A novel triplet regimen with paclitaxel, carboplatin and gemcitabine (PACCAGE) as induction chemotherapy for locally advanced unresectable non small cell lung cancer (NSCLC)

Summary

Phase II study of 3 cycles of triplet induction chemotherapy (response, toxicity) followed by radiotherapy in locally advanced non small cell lung cancer (NSCLC).

Background

Patients with locally advanced inoperable non-small cell lung cancer are currently treated with concomitant or sequential chemotherapy and radiotherapy. However, the outcome of existing treatment modalities is unsatisfactory. Development of new strategies including more efficient systemic chemotherapy is warranted.

Objective

To study the antitumour activity and toxicity of a triplet combination of paclitaxel, carboplatin and gemcitabine as induction chemotherapy before radiotherapy, in locally advanced NSCLC and to evaluate time to progression and survival.

Methods

Three cycles of paclitaxel (175 mg/m² by 3 h infusion on day 1), carboplatin (AUC 5 mg/(ml min) by IV bolus on day 1) and gemcitabine (1000 mg/m² by IV bolus on day 1 and 8) were administered every 3 weeks in reasonably fit patients. Fractionated radiotherapy with curative intent was initiated 4 weeks after the last chemotherapy administration. Toxicity was assessed weekly during cycle 1 and on day 1 and 8 in cycles 2 and 3. Response evaluation was performed at the end of cycle 3.

Results

Forty-eight patients (20 stage IIIA and 28 stage IIIB) received a total of 134 cycles of chemotherapy. Forty-two patients received the intended 3 cycles. Thirty patients obtained an objective response (1 complete and 29 partial response) or 62.5% on the intent to treat analysis (95% confidence interval: 49–76%). None of the responders became eligible for surgery. The median time to progression and survival for all patients was 10.1 and 15.7 month, respectively. A significant difference was observed in survival parameters between stage IIIA and stage IIIB patients.

Haematological toxicity grade 3/4, mainly neutropenia and thrombocytopenia, was most prominent on day 15 of the treatment cycles. Haematological support by means of recombinant erythropoietin, red blood cell or platelet transfusion, filgrastim administration or a combination was needed in 21 patients. None of the patients discontinued chemotherapy because of haematotoxicity.

Grade 3/4 non-haematological toxicity leading to chemotherapy withdrawal occurred early during induction (2 and 1 in cycles 1 and 2, respectively).

Conclusion

Three cycles of the novel triplet combination of paclitaxel, carboplatin and gemcitabine (PACCAGE) is an active and feasible induction regimen for patients with locally advanced inoperable NSCLC. Neutropenia and to a lesser extent thrombocytopenia represent the main haematological toxicity. Whether this triplet regimen can improve outcome when compared to specific cisplatin doublet regimens should be evaluated in a phase III study.

Introduction

The treatment of patients with stage IIIB-IV NSCLC with chemotherapy has evolved during the last decade. Cisplatin based doublet chemotherapy produced a significant but albeit modest improvement in overall survival, quality of life and symptom control as compared to best supportive care [1], [2], [3], [4]. Several new agents have been introduced in the clinic and shown to be active in NSCLC, with response rates of approximately 20% for single drugs and a favourable toxicity profile [5]. In particular, paclitaxel used in different schedules has produced response rates exceeding 20% and a 1-year survival in the range of 40% [6], [7]. Subsequently, paclitaxel has been safely combined with cisplatin [8] and carboplatin [9]. The latter combination has proved active, tolerable and easy to administer and has been included in several phase III trials. Currently a chemotherapy regimen combining a platinum-derivative (either cis- or carboplatin) and one of the more recent drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine) is considered standard therapy for stage IIIB-IV NSCLC [5], [10]. The modest toxicity of the two-drug combination of paclitaxel and carboplatin and the favourable toxicity profile of gemcitabine lead to the exploration of a three-drug combination with gemcitabine [11]. Phase I–II studies indicated the feasibility of this approach in advanced stage NSCLC: the triplet regimen with paclitaxel, carboplatin and gemcitabine was active in this setting at the expense of mainly myelosuppression [12], [13], [14]. A recently published phase II–III trial in stage IIIB–IV NSCLC demonstrated a significant increase in response, time to progression and survival when gemcitabine was added to paclitaxel and carboplatin versus paclitaxel and carboplatin alone [15].

The integration of chemotherapy and radiotherapy in a multidisciplinary program has led to a significant superior survival compared to radiotherapy alone in locally advanced unresectable stage IIIA–IIIB NSCLC [16]. Controversy still exists with respect to the optimal timing of both treatment modalities (sequential or concomitant). Nevertheless if the results of the available randomised studies of sequential versus concomitant chemo-radiotherapy are pooled, the concomitant administration appears to produce a survival advantage at the expense of acute local toxicity mainly esophagitis and pneumonitis [17], [18], [19], [20], [21], [22]. Most of these results have been published in full and both strategies are an acceptable standard. We report here the results of a phase II study of 3 cycles of the triplet paclitaxel, carboplatin and gemcitabine preceding definitive radiotherapy in locally advanced unresectable stage IIIA–IIIB NSCLC. Because induction chemotherapy was followed by radiotherapy in eligible patients, time to progression and survival data are detailed as well.