Paclitaxel in the Treatment of Lung Cancer. David S. Ettinger, M.D. The Johns Hopkins Oncology Center, Baltimore, MD 21287

Paclitaxel is a novel diterpene plant product isolated from the western yew, taxus brevifolia. It exerts its cytotoxic effects by interfering with microtubule structure and function.

Initial phase 1 studies utilized 1 to 6hr infusions of Paclitaxel every 3 weeks; however, because of allergic reactions, later phase 1 studies utilized a 24-hr continuous infusion schedule of the drug administration given every 3 weeks. This together with a premeditation regimen, significantly reduced the occurrence of the allergic reactions. The recommended phase II dose was 250 mg/m’ as a 24-hr continuous infusion, repeated every 21 days.

The results of 4 phase II studies of Paclitaxel in the treatment of lung cancer are reviewed. One study, conducted by the Eastern Cooperative Oncology Group (ECOG), from June 1990 to March 1991 involved 25 previously untreated patients with NSCLC. Twenty-four patients were considered evaluable. Patients received Paclitaxel 250 mg/m* IV over 24-hours every 3 weeks. There were 5 partial responses (21%) seen lasting from 3.7 months to more than 15.4 months. Two patients had stable disease (8%) while 16 patients had progressive disease. The median survival time was 24.1 weeks while the one-year survival rate was 41.7%. The major toxicity was myelosupression, namely leukopenia (12.5% grade 3; 62.5% grade 4). One patient died of drug-related sepsis.

The other NSCLC study was conducted by the M.D. Anderson Cancer Center between June 1990 and May 1991. Twenty-seven previously untreated patients received Paclitaxel 200 mg/m’ IV over 24 hours every 3 weeks. Twenty-five patients were evaluable. There was 1 complete response (4%) and 5 partial responses (20%) observed. An additional seven patients (28%) had minor responses. The median survival was 40 weeks. The dose-limiting toxicity was neutropenia.

In two phase II studies, Paclitaxel was administered to patients with extensive- stage SCLC. From October 1990 to October 1991, ECOG entered 36 previously untreated extensive-stage SCLC patients evaluating Paclitaxel 250mg/m2 administered intraveneously over 24 hours every 3 weeks. At the time of the study, because of a limited drug supply, patients could receive a maximum of 4 doses of Paclitaxel as induction therapy even if they were responding to the drug. Patients with disease progression, stable disease a or partial response after 4 cycles of therapy received salvage chemotherapy consisting of Etoposide plus Cispletin. Thirty-four patients were evaluable for toxicity while 32 patients were evaluable for response. There were 11 partial responses (34%) observed. An additional 6 patients (19%) had stable disease of which three of these patients had greater than 50% shrinking of their tumor; however, there were no 4-week followup measurements for them to be considered responders, due to their receiving salvage chemotherapy at 3 weeks. The estimated median survival was 45. The major toxicity was leukopenia (12% grade 3; 56% grade 4).

The North Central Cancer Treatment Group evaluated Taxol 250mg/m2 IV over 24- hours plus G-CSF 5pg/kg days 2-l 5 every 3 weeks in previously untreated patients with extensive-stage SCLC. Patients experiencing disease progression were crossed over to

etoposide plus cisplatin. Forty-three patients were entered on study with 37 patients evaluable for response. There were no complete responses, 15 partial responses and IO regressions for a major response rate of 68%. In 19% of courses of Paclitaxel, grade 4 leukopenia was observed.

ECOG is conducting a 3-arm randomized phase III study in patients with advanced NSCLC comparing Etoposide plus Cisplatin to low dose Paclitaxel plus Cisplatin versus high dose Paclitaxel plus Cisplatin plus G-CSF, The doses of Paclitaxel are 135 mg/m’ and 250 mg/m’ respectively. They are administered as a 24-hour infusion. Phase II studies of Paclitaxel administered as a 3-hour infusion plus Carboplatin in patients with NSCLC are ongoing. Other combination chemotherapy regimens possible in the treatment of lung cancer include Paclitaxel combined with one or more of the following drugs: Edatrexate, CPT-1 1 Topotecan, Vinorelbine or Ifosfamide. The combination of Paclitaxel, Etoposide and Cisplatin is being evaluated in the treatment of both NSCLC and SCLC.

At least in one study published thus far, Paclitaxel has been shown to cause radiosensitization. This is due in part to the ability of Paclitaxel to block and/or prolong cells in G, or M phase of the cell cycle. Based on this finding, phase I-II studies of Paclitaxel given concurrently with radiation therapy in stage III NSCLC are ongoing. Such studies involve the use of low-dose Paclitaxel given frequently as well as higher doses (i.e. therapeutic) of the drug administered intermittently. In one study Cisplatin is also utilized along with Paclitaxel, administered concurrently with radiation therapy.

Paclitaxel is a new agent which has activity against NSCLC and SCLC. Further studies are needed to evaluate Paclitaxel in combination with other active agents in the treatment of patients with lung cancer.

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