Chemotherapy for advanced non-small cell lung cancer (NSCLC)

Chemotherapy for advanced non-small cell lung cancer (NSCLC)

Lung Cancer 38 (2002) S47 /S50 www.elsevier.com/locate/lungcan Chemotherapy for advanced non-small cell lung cancer (NSCLC) Christian Manegold  Dep...

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Lung Cancer 38 (2002) S47 /S50 www.elsevier.com/locate/lungcan

Chemotherapy for advanced non-small cell lung cancer (NSCLC) Christian Manegold  Department of Internal Medicine/Medical Oncology, Thoraxklinik-Heidelberg gGmbH, Amalienstraße 5, 69129 Heidelberg, Germany

1. Introduction Chemotherapy’s role in the treatment of NSCLC has increased greatly over the last years. One of the main reasons for chemotherapy’s increased acceptance has been the development of new substances with unique mechanisms of action and high single-agent activity, combined with favourable toxicity. Cytotoxic drugs are currently used as single agents or in combination for first- and second-line therapy to achieve palliation in locally advanced and metastatic disease.

2. Platin-based combination chemotherapy According to the ASCO-Guidelines the following factors should be taken into consideration, when a decision about chemotherapy needs to be made for advanced NSCLC [1]: / Chemotherapy is appropriate for selected patients and prolongs survival in patients with good performance status. / Chemotherapy should be platinum-based, initiated while the patient has good performance status and should not exceed eight treatment cycles. The current recommendations stem from randomized studies which compared chemotherapy to best supportive care (BSC). These studies revealed a moderate but statistically significant survival advantage for the patients receiving chemotherapy. These positive results have recently been confirmed for the combination Mitomycin C/Ifosfamide/Cisplatin [2]. The clinical avail-

ability of new agents such as Docetaxel and Paclitaxel, Vinorelbine, Gemcitabine and the topoisemase-I-inhibitors increase the chemotherapeutic options for platinum-based chemotherapy considerably. Randomized trials comparing regimens with new combinations to older, platinum-containing regimens [7 /11] or to singleagent therapy with Cisplatin [3 /6]underline the greater possibilities which the new agents can offer. The difficulty of choosing the most appropriate chemotherapy became especially clear when oncologists were confronted with the results of the ECOG 1594study comparing Cisplatin/24-h Paclitaxel to Cisplatin/ Docetaxel, Cisplatin/Gemcitabine or Carboplatin/3-h Paclitaxel [12]. Not only did ECOG 1594 show no survival differences among the treatment arms; this trial also documented disappointingly low response rates for platinum-containing regimens in advanced non-small cell lung cancer. At this point it is, therefore, impossible to state conclusively what role the various platinum-containing regimens will play in the future. However, ECOG 1594 also made clear that Gemcitabine/Cisplatin is one of the effective combinations. Furthermore, there are a number of reasons why a clinician, would tend to choose this combination for advanced NSCLC patients in good clinical condition. Not only are according to ECOG 1594 the response rate, median survival, time to progression and 1-year survival rate as good or significantly better than the other combinations, above all it is the practicability and tolerability of the 3-week schedule that makes Gemcitabine/Cisplatin appear to be one of the most reasonable standard-platinum-based chemotherapies [13].

3. Platinum-free combination chemotherapy  Tel.: /49-6221-396-283; fax: /49-6221-396-436 E-mail address: [email protected] (C. Manegold).

Given the results from ECOG 1594, one of the pertinent questions would now seem to be whether,

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and in what form, a Cisplatin-free combination therapy with new agents such as Docetaxel/Gemcitabine, Paclitaxel/Gemcitabine, or Vinorelbine/Gemcitabine should replace the platinum-based regimens currently recommended. There is hope that EORTC 08975, a recently completed three-arm randomized study which enrolled about 500 patients, will answer this question. EORTC 08975 compared two popular Cisplatin-based regimens (Cisplatin/Paclitaxel; Cisplatin/Gemcitabine) to the Cisplatin-free combination Gemcitabine/Paclitaxel in patients having stage IIIB or IV NSCLC and having a performance status of 0/2. A strong indication that platinum-free combinations in terms of survival and toxicity are not inferior to platinum-based regimens comes from two randomized Greek two-arm trials which included about 300 patients each [14,15].

4. Single agent chemotherapy Already it has become clear that performance status 2 patients do not benefit from platinum-containing regimens [16 /19]. Results from 1991 have recently been confirmed, which showed that PS-2 patients gained a significantly lower median survival time and a lower 1year survival rate. For these patients and for elderly patients, singleagent therapy using the new drugs may be the more attractive chemotherapeutic option for palliation because of their high efficacy and lower toxicity. For Gemcitabine this promising single-agent activity, combined with favourable toxicity, has been confirmed in two randomized phase II studies showing a response rate of about 20% and a median survival of about 8 months [20,21]. Promising results for single-agent therapy in patients with advanced NSCLC were also obtained in our recently completed phase II study, in which patients were randomized to either first-line single-agent Gemcitabine or single-agent Docetaxel. Then, in case of tumor progression during or after completion of first-line therapy, patients received second-line therapy with the corresponding alternative agent [22]. In patients receiving Gemcitabine first-line, the median overall survival was 8 months and the 1-year survival rate 31%. Single-agent therapy is also superior to BSC. This superiority has been documented for Vinorelbine, Paclitaxel, Docetaxel and Gemcitabine [23 /26]. Results indicate a significantly longer overall survival and a statistically significant improvement of clinical symptoms [23,25]. Results have also demonstated Gemcitabine’s clinical benefit [26], whereas 79% of the patients receiving only BSC required palliative radiotherapy, only 49% needed radiotherapy in the Gemcitabinearm. The mediane time to radiotherapy was 29 weeks

for Gemcitabine/BSC and about 4 weeks for BSC alone. Patients on Gemcitabine/BSC reported better quality of life and reduced disease related symptoms compared with those on BSC only. The response rate for Gemcitabine was 19%.

5. Chemotherapy for the elderly patient Certainly the availability of new agents has increased the chemotherapeutic options in general, but the options have increased even more for elderly Patients having advanced NSCLC. Vinorelbine was the first new agent tested in randomized trials in the elderly population. The ELVIS-trial found a statistically significant survival advantage for patients receiving Vinorelbine and clearly established the potential benefit of single-agent therapy for elderly patients [23]. A retrospective review focusing on patients over 65 enrolled in four phase II trials has recently been completed using single-agent Gemcitabine [27]. The results showed Gemcitabine proved to be both active and well tolerated in elderly patients. No differences could be seen in response rates, response duration, median survival and 1-year survival rates between the elderly and the younger patients. The question of whether or not the addition of Gemcitabine to Vinorelbine improves treatment outcome in the elderly has also recently been addressed in a randomized study [28]. Interim analysis data from 120 patients showed that the combination is superior to single-agent Vinorelbine, with a statistically significant longer median survival time and a significantly higher 1-year survival rate. The combination was also associated with a clear delay in symptom and quality of life deterioration.

6. Second line chemotherapy As chemotherapy gains wider acceptance for advanced and early stage NSCLC, the need for effective second-line chemotherapy is also growing. Over the last years there have been several trials which strongly indicate that some of these new drugs are not only effective in first-line use, but also show considerable activity when used for second-line therapy [29,30]. On the basis of two randomised phase III studies, Docetaxel has recently become the first cytotoxic agent to be registered for second-line therapy in NSCLC [31,32]. Both of these studies demonstrated that 75 mg/m2 Docetaxel given every 3 weeks significantly prolonged survival and that it offered clinically meaningful benefits to patients having acceptable performance status, when compared to BSC or to single-agent Vinorelbine or Ifosfamide. Promising results for second-line singleagent Gemcitabine have also been reported from a large

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phase II trial, in which about 19% of the patients achieved a partial response and the median duration of response was about 7 months [33]. The high efficacy combined with favourable toxicity as reported here would suggest that Gemcitabine could be another option as a second-line treatment for patients showing either a previous response to or stable disease after platinum-based first-line therapy.

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