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Relief of Symptoms After Gefitinib Is Associated With Improvement of Rest/Activity Rhythm in Advanced Lung Cancer

Department of Oncology and Neurosciences, University "G. D'Annunzio" Foundation, Chieti, Italy; INSERM, U 776, Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif Cedex, France

Tyvin Rich

Department of Radiation Oncology, University of Virginia Health System, Charlottesville,VA

Francis Lévi, Pasquale F. Innominato

INSERM, U 776, Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif Cedex, France

Nicola Tinari, Luciana Irtelli, Michele De Tursi, Antonino Grassadonia, Stefano Iacobelli

Department of Oncology and Neurosciences, University "G. D'Annunzio" Foundation, Chieti, Italy

To the Editor:

We read with interest the article by Bezjak et al¹ on the clinical benefits induced by erlotinib treatment in patients with advanced non–small-cell lung cancer (NSCLC) progressing after prior chemotherapy. The authors report that patients receiving erlotinib had significantly longer median time to deterioration of dysphnea, cough, and pain as compared with placebo controls. Interestingly, quality of life (QOL) improvement was observed in approximately 22% of patients with progressive disease. These results substantially confirm those of the Iressa Dose Evaluation for Advanced Lung Cancer (IDEAL 1 and IDEAL 2) trials of single agent gefitinib in pretreated patients with NSCLC, where symptom improvement was found in approximately 40% of the patients whereas objective responses were observed in 12% to 18%.² The reported discordance between tumor response and QOL improvement raises the possibility that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors may exert their effects not only on tumor, but also on the host.

It is known that NSCLC patients experience disrupted rest activity (R/A) daily rhythms as measured by wrist actigraphy, a tool to objectively measure circadian function.³ Altered R/A rhythms and poor QOL have been found to be correlated with elevated transforming growth factor (TGF)-, tumor necrosis factor-, and interleukin-6 serum levels.⁴ These data are consistent with the hypothesis that pro-inflammatory cytokines or EGFR ligands signal the CNS to cause disruption of the hypothalamic-pituitary-adrenal axis or the autonomous nervous system.⁵ Moreover, a disruption of the circadian system is suggested by data showing that injection of TGF- into the hypothalamic subparaventricular zone blocks signaling from the supra-chiasmatic nucleus to downstream circadian relays that modulate the R/A cycle, feeding, and cortisol rhythms.⁶

We evaluated modifications of the 24-hour R/A patterns and QOL in 10 patients with advanced NSCLC treated with gefitinib monotheraphy (250 mg orally once daily between 9:00 and 12:00 AM). A series of four patients with advanced NSCLC receiving cisplatin-based chemotherapy were used as a control. All patients had not overt brain, meningeal metastases, or any other neurologic disease. In each patient, R/A rhythm was monitored with a wrist-worn actigraph (Actigraph; Ambulatory Monitoring Inc, Ardsley, NY) for 3 continuous days before the beginning of treatment, 2 and 4 weeks after treatment initiation, and monthly thereafter, until gefitinib discontinuation. R/A rhythm pattern was objectively estimated using a robust and validated parameter, the autocorrelation coefficient at 24 hours (r24), which provides a measure of the regularity of the activity pattern over 24 hours period.⁷ A value of r24 = 0.47 was regarded as the lower limit of normal range.⁴ Health-related QOL was assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 and the Functional Assessment of Cancer Therapy-Lung questionnaires. The two questionnaires were completed before each actigraphic recording.

At baseline, r24 values of the patients candidate to receive gefitinib ranged between 0.15 and 0.73 with a median of 0.53; they were in the range of normality ( 0.47) in six patients and dampened (< 0.47) in four. In these latter patients, a 4-month treatment with gefitinib induced a marked improvement of the circadian rhythm in three, while it was without effect in one (Fig 1A). Patients experiencing a normalization of r24 also had a clinically meaningful improvement of global QOL, physical functioning, fatigue, and appetite. Conversely, worsening of r24 and symptoms was observed in all but one of the four patients receiving cisplatin-based chemotherapy for the same length of time (Fig 1B). In gefitinib-treated patients, R/A improvement was independent of tumor response, and occurred at the first postbaseline assessment in two patients, and at the second in one (not shown).

View larger version (36K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Recording of rest activity (R/A) cycles in patients treated with (A) gefitinib or (B) chemotherapy for a 4-month period. Left panels refer to pretreatment (basal) values and right panels to values obtained after treatment. Note CG, LC, DBA, DF, DA, BC, FR, and PL are initials of patients.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Bezjak A. Dongsheng T, Seymour L, et al: Symptom improvement in lung cancer patients treated with erlotinib: Quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group study BR. 21. J Clin Oncol 24:3831-3836, 2006[Abstract/Free Full Text]

2. Natale RB: Effects of ZD1839 (Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced non-small cell lung cancer. Semin Oncol 31:23-30, 2004[Medline]

3. Levin RD, Daehler MA, Grutsch JF, et al: Circadian function in patients with advanced non-small-cell lung cancer. Br J Cancer 93:1202-1208, 2005[CrossRef][Medline]

4. Rich T, Innominato PF, Boerner J, et al: Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res 11:1757-1764, 2005[Abstract/Free Full Text]

5. Lee BN, Dantzer R, Langley KE, et al: A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation 11:279-292, 2004[CrossRef][Medline]

6. Kramer A, Yang FC, Snodgrass P, et al: Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294:2511-2515, 2001[Abstract/Free Full Text]

7. Mormont MC, Waterhouse J, Bleuzen P, et al: Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res 6:3038-3045, 2000[Abstract/Free Full Text]

8. Ceresoli GL, Cappuzzo F, Gregorc V, et al: Gefitinib in patients with brain metastases from non-small-cell lung cancer: A prospective trial. Ann Oncol 15:1042-1047, 2004[Abstract/Free Full Text]

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