Italian clinical research in non-small-cell lung cancer

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1 Annals of Oncology 16 (Supplement 4): iv110 iv115, 2005 doi: /annonc/mdi919 Italian clinical research in non-small-cell lung cancer C. Gridelli 1, A. Rossi 1, D. Galetta 2, P. Maione 1, C. Ferrara 1, C. Guerriero 1, F. Del Gaizo 1, D. Nicolella 1, G. Colantuoni, V. Gebbia 3 & G. Colucci 2 1 Division of Medical Oncology, S.G. Moscati Hospital, Avellino; 2 Dept. of Medical Oncology; Oncology Institute, Bari; 3 Division of Medical Oncology, La Maddalena Hospital, Palermo, Italy Lung cancer is the most common cause of cancer deaths in both men and women worldwide and has a poor prognosis. Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. Surgery is the only curative treatment of NSCLC but only 15 20% of tumours can be radically resected with a survival of about 40% at 5 years. Considering these disappointing results NSCLC is one of the most frequent subjects of clinical research worldwide. Italy is playing an important role in the clinical research of NSCLC performing phase I, II and III trials, prevalently by cooperative groups, and achieving important results that contributed to define the standard treatment for NSCLC patients. In particular, Italy is leader in the clinical research of the treatment of advanced NSCLC elderly patients. Today, large controlled clinical trials are ongoing. In this paper we analyse and discuss the main trials performed by Italian groups in the fields of NSCLC. Key words: Italian clinical research, NSCLC, lung cancer Introduction Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in Europe and in other Western countries [1 3]. Non-small-cell lung cancer (NSCLC) including squamous carcinoma, adenonocarcinoma and large cell carcinoma represents approximately 80% of all lung cancers. Surgery is the only curative treatment of NSCLC. Unfortunately, only 15 20% of tumours can be radically resected, and, overall, surgically-treated patient survival is only around 40% at 5 years. Most patients at diagnosis have advanced disease with a very poor prognosis. Considering these disappointing results NSCLC is one of the most frequent subjects of clinical research worldwide. In Italy there is a growing interest in the research on NSCLC with several groups that have greatly contributed to the expansion of our knowledge in this field. In this paper we analyse and discuss the main trials performed by Italian groups in the field of NSCLC. Early stages disease Surgery is the only curative treatment of NSCLC, and, despite that, surgically-treated patient survival is only around 40% at 5 years. Postoperative treatments such as chemotherapy and radiotherapy have been investigated. A meta-analysis Correspondence to: Dr Cesare Gridelli, Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta, 83100, Avellino, Italy. Tel: ; Fax: ; cgridelli@libero.it evaluating data available from 4357 patients included in clinical trials comparing surgery alone to surgery plus chemotherapy showed a survival benefit of 5% at 5 years for cisplatinbased chemotherapy [4]. These results have stimulated clinical research in that field with several clinical trials on platinum plus new drugs, such as vinorelbine and paclitaxel, whose final results are available [5 12]. Italy plays an important role in this setting, in fact, Italian groups in collaboration with European Organization for Research and Treatment of Cancer performed the large randomized trial, the Adjuvant Lung Project of Italy (ALPI). In this trial 1209 patients with stage I, II or IIIA NSCLC, were randomly assigned to receive surgery alone or surgery plus adjuvant chemotherapy consisting of the three-drug combination of mitomycin C (8 mg/m 2 on day 1), vindesine (3 mg/m 2 on days 1 and 8) and cisplatin (100 mg/m 2 on day 1) (MVP regimen), every three weeks for three cycles. Radiotherapy was permitted on investigator decision. After a median follow-up of 64.5 months, there was no statistical difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P =.589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P =.128). Only 69% of patients received the three planned cycles of MVP. This trial failed to demonstrate a statistically-significant survival benefit for adjuvant chemotherapy in completely resected NSCLC [6]. On the contrary, the majority of recent trials [7 12] reported positive results with an advantage, in terms of survival, for adjuvant chemotherapy with new doublets cisplatin plus vinorelbine or carboplatin plus paclitaxel. So, taken globally, these data suggest that postoperative chemotherapy improves survival after surgery in patients with stage IB to IIIA NSCLC, q 2005 European Society for Medical Oncology

2 iv111 and the awareness of the efficacy of this approach is progressively growing in the scientific community, although the topic has to be considered still controversial. More information could be taken from a new meta-analysis evaluating all these third-generation adjuvant trials which is already planned. Several prospectively randomized trials of neoadjuvant chemotherapy have been completed. Those trials took N2 patients and randomized them to preoperative chemotherapy, radiotherapy, or no therapy, and all patients underwent surgery. Unfortunately, all three trials have only 30 patients in each arm. Two trials are positive and one trial is equivalent [13 15]. Recently a large French randomized trial compared preoperative chemotherapy (mitomycin, ifosfamide and cisplatin) to surgery alone in resectable stage I, II and IIIA NSCLC. Survival was longer in the preoperative chemotherapy group, and probability of being alive was 9 10% higher in this group at years 3 through 5. However, this result was not statistically significant (P = 0.09) possibly because of low statistical power to detect an improvement of this magnitude. Survival differences were statistically significant only for the subgroup of patients with stage I and II disease [16]. Some large randomized trials on neoadjuvant chemotherapy are in progress in both United States and Europe and will clarify the role of this approach. In Italy, a randomized phase III trial in early stages (T2N0, T1-2N1, T3N0, T3N1), named ChEST (Chemotherapy for Early Stages Trial), has been stopped early due to slow accrual. At present, the question of the value of induction therapy followed by surgery remains unanswered. Neoadjuvant chemotherapy in the early stages is an experimental approach under investigation in the general patient population and should not be considered in clinical practice. Locally-advanced disease It has been shown that chemo-radiotherapy is more efficient than either chemotherapy alone or radiation alone, for the therapeutic management of localized unresectable NSCLC [4]. After several prospective randomized trials comparing sequential and concurrent chemo-radiotherapy to radiation alone and demonstrating the superiority of the combined approaches, more recent randomized trials compared a sequential to a concurrent approach reporting a survival benefit in favour of concurrent chemo-radiotherapy [17, 18]. The Italian research in this field is poor due to problems related to radiotherapy administration. In fact, the radiotherapy centres are very few when compared with the requested treatments, and consequently it is difficult to plan combined chemoradiotherapy trials. Despite this, small phase I-II trials have been performed. Two phase II trials evaluated, as induction chemotherapy, a three-drug combination with cisplatin (50 mg/m 2 ), paclitaxel (125 mg/m 2 ) and gemcitabine (1000 mg/m 2 )ondays1 and 8, every 3 weeks, for 3 cycles followed by surgery or radiotherapy showing an interesting response rate [19, 20]. Another interesting Italian-European trial was a randomized phase II study evaluating the feasibility of thoracic radiotherapy (total dose 60 Gy) with or without weekly docetaxel (20 mg/m 2 ) following 2 cycles of induction chemotherapy with cisplatin (40 mg/m 2 on days 1 and 2) plus docetaxel (85 mg/m 2 on day 1) every 3 weeks, in unresectable stage IIIA/IIIB NSCLC. A total of 108 patients were recruited reporting a response rate to induction chemotherapy of 43% with a grade 3 4 neutropenia of 46%. Response rates after local treatment in the 78 randomized patients were 74% for the chemo-radiotherapy group and 71% for the control group with mild toxicity [21]. Moreover, in two phase I trials, a third-generation drug was administered as daily radiosensitizers [22, 23]. A randomized phase III trial by the Italian Lung Cancer Project (ILCP) is ongoing. In this trial unresectable staged III NSCLC patients after induction chemotherapy with platinum-based regimens and subsequent consolidation with surgery or radiotherapy are randomized to receive gefitinib (ZD1839, Iressa ), an orally available Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, or placebo for two years. Advanced disease Italy is playing an important role in the clinical research of advanced NSCLC. Several Italian groups performed phase I, II and III trials reporting very interesting results that contributed to define the standard treatment for advanced NSCLC patients. Platinum-based chemotherapy in advanced NSCLC is the most common approach all over the world. New generation platinum-based doublets including gemcitabine or vinorelbine reported similar activity but lower toxicity when compared with old generation platinum-based triplets [24, 25]. The Gruppo Oncologico Italia Meridionale (GOIM) performed a randomized phase III trial comparing the MVP regimen versus cisplatin plus vinorelbine combination. Data achieved in this study suggested that cisplatin plus vinorelbine is similar to MVP in terms of overall response rate, time to progressive disease, and overall survival but better tolerated [25]. A second randomised trial by the GOIM showed that the doublet regimen of vinorelbine and cisplatin is equiactive to the combination of gemcitabine and cisplatin in terms of time to progression and median survival [26]. The ILCP [27] randomised 612 patients to receive gemcitabine (1250 mg/m 2 on days 1 and 8) plus cisplatin (75 mg/m 2 on day 2) every 3 weeks (GC arm), or paclitaxel (225 mg/m 2 on day 1) plus carboplatin (area under the concentration-time curve of 6 mg/ml-min on day 1) every 3 weeks (PCb arm), or vinorelbine (25 mg/m 2 /week for 12 weeks than every other week) plus cisplatin (100 mg/m 2 on day 1) every 4 weeks (VC arm). The study showed similar efficacy of new generation doublets with a different toxicity profile. However, platinum-based chemotherapy induces remarkable toxicity often affecting the patient s quality of life which remains the primary goal of treatment. Three main phase III trials, investigating non-platinum-based regimens, showed no statistical significant survival advantage for platinum-based chemotherapy, although two of them reported a survival trend for platinum-based treatments

3 iv112 [28 30]. In particular, one of these trials resulted from Italian Canadian cooperation [30]. A total of 501 advanced NSCLC patients were randomized to receive gemcitabine (1000 mg/m 2 on days 1 and 8) plus vinorelbine (25 mg/m 2 on days 1 and 8) every 3 weeks or cisplatin-based regimens (cisplatin 80 mg/m 2 on day 1 plus either gemcitabine 1200 mg/m 2 on days 1 and 8 or vinorelbine 30 mg/m 2 on days 1 and 8, every 3 weeks). Global quality of life was not improved with gemcitabine plus vinorelbine regimen (experimental arm), although advantages in some components were apparent. The conclusions were that the experimental arm is less toxic than standard cisplatin-based chemotherapy with a non-significant slight survival advantage with cisplatin-based chemotherapy. Not platinum-based chemotherapy could be offered to advanced NSCLC patients who express concern about toxicity. We have recently completed the accrual with GOIM cooperation to a multicenter randomized phase III trial on coxibs in advanced NSCLC. This trial, named GECO (GEmcitabine COxib), will evaluate the efficacy in terms of survival of the addition of rofecoxib, a selective COX-2 inhibitor, to cisplatin (80 mg/m 2 on day 1) plus gemcitabine (1200 mg/m 2 on days 1 and 8) chemotherapy and of the prolonged fixedrate infusion (10 mg/m 2 /min) of gemcitabine. Rofecoxib was administered at the dose of 50 mg/day, once daily [31]. This 4-arm study is being performed according to a factorial design. The potential role of COX 2 inhibitors in cancer therapy has to be discussed again, following the withdrawal of rofecoxib by Merck (on September 2004), because of an excess risk of myocardial infarctions and strokes in non-cancer settings [32]. All ongoing clinical trials on rofecoxib have been interrupted. Consequently, we stopped the accrual, after the enrolment of 301 patients, to the 2 arms of study containing rofecoxib. Moreover, we immediately stopped the administration of rofecoxib to the patients already randomized in the rofecoxib arms. So the randomization of the last 99 patients continued only in the two arms evaluating the gemcitabine infusion rates. Elderly patients Lung cancer may be considered typical of advanced age. More than 50% of lung cancer patients are diagnosed over the age of 65 and about 30% over the age of 70 [33, 34]. Italy is leader in the clinical research of the treatment of advanced NSCLC elderly patients. In fact, the first phase III trials addressed to this group of patients were carried out in Italy. The first randomized phase III trial in advanced NSCLC elderly patients was the Elderly Lung cancer Vinorelbine Italian Study (ELVIS). In this trial, 161 chemotherapy-naïve patients (>_ 70 years) were randomized to receive vinorelbine (30 mg/m 2 on days 1 and 8, every 3 weeks) or best supportive care [35]. A significant survival advantage with a better quality of life was observed for vinorelbine compared with the control group. Two phase III trials have compared gemcitabine plus vinorelbine combinations with single-agent therapy [36, 37]. A small study of gemcitabine 1200 mg/m 2 plus vinorelbine 30 mg/m 2 versus vinorelbine 30 mg/m 2 alone (n = 120 patients) closed early when an interim analysis showed that the combination conferred a significant survival advantage over the single agent (median survival: 29 versus 18 weeks, P<0.01) and a better overall response rate [36]. However, the 18-week survival for single-agent vinorelbine in this study is markedly lower than the 28- to 38-week survival times reported in five large randomised trials, including two studies dedicated entirely to elderly patients [35, 37 40]. The Multicenter Italian Lung cancer in the Elderly Study (MILES) trial, with GOIM cooperation, enrolling 700 patients with NSCLC is the largest phase III study of the elderly published to date [37]. Patients were randomised to receive singleagent chemotherapy with vinorelbine 30 mg/m 2 or gemcitabine 1200 mg/m 2 or combination therapy with vinorelbine 25 mg/m 2 plus gemcitabine 1000 mg/m 2, all treatments recycled every 3 weeks. Combination treatment had no advantage in terms of response rate, time to progression, survival or quality of life over single-agent therapy. Moreover, although toxicity was considered acceptable in all groups, it was higher with the combination than with the single agents. The authors concluded that single-agent therapy with vinorelbine or gemcitabine is preferable to the combination for treatment of advanced NSCLC in elderly patients. Based on the results of this large randomised trial, recent American Society of Clinical Oncology (ASCO) guidelines recommend singleagent chemotherapy for the treatment of advanced NSCLC in elderly patients [41]. Table 1 summarises the randomized phase III trials in advanced NSCLC elderly patients. We evaluated the role of cisplatin-based chemotherapy in advanced NSCLC elderly patients in the MILES 02 phase II randomised trial, in which the patients could receive Table 1. Results from phase III trials of advanced non-small-cell lung cancer in elderly patients Author Regimen Age (years) No.pts OR (%) ELVIS trial, 1999 Vinorelbine [35] vs >_ 70 Best Supportive Care 78 NA 4.8 Gridelli, 2003 Vinorelbine or Gemcitabine MILES trial [37] vs >_ 70 Vinorelbine Gemcitabine Frasci, 2000 Vinorelbine SICOG trial [36] vs >_ 70 Vinorelbine + Gemcitabine MST (months) ELVIS = Elderly Lung cancer Vinorelbine Italian Study; MILES = Multicenter Italian Lung cancer in the Elderly Study; OR = objective response; MST = median survival time; NA = not applicable; SICOG = Southern Italy Cooperative Oncology Group.

4 iv113 single-agent gemcitabine 1200 mg/m 2 at fixed-rate infusion (10 mg/m 2 /minute) or cisplatin (administered at attenuated doses of 50, 60 or 70 mg/m 2 ) plus either gemcitabine 1000 mg/m 2 or vinorelbine 25 mg/m 2. The trial reached the planned accrual of 210 patients and after having analysed the results of this phase II study, a phase III trial should be developed. Another phase II randomized trial conducted in collaboration with European groups evaluated the efficacy (primary objective: time to progressive disease) and toxicity of singleagent pemetrexed (500 mg/m 2 on day 1 every 3 weeks for 8 cycles), and sequential pemetrexed/gemcitabine (pemetrexed 500 mg/m 2 for cycles 1 and 2 followed by gemcitabine 1200 mg/m 2 on days 1 and 8 of cycles 3 and 4; this 4-cycle schedule was repeated once for a total of 8 cycles) for the treatment of advanced NSCLC elderly patients or patients ineligible for platinum-based chemotherapy. This trial completed the accrual of 92 planned patients and the results are being analysed. Targeted therapies To date, cisplatin-based chemotherapy including the present available drugs, will be unable to improve further survival. The investigation of new treatment strategies is mandatory. Our increased understanding of tumour cell biology and the identification of several molecular targets for NSCLC have led to the development of a number of new biological anti-tumour agents which have been evaluated in NSCLC [42]. Italian groups carried out important trials in this setting also in collaboration with International centres increasing the knowledge of these new molecules. Nevertheless, clinicallymeaningful advances have already been achieved in chemotherapy refractory advanced NSCLC patients, with gefitinib (ZD1839, Iressa ) and erlotinib (OSI-774, Tarceva ), two EGFR tyrosine kinase inhibitors, representing a further chance of tumor control, symptom palliation and survival prolongation in this clinical setting [43 45]. Unfortunately, two large randomized phase III trials (Iressa NSCLC Trial Assessing Combination Treatment INTACT 1 and 2 trials) combining gefitinib and polychemotherapy (cisplatin plus gemcitabine and carboplatin plus paclitaxel) in advanced NSCLC have been completed with disappointing results [46, 47]. In fact, gefitinib showed no added benefit in survival or any other outcome when combined to polychemotherapy. Disappointing results were also reported by an Italian phase II randomized trial in which advanced NSCLC elderly patients could receive gefitinib (250 mg/daily) plus either vinorelbine (30 mg/m 2 days 1 and 8, every 3 weeks) or gemcitabine (1200 mg/m 2 days 1 and 8, every 3 weeks). Gefitinib combined with gemcitabine showed low activity, but was generally well tolerated. In contrast, toxicity was unacceptable in the vinorelbine arm in which 18 out of 25 patients (72%) had grade 3 4 neutropenia, and there were 3 treatment-related deaths with no objective responses reported [48]. Prospective of gefitinib development in the treatment of advanced NSCLC include maintenance after chemotherapy, combination with other new biologic agents, and single-agent as first-line treatment for special patient populations [49]. Subset analysis of several Italian experiences that have included patients aged >_ 70 years suggests that gefitinib is active and generally well tolerated in this population [50 52]. We are launching trials with new targeted therapies. A randomized phase II study, named CALC-1 (Cetuximab in Advanced Lung Cancer), in which cetuximab (IMC-C225), a human-mouse chimeric anti-egfr monoclonal antibody, is administered in combination with gemcitabine or gemcitabine followed by cetuximab in advanced NSCLC patients unsuitable for combination chemotherapy. Another randomized phase II study evaluates the combination of pemetrexed plus gefitinib given with an intermittent schedule or pemetrexed followed by gefitinib or gefitinib followed by pemetrexed as first line treatment of advanced NSCLC elderly patients. Conclusions Lung cancer is the most frequent cause of cancer deaths in the western world today. 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