anemia and ESA's

[Guest guest]

http://tinyurl.com/ytz7c4

Regulatory

and fiscal considerations aside, why might ESAs have different

effects on survival in patients with anemia of cancer compared with

chemotherapy-induced anemia? There are several possible

explanations, but one of the more interesting relates to the

different relative risks of transfusion in the two groups of

patients. Among patients with chemotherapy-associated anemia, the

transfusion rate in those who receive ESAs is typically approximately

20%, compared with 45% for placebo-treated patients.22,23

In contrast, in the Amgen 103 study, the placebo group's transfusion

rate was only 23.9%, which is similar to other studies in the anemia

of cancer.

Perhaps transfusions are harmful to patients with cancer

by way of transfusion-related immune modulation, which is a real

biologic phenomenon but is of uncertain clinical significance.24

If ESAs are also potentially harmful, but are less risky than

transfusions, then benefits from the transfusion-sparing effect of

ESA use in chemotherapy-associated anemia would trump any adverse

effects from the ESA itself. In contrast, because the

transfusion-sparing effect is not significant in patients who are

not getting myelosuppressive chemotherapy, negative effects of the

ESA dominate. This hypothesis is speculative but warrants further

exploration.

The most

difficult practical issue in restricting ESA use to patients with

chemotherapy-induced anemia is in knowing just when patients fit

into that category. Treatment for cancer often proceeds

by fits and starts, with pauses in therapy because of achievement of

maximal response or excessive toxicity. When therapy is on hold but

anemia persists, it is often ambiguous when anemia is no longer due

to the effect of a drug. At the other end of the spectrum, patients

with cancer

are often anemic at diagnosis; if such patients are still anemic

after a month or two of treatment, should that anemia be considered

as owing to cancer, its treatment, or both?

Published studies of ESAs offer little guidance for clinical

decision-making in this area, because investigators have not always

carefully defined the patients enrolling in their studies.

Another

practical problem faced by clinicians is that cancer treatment is

changing. Contemporary chemotherapy is (thankfully!) different from

the chemotherapy used 20 years ago when the first clinical studies

with epoetin began. Although most patients with advanced cancer

are still treated with traditional cytotoxic agents, as in the late

1980s, a growing number of kinase inhibitors, monoclonal antibodies,

immunomodulatory agents, hormonal antagonists and partial agonists,

epigenetic pattern modifiers, and other biologic therapies have made

their way into the clinic, to the great benefit of our patients.

These advances bring new dilemmas: is anemia that develops during

treatment with these newer agents the same as old-fashioned

chemotherapy-induced anemia from cytotoxics? Several of the new

biologics do have important effects on erythropoiesis. For instance,

almost 90% of patients with gastrointestinal stromal tumors develop

anemia during imatinib therapy, and this anemia is classified as

grade 3 or 4 in 10% of patients.25

Likewise, sunitinib monotherapy for metastatic renal cell carcinoma

is associated with a 26% rate of clinically significant anemia,

whereas the rate of grade 3 or 4 anemia with sirolimus for the same

disease is approximately 9%.26,27

These agents are not cytotoxic or myelosuppressive in the

traditional sense, so the safety of ESAs in this setting is not

established. Yet neither is there any evidence that ESAs are unsafe

when given with newer biologics; there is simply no evidence at all.

If there

is one thing that the 2007 annus horribilis

for ESAs has reminded us, it is that even when therapies are used

for a long time in large numbers of patients, there are always

plenty of unanswered questions. The need for more clinical trials is

endless. For now, the American Society of Hematology/American Society

of Clinical Oncology clinical practice guideline for ESA use—which

was recently revised, and which I was not involved in developing but

support wholeheartedly—is conservative, thoughtful, and based

on careful review of complex evidence by experts.28,29

This guideline should be required reading for all hematologists and

oncologists treating patients. Medicare bureaucrats and members of

the United States Congress currently reviewing governmental ESA

policy might learn something from them as well.