Induction chemotherapy with cisplatin and gemcitabine followed by concurrent chemoradiation with twice-weekly gemcitabine in unresectable stage III non-small cell lung cancer: Final results of a phase II study
Introduction
Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with locally advanced disease. Some of these patients can benefit from a surgical approach [1], [2], but the great majority of patients with stage IIIb, and many with stage IIIa (e.g. N-2 bulky) are not eligible for surgery. It is presently accepted that the best treatment for these patients is the combination of chemotherapy and radiotherapy. Some comparative clinical studies [3], [4], [5] show that concurrent chemoradiotherapy (CCR) is more effective than sequential treatment, though at the expense of a major nonhematological toxicity (mainly esophagitis and pneumonitis).
Despite these new therapeutic approaches, the results remain poor, with 3-year survival below 20%. Two possible strategies are available to improve this situation. First, the incorporation of induction or adjuvant chemotherapy to concurrent treatment, as represented in the studies CALGB-9431 and SWOG 9504, respectively [6], [7]. The second strategy consists of using more radiosensitive drugs, such as gemcitabine, in concurrent chemoradiotherapy.
The optimal dose for the administration of gemcitabine combined with radiotherapy has been evaluated in various phase I trials [8], [9], [10], [11]. In these studies, the recommended weekly dose of gemcitabine concurrent to radiotherapy was between 100 and 375 mg/m2, depending on the dose of radiotherapy, the type of planning (2D or 3D), and the volume of treatment. In the first phase II trial published, gemcitabine was administered at full weekly doses of 1 g/m2 during six consecutive weeks, combined with 60 Gy of thoracic radiation [12]. High levels of toxicity were observed, resulting in serious esophagitis and pneumonitis, with three toxic deaths in the eight patients included. Other phase II studies were subsequently published, based on the results of the phase I trials mentioned, obtaining mean survival of about 15 months [13], [14], [15]. In addition, we must mention the phase II randomized trial carried out by CALGB [6], comparing three classical combinations of chemotherapy (cisplatin–gemcitabine, cisplatin–vinorelbine and cisplatin–paclitaxel) concurrent to radiotherapy. In the gemcitabine arm, after two cycles of induction, radiotherapy was combined with the administration of cisplatin 80 mg/m2 every 3 weeks, and gemcitabine 600 mg/m2 on days 1 and 8 of each cycle. Esophagitis grades III and IV was observed in 52% of cases. Overall response and survival were similar in the three treatment arms.
Nevertheless, experiments in vitro showed that gemcitabine radio sensitization did not exceed 72 h. Thus, twice-weekly administration of gemcitabine would seem an attractive schedule [16]. Using this scheme, Blackstock presented the preliminary results of a phase I trial in ASTRO 1999 [17].
On the basis of these results, the Associació Catalana per a la Recerca Oncològica i les seves implicacions Sanitàries i Socials (ACROSS) undertook a phase II study to evaluate the efficacy and toxicity of a radiotherapy treatment concomitant with gemcitabine administered twice-weekly, in patients with locally advanced and unresectable NSCLC, following induction chemotherapy with cisplatin and gemcitabine.
Section snippets
Methods
This was a multicentric, non-randomized phase II study. The institutional ethics committees of each participating center approved the study protocol.
Patient characteristics
Fifty-six patients were included in 8 centers between April 2000 and April 2003: 22 were included before the previously described dose reduction (group A), and 34 after (group B). One patient in group B was not eligible for efficacy analysis as PTV volumes obtained were above acceptable levels. He was nevertheless included in the toxicity analysis, as he had received one cycle of induction.
Table 1 summarizes patients’ characteristics: all the patients included except one were males. 46 patients
Discussion
In our study, we analyzed the efficacy and toxicity of concomitant radiotherapy with gemcitabine administered at low doses twice a week, in patients with locally advanced unresectable NSCLC, following three cycles of induction chemotherapy with cisplatin and gemcitabine. Our results are encouraging with regard to efficacy objectives: response rate and global and progression-free survival. However, the nonhematological toxicity detected, though not very different from that communicated in other
Acknowledgements
This study has been supported financially by Eli Lilly, Spain.
We wish to thank Sylva Astrik Torossian (Consorci Hospitalari Parc Tauli. Sabadell, Spain) for her linguistic support.
Conflict of interest: The authors disclose any financial and personal relationship with other people or organisation that could inappropriately influence the study.
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