case study documenting the anticancer activity of ZD1839 (Iressa) in the brain.pdf

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Annals of Oncology 14: 656658, 2003

Letters to the Editor

2003 European Society for Medical Oncology

A case study documenting theanticancer activity of ZD1839

(Iressa) in the brain

ZD1839 (Iressa) is a synthetic, oral anilinoquinazoline with sub-

micromolar specificity for the epidermal growth factor receptor

(EGFR). In non-small-cell lung cancer (NSCLC), ZD1839 has

shown significant antitumor activity, even in heavily pretreated

patients. We present a patient with NSCLC who has brain meta-

stases and was enrolled in hospice care prior to therapy with

ZD1839, which produced a sustained clinical response.

A 60-year-old woman was diagnosed with metastatic adeno-carcinoma of the lung in March 1999 when she presented with

visual auras. A magnetic resonance imaging (MRI) scan of the

brain demonstrated three enhancing brain lesions and a computed

tomography scan of the chest revealed a 2.5 3.5 cm left lung

mass. Pathology samples from bronchoscopy and craniotomy

confirmed metastatic adenocarcinoma. She was treated with

whole brain radiotherapy followed by stereotactic radiosurgery,

which effectively treated any residual brain lesions. Her treat-

ments were well tolerated. She then received a phase I/II study

treatment of an alternating schedule of docetaxol, gemcitabine,

cisplatin and vinorelbine on a 28-day cycle [1]. She received four

full cycles of treatment from May to October 1999. Her left chest

lesion reduced in size to 1.5 1.5 cm and persisted as the only

known site of active disease. She then received regional chest

radiotherapy in November 1999 of 55 Gy.

She was then monitored without therapy. She presented

8 months after her last treatment with recurrence of auras in July

2000. New brain lesions were detected by a brain MRI scan.

These increased in size over the next 5 months, leading to a second

stereotactic radiosurgery. Her left chest lesion had remained

stable in size since the chest radiotherapy.

In October 2001, imaging studies demonstrated three newbrain lesions (Figure 1A), the largest being in the left parietal

lobe. She complained of new neurological symptoms of numb-

ness and tingling on the right arm and face with gait instability.

She had received the maximal dose of cranial radiotherapy,

preventing further palliative radiation treatments. She was placed

on steroids, and in a span of 3 months her disease progressed.

When she developed difficulties with gait, speech and self-care,

she was placed in hospice support. She qualified for compas-

sionate care, and although bedridden, elected to start on ZD1839

at 250 mg daily after two loading doses.

Figure 1. Coronal sections of a T1 weighted enhanced magnetic resonance imaging study of the brain. (A) Performed in October 2001, confirming

recurrence of disease in the left parietal lobe (see arrow). This study preceded her most severe clinical state by 3 months. (B) Using the same scanning

protocol, this study was performed in June 2002, demonstrating a decrease in the size of the enhancing lesion.


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At her next appointment, 2 months later, she had self-discharged

from hospice care as she was able to ambulate, and had increased

weight and alertness. Her dexamethasone dose of 4 mg twice a

day was soon tapered and discontinued. A repeat MRI scan of the

brain, 5 months after starting ZD1839 therapy, demonstrated

shrinkage of the metastatic lesions (Figure 1B). She is currently

active and able to perform her activities of daily living independ-

ently, including driving an automobile, and continues to have

stable systemic disease. She has had no noted side-effects from

ZD1839 therapy.

This is the first clinical report to demonstrate that ZD1839 has

anticancer activity in the brain. ZD1839 has excellent cell pene-

tration and based on its chemical structure and low molecular

weight probably crosses the bloodbrain barrier [2]. A single pre-

clinical study in mice has shown that ZD1839 retains therapeutic

activity on intracranial tumors that over-express EGFR [3]. Our

results, therefore, may not be unexpected, but clinical document-

ation is needed.

The advantages of an oral, non-toxic therapy are immeasur-

able. Our patient, being bedridden and completely disabled, would

neither have been offered nor probably received benefit from

traditional chemotherapy. ZD1839 is non-myelosuppressive, as

EGFR is not expressed in cells of hematopoietic origin, making

it suitable for chronic therapy [4]. From phase I studies, the

common side-effects of grade I/II skin rash, diarrhea, and nausea

and vomiting have proved tolerable [5]. As EGFR is over

expressed in the majority of NSCLC cases, we recommend

consideration of a treatment trial with ZD1839, or a close analog

with antiEGFR activity, prior to hospice placement.

J. L. Villano*, A. M. Mauer & E. E. Vokes

Section of Hematology/Oncology, Department of Medicine, University of

Chicago, Chicago, IL, USA

(*E-mail: [email protected])

References

1. Vokes EE, Charoentum C, Gordon GS et al. Phase I study of dose-dense

alternating doublets in advanced non-small-cell lung cancer. Clin Lung

Cancer 2002; 3: 265270.

2. Barker AJ, Gibson KH, Grundy W et al. Studies leading to the identifi-

cation of ZD1839 (IRESSA): an orally active, selective epidermal

growth factor receptor tyrosine kinase inhibitor targeted to the treatment

of cancer. Bioorg Med Chem Lett 2001; 11: 19111914.

3. Heimberger AB, Archer GE, McLendon RE et al. Oral administration of

the specific EGFR tyrosine kinase inhibitor, ZD1839 (Iressa), is active

against EGFR-overexpressing intracranial tumors. In: Proceedings of

the 11th NCIEORTCAACR Symposium on New Drugs in Cancer

Therapy, Amsterdam. Clin Cancer Res 2000; 6 (Suppl): (Abstr 380).4. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth

factor-related peptides and their receptors in human malignancies. Crit

Rev Oncol Hematol 1995; 19: 183232.

5. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epi-

dermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated

and active in patients with solid, malignant tumors: results of a phase I

trial. J Clin Oncol 2002; 20: 22402250.

DOI: 10.1093/annonc/mdg0153


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case study documenting the anticancer activity of ZD1839 (Iressa) in the brain.pdf