Neoadjuvant Therapy W/ Carboplatin, Gemcitabine, Thalidomide

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Neoadjuvant Therapy With Carboplatin, Gemcitabine Plus Thalidomide for Stage IIB and IIIA Non-Small-Cell Lung Cancer: Presented at ESMO

By Chris Berrie

LUGANO, SWITZERLAND -- July 9, 2007 -- A combination of thalidomide with carboplatin and gemcitabine has promising results and shows acceptable toxicity in neoadjuvant treatment of patients with inoperable, locally advanced non-small-cell lung cancer (NSCLC), according to a phase 2 study.

The research was presented here on July 7th at the European Society for Medical Oncology (ESMO) Conference.

Carboplatin plus gemcitabine is the most common combination for treatment of patients with locally advanced NSCLC, but its effectiveness is known to plateau, indicating the need to enhance such treatments with an approach that works through a different mechanism of action.

"We thought that maybe addition of an antiangiogenic or immunomodulatory molecule such as thalidomide can make the difference in addition to chemotherapy, by inducing higher response rates," explained principal investigator Arkadiusz Z. Dudek, MD, PhD, Assistant Professor of Medicine, Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minnesota, Minneapolis, United States.

Thus, patients who could not otherwise be considered for surgery might benefit by inducing higher response rates, Dr. Dudek said. "Then it would allow us to push all this group of patients to surgery and to possible long-term disease control," he added.

For their study, Dr. Dudek and colleagues enrolled patients with no prior chemotherapy who were diagnosed with inoperable stage 2 or 3A NSCLC and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1.

The study's primary objective was to assess the activity of this combination regimen on locally advanced disease, with secondary monitoring for thalidomide activity and mechanism of action, and for toxicity and safety.

A total of 19 patients (median age, 57 years; male, 47.4%) were enrolled, with ECOG PS 0/1 of 73.7%/26.3%. Patients were diagnosed with stage 2B (26.3%) or stage 3A (73.7%) disease -- adenocarcinoma (47.4%); squamous cell carcinoma (31.6%); adenosquamous cell carcinoma (10.5%); unspecified (10.5%). Two of these are excluded from the analysis due to very recent recruitment.

With a requirement for a Karnofsky performance status of >70 at enrolment, the breakdown of the first 17 patients was as follows: 100, 82%; 90, 6%; and 80, 12%.

Treatment consisted of a 21-day cycle that aimed to provide three cycles prior to surgery. Each cycle comprised: gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1 and 8, followed by carboplatin IV for an area under the curve (AUC) of 5.5 over 30 minutes on day 1 (with 5HT3 antiemetics), and thalidomide 200 mg orally daily following a dose escalation over days 1 to 3 of 50 mg, 100 mg and 150 mg, respectively.

An almost complete pathological response was seen for 5.9% (n = 1), with partial response in 58.9% of patients. An additional 17.6% showed stable disease, while 2 patients (11.8%) showed disease progression.

Eleven patients went on to have surgery. "So our goal was attained, as basically 64.8% of patients had in fact surgery, when they wouldn't have had otherwise," Dr. Dudek said.

After a median follow-up of 13 months (range, 6-14 months), 82.4% of patients are alive, and 47.1% are without disease recurrence.

Grade 3/4 adverse events included: neutropenia (47.0%); thrombocytopenia (11.8%); anaemia (5.9%); heartburn (5.9%); and syncope (5.9%). Thalidomide was not considered to affect treatment toxicity significantly.

Although these data cannot be used to draw specific predictions for the future use of thalidomide as neoadjuvant treatment for patients with locally advanced NSCLC, Dr. Dudek did indicate that they remain interested in antiangiogenics.

"Possibly in the future, we will either use thalidomide or some other so-called 'weaker' antiangiogenic agent, to allow less toxicity and yet increase the operability of these patients," he added.

This study was sponsored by Lilly.

[Presentation title: Phase 2 Trial of Neoadjuvant Therapy With Carboplatin, Gemcitabine Plus Thalidomide for Stage IIB and IIIA Non-Small-Cell Lung Cancer (NSCLC). Abstract 86P]