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Ospedale A Carle
Azienda Ospedaliera “S Croce e Carle”
During the last century, a dramatic epidemic of lung cancer deaths has occurred in many countries.(1) Today, lung cancer represents a major public health concern worldwide, accounting for about 12% of all new cancers in both sexes.(2) The increase of age constitutes the greatest risk factor for the development of cancer. A second risk factor, predominant in lung cancer development, is cigarette smoking.(3–6) Other risk factors for lung cancer, including exposure to residential radon, occupational exposures, diet and family history, have been shown to increase the risk of lung cancer independently of cigarette smoking.(7)
Changes in tobacco smoking habits and in other risk factors may have affected trends in lung cancer epidemiology.(7) Over the last 20 years, the incidence of lung cancer among men has fallen in the Western world. Lung cancer mortality rates are decreasing in the USA(5) and in several countries of north-west Europe.(6,8) On the contrary, the proportion of affected females and aged individuals, as well as the proportion of adenocarcinoma cell types, is increasing. In the USA, the incidence of adenocarcinomas has increased significantly since 1974, overall and within each sex.(9) The increase was higher among females (86% increase) and in both sexes over age 65 years.(9)
The majority of patients with lung cancer have nonsmall-cell carcinoma (NSCLC) and present with locally advanced (stage IIIa and IIIb) or metastatic disease (stage IV).(10) In these patients, who are inoperable at presentation, chemotherapy – with or without thoracic irradiation – remains the standard.(11–15) However, there is no consensus on which combination or treatment schedule should be used in everyday practice.(16) Randomised trials seem to support the use of two-drug combinations containing a platinum derivative and at least one new agent, such as vinorelbine, gemcitabine or the taxanes (see Table 1).(17) It is important to note that, while cycles of cisplatin (or carboplatinum) are still usually administered at three- or four-week intervals, administration of these new agents is more often based on weekly or nearly weekly schedules.(17)
The rationale for weekly administration is that more frequent delivery of moderate doses may achieve greater efficacy than standard doses every three weeks, through a more sustained exposure of dividing tumour cells to the cytotoxic effects of these drugs. This dose-dense approach to treatment may inhibit tumour regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy. More frequent exposure to cytotoxic agents may also enhance their apoptotic and antiangiogenic effects. Weekly therapy also has the advantage of improving the therapeutic index. Clinical studies show that weekly chemotherapy is effective and that toxicity is acceptable.
Clinical experience with weekly chemotherapy of lung cancer is already significant, not only in chemotherapy-naive patients but also in pretreated and in elderly or unfit patients.
Single-agent weekly paclitaxel, at doses of 50–200mg/m(2)/ week, was associated with response rates of 23–56% and acceptable toxicity.(18) Weekly paclitaxel was combined with carboplatin and vinorelbine in two-drug combinations, and with cisplatin plus gemcitabine and cisplatin plus vinorelbine in three-drug regimens.(18) Paclitaxel (40mg/m(2)) and cisplatin (20mg/m(2)) were administered weekly, without interruption, in 22 chemotherapy-naive patients with NSCLC.(19) Objective response rate was 40.9%, while stable and progressive diseases accounted for 40.9% and 18.2%, respectively.(19)
Elderly or unfit patients
Two recent phase II studies(20,21) and one randomised multicentre trial(22) have suggested that the drug of choice in this population might be vinorelbine. In an early phase II trial,(21) 83 unfit patients (23 of whom were aged 70 or older) were treated with weekly vinorelbine at doses of 25–30mg/m(2). The authors reported a 30.2% response rate (39.1% in the older subgroup), mild toxicity and an overall median survival of nine months. In another phase II study,(20) 43 elderly patients received vinorelbine at a dose of 30mg/m(2) every week for 12 doses. Ten patients (23%) obtained a partial response. Median time to progression was 11 weeks and median survival 36 weeks. A subsequent multicentre randomised study compared vinorelbine (30mg/m(2) on days 1 and 8 of a 21-day treatment cycle) alone with the best supportive care (ELVIS trial).(22) The median survival for vinorelbine recipients was 28 weeks (21 weeks for patients on supportive care alone, two-sided; p=0.03). In a recent study by our group, 46 patients aged 70 years or older were treated with weekly vinorelbine at a dose of 25mg/m(2). Two patients responded, and another 36 had tumour stabilisation. The median time to progression was 19 weeks, and the median survival 34 weeks.(23)
Recent reports indicate that in elderly patients single-agent gemcitabine may also ensure response rates of 20–30%, (24,25) with acceptable toxicity and improvement in symptoms and quality of life.(26) Recently, we reported a study of gemcitabine given at a dose of 1,250mg/m(2) (days 1, 8 and 15 of a 28-day cycle) in 45 unfit patients. Four patients responded (9%); the estimated median time to progression was 17 weeks, with a median survival of 35 weeks.(27)
The weekly administration of another taxane, docetaxel, was also found to reduce myelosuppression and other nonhaematological toxicities compared with administration every three weeks.(28)
Since our first review of the topic,(29) second-line treatment has become increasingly accepted.(30) The taxanes (ie, paclitaxel and docetaxel), given singly or in combination, are more often used in this setting. In a multicentre trial,(31) weekly paclitaxel (80mg/m(2)) was given in 62 pretreated patients with advanced NSCLC. Overall objective response rate was 8% and median survival 5.2 months.
In a Spanish phase II study, 40 patients received weekly paclitaxel 80mg/m(2) as a one-hour infusion. The overall response rate was 37.5%, with two complete and 13 partial responses; the median survival was 9.7 months and the median time to progression 5.4 months.(32) In another study by our group,(33) paclitaxel was given in 38 patients at a dose of 100mg/m(2) every week. Six patients obtained a partial response; the estimated median time to progression was 20 weeks, the median survival 58 weeks.(33)
Single-agent docetaxel is also active in pretreated NSCLC patients and regarded as the standard treatment in second-line chemotherapy; seven phase II studies have shown response rates of about 20% and nine months of median survival.(34) Two phase III studies documented a survival benefit at one year compared with best supportive care and vinorelbine or ifosfamide.(34) Recent trials indicate acceptable activity and a good safety profile of weekly docetaxel with doses of 25–43mg/m(2).(34,35)
Despite progress made over the last years, overall five-year survival rates still remain low in lung cancer. Weekly chemotherapy represents a technical improvement in chemotherapy administration. However, much work has yet to be done. New classes of biological agents that target the numerous pathways of lung cancer cells are currently under investigation. It is to be hoped that novel agents will change dramatically the current prospect of cure.
International Association for the Study of Lung Cancer
Cuneo Lung Cancer Study Group