In order to derive maximum benefit from treatment with
chemotherapeutic agents, adherence to the established chemotherapy
dose and schedule is imperative.[1,2] This is well supported by the
demonstration, in retrospective and prospective studies, of
higher rates of disease remission and overall survival rates among
patients with cancer who received standard or near-standard doses of
chemotherapeutic agents in comparison with those patients who
received reduced doses. In addition, some trial data suggest improved
outcomes in patients who are able to tolerate higher than standard
doses of chemotherapy for treatment of solid tumor malignancies.[4-6]
However, delivering the full amount of the calculated dose is not
always possible because of the toxic effects on bone
marrowparticularly hematologic toxicities such as neutropenia
and thrombocytopeniainvariably caused by anticancer treatments.
Improving Outcomes by Optimizing Platelet Support
Although granulocyte colony-stimulating factor (G-CSF, filgrastim
[Neupogen]) and granulocyte-macrophage colony-stimulating factor
(GM-CSF, molgramostim [Leucomax]) are capable of ameliorating the
risk of neutropenic infections, they do not address the problem of
thrombocytopenia. In fact, they may actually aggravate
thrombocytopenia by permitting the use of more highly myelotoxic
agents or more dose-intensive oncology regimens.[7,8] As a result,
thrombocytopenia induced by anticancer therapy has emerged as the
major dose-limiting hematologic toxicity among patients with cancer.
The standard practice of reducing drug doses or delaying the next
cycle of chemotherapy in patients with low platelet counts may be
acceptable for patients receiving palliative chemotherapy. However,
because of the reduced likelihood of cure or disease remission, this
reactive style of toxicity management is less acceptable for patients
receiving aggressive chemotherapy with a curative intent. Perhaps a
more proactive approach should be considered now that the
availability of platelet growth factors has provided clinicians with
a means of supporting platelet homeostasis during chemotherapy. This
approach presents the possibility of enabling cancer patients to
receive full doses of chemotherapy without interruption, potentially
improving tumor control and, ultimately, survival.
Epidemiologic data indicate that approximately one-quarter of the
patients undergoing chemotherapy for nonmyeloid malignancies can
expect reductions in platelet counts to nadirs £
50,000/µL.[9,10] For these patients, the standard management
strategy has been to continue chemotherapy using reduced drug doses
if platelets are at £
50,000/µL, or to delay administering the next cycle until
platelets have recovered to ³
100,000/µL. Therefore, the probability of cure may be
compromised because of slow platelet recovery.
With the increasing knowledge of the diverse regulatory role of
cytokines and growth factors in biological systems and the rapid
development of human recombinant forms, the development of a
clinically useful platelet growth factor was inevitable. Recombinant
human interleukin-11 (rhIL-11, also known as oprelvekin [Neumega]) is
currently the only drug approved by the US Food and Drug
Administration for the prevention of chemotherapy-induced
thrombocytopenia in patients with nonmyeloid malignancies. This
multifunctional cytokine is defined as a thrombopoietic
(platelet) growth factor with efficacy established in
controlled clinical trials.
Both adult and pediatric patients with solid tumors or lymphomas have
been safely treated with rhIL-11. Adults have benefited from rhIL-11
therapy in terms of preventing the development of platelet nadirs <
20,000/µL, accelerating platelet recovery, and/or subsequently
reducing the requirement for platelet transfusions. Positive trends
have been seen in children as well, but no definitive controlled
pediatric trials have been performed. rhIL-11 is generally well
tolerated, with little cause for discontinuation in controlled
clinical trials. Edema is the most frequently reported adverse event,
but it is usually easily managed and reversible.
Prophylactic therapy with rhIL-11 must be started within 24 hours
after the last dose of chemotherapy and continued for 10 to 21 days
until platelet counts of ³
50,000/µL are achieved. Early initiation of therapy takes into
account the stimulatory role of rhIL-11 throughout both early and
later stages of megakaryocytopoiesis, providing for the release of
newly formed platelets into circulation at approximately the same
time as the expected postchemotherapy platelet nadir. Bearing in mind
the maturation time of megakaryocytes, it is clear that rhIL-11 is
not designed to function as rescue therapy once patients
have become severely thrombocytopenic (platelet count < 20,000/µL).
For the purpose of supporting the delivery of unmodified chemotherapy
regimens, rhIL-11 therapy should be initiated prophylactically, when
there is a high probability that platelet reductions resulting in
dose reduction and/or delay will occur (platelet counts of £
50,000 or even £ 70,000/µL).
During myelosuppressive chemotherapy, the administration of
subsequent cycles is routinely delayed until the platelet count has
recovered to 100,000/µL as mandated by almost all protocols for
investigations of chemotherapeutic regimens.[7,11-16]
A demonstrated ancillary benefit of rhIL-11 therapys
thrombopoietic effect is avoidance of platelet transfusions.
Considering the numerous transfusion-related complications, this
would be welcomed by both clinicians and patients. For example, the
recently and highly publicized risk of contracting bacterial and
viral infections from transfused blood products is undoubtedly a
major concern. Among patients with cancer who are already
immunosuppressed, contracting infections from treatments intended to
support their well-being is an irony they can ill afford.
Furthermore, the development of refractoriness to repeated platelet
transfusions is a significant risk.
In summary, when used appropriately, rhIL-11 enhances platelet
recovery and, thus, facilitates the maintenance of aggressive
chemotherapy regimens without dose modification, thereby enabling the
best possible outcome in patients with nonmyeloid malignancies.
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