy administration and sequence of agents on those patterns is also examined.

RESULTS:

Thirty-five subjects developed extraperitoneal recurrent ovarian cancer, with 26 subjects (74%) after IP treatment, and 9 subjects (26%) after IV treatment. Of these extraperitoneal recurrences, 26 were in the thoracic/pulmonary cavity, 7 were within the central nervous system (CNS), and 2 were in the cutaneous (skin) tissues. The CNS and cutaneous lesions were secondary recurrences, and all occurred in subjects who had initially received IP cisplatin/paclitaxel followed by IV BEV for recurrent disease.

CONCLUSIONS:

Extraperitoneal recurrences were more common in women treated with IP chemotherapy for ovarian cancer. Specifically, women treated with IV BEV as secondary therapy after IP were at particularly high risk of extraperitoneal metastases, including in the CNS and cutaneous tissues. Physicians should be aware of the possibility of unusual metastases after the combination of IP chemotherapy and BEV, and future prospective studies of this population should carefully evaluate recurrence site patterns.

EvidenceUpdates + professional commentaries (numerous): Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women`s Health Initiative limited access dataset and meta-analysis

OBJECTIVES: To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women`s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.

DESIGN: Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies.........

Conclusions: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

Review - EvidenceUpdates: Congestive heart failure risk in patients with breast cancer treated with bevacizumab/Avastin (including professional commentary)

1) link including professional commentary (BMJ Evidence Centre/McMaster)

2) additional link to abstract (JCO)

Genomics|Update|Current - Recommendation on Genetic Testing for Risk of Cardiovascular Disease

Recommendation on Genetic Testing for Risk of Cardiovascular Disease
 
This month the independent Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group has released a new evidence-based recommendation on the use of “cardiogenomic profiles” (or “heart health”) genetic tests. These tests are being marketed to physicians and the general public as a way to find out a person’s risk for cardiovascular disease, and some can be ordered online without the involvement of a physician. The EGAPP Working Group did not find enough evidence to indicate whether these tests should or should not be used to determine future cardiovascular risk in the general population, and currently discourages the use of this testing except in research settings. Access the EGAPP recommendation. Read more about the EGAPP recommendation.

abstract: Monitoring long-term treatment with pegylated liposomal doxorubicin: how important is intensive cardiac follow-up?

"PLD is cardiac safe for long-term treatment of metastatic solid tumors. Its maximal cumulative dose remains undefined. "

How to Avoid a Heart Attack: Putting It All Together -Journal of the American Osteopathic Association

Note: this is not specific to treatment-related cardiovascular concerns

Conclusion
The central question posed in the letter to the editor by Juhl et al2 is whether supplements of vitamins E and C and the B vitamins have demonstrated an evidence-based reduction in patients' cardiovascular risk. Unfortunately, the authors' criticism of the perceived deficiencies of a previously published study1 does not constitute evidence to support their position; it serves only to point out those perceived flaws.

Multiple meta-analyses and reviews of published medical literature have convincingly established that there are few, if any, objective, evidence-based, well-designed trials to support the use of supplements of vitamins E or C or those in the B family to reduce risk of cardiovascular events. Furthermore, I am unaware of any study that advocates the use of these supplements to help patients or to rejuvenate our ailing medical delivery system.

If Dr Juhl and his coauthors2 seek to establish the medical value of these supplements, I would recommend that they design, participate in, and publish a study to establish their yet unproven hypothesis. Until such a goal is accomplished, my opinion (shared by researchers at the Mayo Clinic,3 the Cleveland Clinic,5 the AHRQ,12 and the American Heart Association19) is that published evidence clearly does not support the use of vitamins E, C, B6, B9, or B12 to improve patients' cardiovascular health.

Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement -- Concensus Statement/Review

Conclusions:
The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause.
At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

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.

Oncology Videos - Consider Your Heart During Cancer Treatment (heart failure during/associated with cancer therapy)

High cumulative incidence of cancer in patients with cardio-renal-anaemia syndrome (chronic kidney disease)

Aims
The combination of chronic kidney disease (CKD), chronic heart failure (HF), and anaemia, the so-called cardio-renal-anaemia syndrome (CRA) is associated with dysregulation of erythropoietin levels and inflammation. Both have been associated with the development of cancer. This study aimed to determine the cumulative incidence of cancer in patients with CRA, as compared with anaemic CKD and control patients.

Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Collaboration Database Systematic Review

CONCLUSIONS:
We are not able to favour either epirubicin or doxorubicin when given with the same dose. Based on the currently available evidence on heart failure, we conclude that in adults with a solid tumour liposomal-encapsulated doxorubicin should be favoured over doxorubicin. For both epirubicin versus doxorubicin and liposomal-encapsulated doxorubicin versus conventional doxorubicin no conclusions can be made about the effects of treatment in children treated with anthracyclines and also not in patients diagnosed with leukaemia. More research is needed. For other combinations of anthracycline derivates not enough evidence was available to make definitive conclusions about the occurrence of cardiotoxicity in patients treated with anthracyclines.

CCardiology

Probably an important review but it would have been more helpful for the general practitioner if the authors also reviewed or at least discussed the role of ACE-Inhibitors given before anthracycline treatment in these patients.

ommentary (1) at present:

Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor Bevacizumab in cancer patients: A meta-analysis of randomized controlled trials

abstract