Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients.
OBJECTIVE
Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue. Tumor necrosis factor (TNF) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies. We used etanercept (TNF-decoy receptor) to maintain dose-intensity of weekly docetaxel.


METHODS
Initially, 12 patients with advanced malignancies were randomly assigned to either docetaxel 43 mg/m2 weekly alone (cohort A) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly (cohort B). Subsequently, higher doses of docetaxel in combination with etanercept were evaluated. Pharmacokinetics (PKs), nuclear factor-kappa B (NF-kappaB) activation, and intracellular cytokines levels were measured. Patients completed weekly questionnaires quantifying asthenia/fatigue.


RESULTS
Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A, and 35 of 36 doses were delivered in cohort B (P = .055). Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity, whereas no patients from cohort A received additional cycles. Escalation to docetaxel 52 mg/m2 weekly with etanercept resulted in neutropenia, not fatigue, as the limiting adverse effect, and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients. Patients randomly selected to receive etanercept/docetaxel self-reported less fatigue (P < .001), and docetaxel PKs show no relevant influence of etanercept. NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose. Antitumor activity was noticed exclusively in patients receiving etanercept.


CONCLUSIONS
The addition of etanercept is safe and had no impact on docetaxel concentrations. The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies.
Monk
J Paul
JP
Division of Hematology/Oncology, Department of Internal Medicine and Center for Biostatistics, The Ohio State University College of Medicine and Public Health, Columbus, OH, USA.
Phillips
Gary
G
Waite
Ross
R
Kuhn
John
J
Schaaf
Larry J
LJ
Otterson
Gregory A
GA
Guttridge
Denis
D
Rhoades
Chris
C
Shah
Manisha
M
Criswell
Tamara
T
Caligiuri
Michael A
MA
Villalona-Calero
Miguel A
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001247:Asthenia / Q000139:chemically induced / Q000517:prevention & control; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D000068800:Etanercept; D005221:Fatigue / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D043823:Taxoids; D014409:Tumor Necrosis Factor-alpha; D000077143:Docetaxel; D000068800:Etanercept