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Assessment of Tumor Necrosis Factor Alpha Blockade As an Intervention to Improve Tolerability of Dose-Intensive Chemotherapy in Cancer Patients

J. Paul Monk, Gary Phillips, Ross Waite, John Kuhn, Larry J. Schaaf, Gregory A. Otterson, Denis Guttridge, Chris Rhoades, Manisha Shah, Tamara Criswell, Michael A. Caligiuri, Miguel A. Villalona-Calero

From the Division of Hematology/Oncology, Department of Internal Medicine and Center for Biostatistics, The Ohio State University College of Medicine and Public Health; The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, Ohio State University, Columbus, OH; and The University of Texas Health Science Center at San Antonio, San Antonio, TX

Address reprint requests to Miguel A. Villalona-Calero, MD, The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital, Ohio State University, B406 Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210-1240; e-mail: MigueL.Villalona{at}osumc.edu

	ABSTRACT

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PURPOSE: 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.

PATIENTS AND 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-B) 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-B activation and increased expression of TNF- were associated with increments in docetaxel dose. Antitumor activity was noticed exclusively in patients receiving etanercept.

CONCLUSION: 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.

	INTRODUCTION

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Cytotoxic chemotherapy has been the most consistent form of treatment for advanced disease in solid tumor oncology for more than 30 years, yet no consensus has developed on the importance of maintaining chemotherapy dose-intensity and/or density.¹ This is in contrast to hematologic malignancies, in which preserving dose-intensity has been associated with improved median survival.^2-4

In recent years, attention has been given to the superior disease-free and overall survival demonstrated by dose-intensity within a conventional chemotherapy dose range⁵ and by dose density^6,7 in patients with axillary node–positive breast cancer. Dose-dense chemotherapy emerges from the concept that, at the same total dose, shorter intervals of administration of a particular chemotherapy agent best avoids repopulation of cancer cells.⁶ Although colony-stimulating factors have been instrumental in the feasibility of dose-dense/dose-intense chemotherapy, other toxicities, including diarrhea, mucositis, and fatigue, often limit the applicability of this approach.

Fatigue, a subjective state of overwhelming and sustained exhaustion and decreased capacity for physical and mental work that is not relieved by rest,⁸ is generally protracted, cumulative, and progressive. No reliably effective therapy is available, which results in substantial impediments to delivering chemotherapy on schedule. A complex network of proinflammatory mediators triggered by the malignancy or by the chemotherapy itself is thought to be involved in the development of fatigue, as well as in the accompanying cachexia, which is a syndrome characterized by loss of adipose tissue and skeletal muscle mass.^8,9 Central to this network is tumor necrosis factor alpha (TNF-), a cytotoxic cytokine secreted by macrophages in response to infection and tumor invasion, which is overexpressed in a number of inflammatory conditions.¹⁰ Because TNF- antagonism reduces fatigue in rheumatoid arthritis,¹¹ it may also decrease the fatigue caused by chemotherapy, resulting in better tolerability of dose-dense/dose-intense schedules.

Although TNF- has historically been studied for its anticancer properties,^12,13 recent evidence suggests that the in vivo effects of TNF- are quite different and probably promote tumor growth instead of hindering it. For example, TNF- from keratinocytes is a tumor promoter in experimental skin cancer.^11,14 Similarly, through activation of the gene transcription factor nuclear factor-kappa B (NF-B), TNF- has been shown to promote tumor progression and survival in experimental models of hepatitis- and colitis-associated cancer.^15,16 Moreover, TNF- blockade with a neutralizing antibody significantly decreased skin tumor development in mice after carcinogen exposure.¹⁷ This would suggest a potential role for TNF- blockade as an adjunct to cancer treatment.

TNF- blockade, a successful strategy for some inflammatory conditions,^18-21 has led to the licensing of etanercept, a recombinant human TNF- receptor that specifically binds and renders soluble TNF- biologically inactive by blocking its interaction with TNF receptors. Because fatigue is the most common toxicity of the tubulin-interactive agent docetaxel when administered on a weekly schedule,²² we conducted a pilot feasibility study of etanercept and weekly docetaxel in patients with refractory solid malignancies. The objectives of the trial were (1) to determine the maximum-tolerated dose (MTD) of weekly docetaxel, (2) to further characterize the toxicities of weekly docetaxel and to determine whether coadministration of etanercept can result in higher tolerated doses of docetaxel and (3) to determine whether inactivation of TNF by etanercept is associated with a decrease in the rate of fatigue.

	PATIENTS AND METHODS

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Eligibility
Patients with solid malignancies refractory to conventional therapy or for which no effective therapy existed were eligible. Eligibility criteria also included the following: age 18 years; Eastern Cooperative Oncology Group performance status of 0 to 2; life expectancy 3 months; no major surgery, radiotherapy, or chemotherapy within 28 days of study entry; absolute neutrophil count of 1,500/µL, platelets 100,000/µL, and hemoglobin 9.0 g/dL; total bilirubin less than 1.5 mg/dL, AST and ALT less than 1.5x the upper normal limits, alkaline phosphatase 2.5x the upper normal limits, and creatinine less than 2.0 mg/dL; no brain metastases unless previously irradiated, stable, and asymptomatic; absence of serious infections or psychiatric disorders that would interfere with consent or follow-up; no pre-existing moderate to severe (grade > 2) peripheral neuropathy; and no significant cardiac disease within 6 months. Pregnant or lactating women were excluded.

Study Design
Docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ) at a dose schedule of 43 mg/m² weekly for 6 weeks every 8 weeks (planned total per-cycle dose, 258 mg/m²) was initially administered to 12 consecutive patients. This docetaxel dose is at the upper end of the recommended doses for this schedule²² and higher than the dose in most recent trials with this schedule.²³ Random assignment allocated six of the 12 patients to receive etanercept (Amgen, Thousand Oaks, CA) 25 mg subcutaneously twice weekly in addition to docetaxel. Given the prolonged half-life of etanercept, a 1-week lead in of etanercept was required to achieve steady-state etanercept concentrations by the time of initiation of docetaxel. In the event of tolerability (< two of six patients experiencing dose-limiting toxicity [DLT]), six additional patients were to receive docetaxel 52 mg/m² weekly for 6 weeks in combination with the same etanercept dose.

Dose Modifications and DLTs
Toxicities were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria version 2 (http://www.jastro.jp/guideline/nci/nci-ctc.doc). The presence of grade 3 or 4 hematologic or nonhematologic toxicity on the day of docetaxel administration mandated withholding of treatment. Resumption of treatment was permitted if the toxicity resolved to grade 2 within 2 weeks. Grade 3 nonhematologic toxicities and all grade 4 toxicities mandated docetaxel reductions by 25%. No dose reductions were planned for etanercept, which was held only for uncontrolled infections.

DLT was defined as any grade 4 neutropenia lasting more than 5 days or accompanied by grade 2 fever; grade 4 thrombocytopenia; grade 3 nonhematologic toxicity that resulted in interruption of docetaxel administration for more than 1 week; or any grade 4 nonhematologic toxicity.

Pretreatment and Follow-Up Assessments
Histories, physical examinations, and routine laboratory studies were performed before treatment and weekly. To measure fatigue, patients completed the Fatigue Symptom Inventory (FSI) each week.^24,25 Although the presence of measurable disease was not a criteria for study entry onto this pilot trial, the extent of malignant disease was evaluated and, when possible, measured before the start of treatment and repeated at the end of each cycle (8 weeks) of docetaxel administration. The Response Evaluation Criteria in Solid Tumors were used for antitumor response evaluation (http://ctep.cancer.gov/guidelines/recist.html). Patients continued on treatment in the absence of progressive disease or DLT.

Molecular Correlates
Sampling for blood mononuclear cells was performed before etanercept initiation (day –7) and before and after docetaxel administration on days 1 and 29. NF-B activation and intracellular levels of TNF-, interleukin (IL) -1b, IL-6, interferon gamma (IFN-), and IL-10 were evaluated. The logic for the examination of these cytokines included the following reasons: TNF is known to stimulate the expression of other cytokines such as IL-1b and IL-6, as well as its own expression, through the activation of NF-B; downregulation of TNF signaling would be predicted to lower inflammation, and levels of the anti-inflammatory IL-10 may increase; and finally, IFN- has a documented effect on fatigue, although its functions operate outside the TNF signaling pathway.^26,27

NF-B activation was measured through a commercially available enzyme-linked immunosorbent assay (Active Motif, Carlsbad CA), as previously described.²⁸ Quantitative real-time polymerase chain reactions (5'–Nuclease TaqMan Assay; Applied Biosystems, Foster City, CA) for human IFN-, TNF-, IL-1b, IL-6, and IL-10 transcripts were performed as singleplex reactions with primer and probe sets specific for the cytokine transcript of interest and an 18s RNA endogenous control. Reactions were performed using an ABI Prism 7700 sequence detector (TaqMan; Applied Biosystems). Data were analyzed according to the comparative concentration threshold method, using endogenous control (18sRNA) transcript levels to normalize differences in sample loading and preparation as previously described.^29,30

Pharmacokinetic Sampling and Assay
Blood specimens were collected after the first and fifth weekly administration of docetaxel to evaluate potential pharmacokinetic (PK) interactions. Heparinized blood samples (7 mL) were drawn from the contralateral arm to the infusion before drug administration (baseline), 1 minute before the end of the 30-minute infusion, and then at 15 and 30 minutes and 1, 2, and 6 hours after the end of infusion. Samples were immediately centrifuged, plasma was removed, and then samples were frozen at –20°C until analysis. Docetaxel concentrations were determined by a high-performance liquid chromatography method previously described.³¹

Fatigue Assessment
In addition to the NCI fatigue grade assessment, each participant completed the FSI every week.^24,25 Fatigue severity in this instrument is measured using four separate items that assess fatigue in the past week as well as current fatigue.^27-29 A subscale evaluating disruption of activities of daily living (perceived interference) permits the generation of a composite score, providing a useful comparative parameter.³² These data were analyzed using Stata's XTGEE (cross-sectional generalized estimating equations) model (Stata Corporation, College Station, TX).³³

Additional Statistical Methods
Repeated-measure analysis of variance (ANOVA) tested the hypothesis that etanercept decreases NF-B activation in patients receiving 43 mg/m² of docetaxel. Other variables in the model included patient, sample day, and treatment day interactions. The model also adjusted for differences in the baseline values of each patient. The two-sample t test was used to compare the two treatment cohorts on day 29 after docetaxel.

ANOVA was used to detect differences between the groups for the expression of each of the five cytokines. Delta cycle times were used for analysis. The two-sample t test looked for differences between cohorts when cytokine delta cycle times were averaged over all time points. A Bonferroni adjustment to the significance level was used to correct for the multiple comparisons. Analysis was run using Stata, version 8.2 (Stata Corporation).

	RESULTS

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General
Twenty-eight patients were enrolled (Table 1). Two patients did not receive docetaxel as a result of consent withdrawal (n = 1) and the development of a paroxysmal atrial flutter (n = 1). These patients are not included in the analysis. Initially, 12 patients were randomly assigned to receive either weekly docetaxel 43 mg/m² alone (cohort A) or docetaxel combined with etanercept (cohort B). Subsequently, 14 additional patients received weekly docetaxel and etanercept in a nonrandomized fashion as follows: docetaxel 52 mg/m², six patients (cohort C); and docetaxel 52 mg/m² with granulocyte colony-stimulating factor (G-CSF) support, eight patients (cohort D).

Hematologic Toxicity
Myelosuppression was mild to moderate at docetaxel 43 mg/m² (Table 3). Four patients, who were all in cohort C (docetaxel 52 mg/m² plus etanercept), developed grade 4 neutropenia. One of these patients also experienced fevers as a result of Pseudomonas sepsis. After recovery, this patient went on to receive four additional uncomplicated doses of weekly docetaxel (43 mg/m²) plus etanercept. The planned addition of G-CSF to cohort D prevented further grade 4 neutropenia in six patients.

Fatigue Assessment
The FSI/interference score of cohort A was significantly greater than the score of cohort B (P < .001; Fig 1). It is of further interest that patients receiving additional cycles of treatment (cohorts B, C, and D) did not experience worsening fatigue, with only three of 20 subsequent cycles associated with NCI grade 3 fatigue and no worsening in the FSI/interference fatigue scale.

View larger version (9K): [in this window] [in a new window]   Fig 1. Average (± standard deviation) Fatigue Symptom Inventory (FSI) Total Body Disruption Score during prior week at docetaxel 43 mg/m2. Results are presented for first cycle of therapy. Arrows depict the times of docetaxel administration.

View larger version (9K): [in this window] [in a new window]   Fig 2. Comparison of mean ± standard deviation docetaxel plasma concentration-time curves for patients receiving docetaxel 43 mg/m2 either alone (n = 5) or in combination with etanercept (n = 6).

View larger version (11K): [in this window] [in a new window]   Fig 3. Mean nuclear factor-kappa B (NF-B) activity in peripheral-blood mononuclear cells according to treatment allocation. Samples were collected on days –7 (before etanercept [Et]), 1, and 29 in the docetaxel (Doc) plus etanercept group and on days 1 and 29 in the docetaxel single-agent group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Maintaining anticancer chemotherapy dose-intensity is complicated by drug-induced adverse effects and by the ill effects produced by the malignancy. Although myelosuppression can be circumvented by colony-stimulating factors, fatigue remains a substantial impediment to delivering chemotherapy on schedule.

The factors mediating fatigue and its often associated muscle-wasting syndrome (cachexia) have not been completely elucidated, yet proinflammatory mediators are thought to be involved in these processes.³⁴ For example, a significant increase in serum TNF- occurs in patients with chronic fatigue syndrome,^35,36 and increased TNF expression is associated with fatigue during acute/convalescent parvovirus B19 infections and in patients with acute leukemia and myelodysplastic syndromes.^37,38

Although TNF signaling is complex, NF-B is one of the major effectors of this pathway. In cultured muscle cells, TNF-induced NF-B activation inhibits skeletal muscle differentiation and promotes muscle turnover.²⁸ In addition, NF-B expression has been documented in mice and human skeletal muscle biopsies,³⁹ which may relate to the ability of NF-B to induce muscle degeneration. In an injury model, inhibitors of NF-B were found to accelerate muscle regeneration,⁴⁰ and numerous inhibitors of NF-B activity, including proteasome inhibitors, antioxidants, IL-10, and DNA decoys, block cachexia in tumor models.^32-34 More recently, genetic studies in mice have validated the involvement of NF-B in muscle wasting associated with cachexia.³⁵

These studies would offer a rationale to study blockade of TNF chronic activation and its downstream NF-B as a strategy to ameliorate the fatigue and cachexia often seen in metastatic disease and their exacerbation by chemotherapy. Interestingly, inhibition of NF-B in both in vitro and in vivo studies has resulted in reversal of inducible chemoresistance and potentiation of anticancer drugs.^36-38,41-44 NF-B activation is associated with resistance to apoptosis in ductal pancreatic adenocarcinoma cells,⁴⁵ whereas inhibition of NF-B sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide or doxorubicin.⁴⁶

The results of this study showed that the combination of docetaxel and etanercept was feasible and allowed for the maintenance of chemotherapy dose-intensity while profoundly reducing the incidence of toxic fatigue. As a result of grade 4 neutropenia at the second dose level, 43 mg/m² of docetaxel in combination with etanercept 25 mg twice weekly is the MTD. However, in combination with G-CSF, etanercept administration also permitted intensification of weekly docetaxel therapy in most patients. Mechanistic studies that were undertaken in these small cohorts of patients may suggest a relationship between docetaxel dose, NF-B activation, and intracellular TNF- expression. A larger number of patients will be necessary to establish a statistically meaningful correlation between the use of etanercept and both a decrease in the docetaxel-mediated NF-B activation and an increased tolerability of weekly docetaxel. Although the data generated are provocative, an important caveat is that assessments of fatigue are difficult to interpret when comparisons are made in the absence of a placebo arm. It is also worthwhile considering that the TNF blockade effect on fatigue may operate through signaling mediators independent of NF-B regulation. For instance, TNF is also a strong activator of mitogen-activated protein kinases p38 and JNK, which leads to the stimulation of the AP-1 transcription factor.⁴⁷ Recent evidence that AP-1 is involved in cancer cachexia⁴⁸ suggests that abrogation of this transcription factor by etanercept may represent an additional signaling effector in TNF-mediated fatigue.

The findings of this pilot study encourage further exploration of TNF blockade to improve the efficiency by which chemotherapy is delivered and is tolerated by patients. A larger study in a more homogenous cancer patient population, in whom quality-of-life and fatigue assessment end points are predetermined, and that is appropriately powered and placebo controlled will be required to define the practical role of this approach. The advent of more potent TNF-blocking agents and the development of specific inactivators of TNF downstream molecules will likely increase the potential benefits derived by this strategy.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Gregory A. Otterson Amgen (A) Denis Guttridge Amgen (A) Michael A. Caligiuri Amgen (A) Miguel A. Villalona-Calero Amgen (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Michael A. Caligiuri, Miguel A. Villalona-Calero Administrative support: Miguel A. Villalona-Calero Provision of study materials or patients: J. Paul Monk, Gregory A. Otterson, Chris Rhoades, Manisha Shah, Miguel A. Villalona-Calero Collection and assembly of data: J. Paul Monk, Tamara Criswell Data analysis and interpretation: J. Paul Monk, Gary Phillips, Larry J. Schaaf, Miguel A. Villalona-Calero Manuscript writing: J. Paul Monk, Michael A. Caligiuri, Miguel A. Villalona-Calero Final approval of manuscript: Miguel A. Villalona-Calero Other: Ross Waite, John Kuhn, Denis Guttridge

 

	ACKNOWLEDGMENTS

 
We acknowledge the Ohio State University Comprehensive Cancer Center Real-Time Polymerase Chain Reaction Shared Resource for their contribution to the correlative data analyses in this study.

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted October 26, 2005; accepted February 14, 2006.

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