A three-arm confirmatory study was conducted by the Radiation Therapy Oncology Group (RTOG), Southwest Oncology Group (SWOG) and ECOG (11). It randomized 450 patients to receive exclusive radiotherapy, chemotherapy with cisplatin-vinblastine followed by 60 Gy radiotherapy, or combined treatment with hyperfractionated radiotherapy (1.2 Gy per fraction, twice a day) to a total of 69.6 Gy. Median survival was 11.4 months for patients receiving exclusive radiotherapy; 13.2 months (P=0.04) for those receiving the combination; and 12 months for hyperfractionated radiotherapy. Overall survival was statistically greater for patients who received combined treatment than for those who had radiotherapy alone.

A third study, conducted by Le Chevalier et al. (12) with 353 patients, compared three induction chemotherapy cycles (cisplatin, vindesine, cyclophosphamide and lomustine) followed by radiotherapy and three more cycles, vs exclusive radiotherapy. With an average follow-up of 40 months, two-year survival of the radiotherapy group was 14% vs 21% for the combination arm (P=0.08). A second analysis (13), with a mean follow-up of 61 months, found statistically significant benefit in overall survival at 3 years of 12% vs 4% (P=0.04) (Table1).

Two other trials, carried out by Jeremic et al. (20,21), analyzed the efficacy of concurrent treatment based in carboplatin plus etoposide. The group of patients with concurrent treatment showed a significant improvement in mean (22 months vs 14 months) and 4-year survival (23% vs 9%, P=0.021) (Table2).

Another similar study was conducted by the RTOG (9410) (23) with 610 stage II and III patients. The chemotherapy treatment was based on cisplatin and vinblastine, and the concurrent treatment arm had significantly better overall survival than the sequential arm (P=0.046).

A phase II trial (24) randomized 102 stage III A and B patients to receive concurrent or sequential treatment with chemotherapy based on cisplatin and vinorelbine. Median survival was greater in the concurrent arm (16.6 vs 12.9 months; P=0.023); and 3-year survival was 18.6% for concurrent treatment vs 9.5%, but the treatment arms were not well-balanced to the detriment of the sequential treatment group.

The French group (25) randomized 112 patients to receiving sequential treatment with two cycles of cisplatin and vinorelbine, followed by radiotherapy, vs cisplatin and etoposide concurrent with radiotherapy. Median survival was 14.5 months for the sequential arm vs 16.3 months for the concurrent treatment arm (P=0.24) (Table3).

The Bronchial Carcinoma Therapy Group (26) studied neoadjuvant treatment with chemotherapy followed by radiation therapy alone, or by concurrent chemo-radiotherapy in stages IIIA and B. Median survival was 14.1 months for the radiotherapy group and 18.7 months for the chemo-radiotherapy group (P=0.091). Mean time to progression was better in the concurrent treatment arm (11.5 vs 6.3 months, P=0.091), with similar toxicity.

A review of various trials published between 2000 and 2005 concluded that 5-year survival for inoperable stages IIIA and B increased from the 7% obtained with radiotherapy alone to 10% with sequential treatment, and as much as 15% for concurrent treatment (27). A meta-analysis of 12 clinical trials with 1,921 patients at various stages analyzed the role of chemotherapy based on cisplatin associated with radiotherapy and concluded that the addition of cisplatin to radiotherapy improves survival, with absolute benefit of 4% at 2 years (P=0.02), and that the combination of cisplatin and etoposide is more effective than cisplatin alone (28).

It should be noted that toxicity increases with concurrent treatment, particularly due to grade 3-4 esophagitis. Patients who are to undergo concurrent therapy regimes need to be selected using strict criteria to exclude those with weight loss or extensive exposure of lungs to radiotherapy.

In an attempt to unify criteria, a meta-analysis was published to clarify whether concurrent or sequential treatment is better (29). This included 1,205 patients with a 6-year follow-up, and demonstrated that concomitant treatment contributed absolute benefit on overall survival at 5 years of 4.5% (15.1% vs 10.5%) over sequential treatment. This was statistically significant (HR=0.84, P=0.004), but at the cost of increasing toxicity in the form of degree 3-4 esophagitis from 3 to 18% (P30).

The CALGB group compared induction chemotherapy with two carboplatin and taxol cycles, followed by concomitant chemo-radiotherapy, vs concomitant chemo-radiotherapy alone (32). Median survival in the chemo-radiotherapy arm was 11.4 months vs 14 in the induction arm (P=0.154), with one-year survival of 48% and 54%, respectively.

At present, there are various regimes with third-generation drugs that could be eligible for treatment designs with radiotherapy as better tolerance has been shown in advanced disease. In this respect, oral cytostatics, such as vinorelbine, could play a major role. Vinorelbine, a semisynthetic alkaloid derived from vinblastine, has several interesting features that favour concomitant use with radiotherapy. One of these is that it can be taken orally. Recently, a study of advanced lung cancer showed that 75% of patients who received vinorelbine preferred the oral formula in combination with carboplatin (36). In randomized clinical trials, oral vinorelbine proved to be an effective drug in combination with cisplatin in treating locally advanced and metastatic lung cancer, and had a good safety profile (37-39). It is absorbed quickly with an elimination half-life of 40 hours, it binds better to plasma proteins (13%) and has a hepatic-gallbladder metabolism (40). It was shown that oral vinorelbine has about 40% bioavailability: thus, oral doses of 60 or 80 mg/m2 vinorelbine were equivalent to endovenous doses of 25 and 30 mg/m2, respectively (41). Food does not affect its pharmacokinetics and the drug causes less nausea and vomiting if it is administered after a light meal (42). Early vomiting after administration of oral vinorelbine does not affect its absolute bioavailability (43), however the prior administration of an antiserotoninergic drug is recommended. If vomiting does occur, the dose does not need repeating. Age does not affect the clearance of oral vinorelbine (44) and it has no interactions with cisplatin, docetaxel, paclitaxel, capecitabine, gemcitabine or cyclophosphamide (45,46). These pharmacokinetic results establish the pathways for accepting the clinical equivalence of oral vinorelbine with the endovenous formula and with equal action.

Vinorelbine has a high response rate both in advanced disease and concomitantly with radiotherapy.

Intravenous vinorelbine combined with cisplatin and radiotherapy showed its effectiveness in a phase II study in which comparisons were made between cisplatin/gemcitabine vs cisplatin/paclitaxel vs cisplatin/vinorelbine in 2 induction cycles followed by concomitant therapy (47). There were no differences in response or survival for any of the three treatment arms (Table4), however there were differences in tolerance. The cisplatin/vinorelbine arm had fewer secondary effects and fewer treatment interruptions (Table5).

The first international study of oral vinorelbine combined with cisplatin and radiotherapy was published in 2008. In this phase-II study (48), which included 54 patients, 2 cycles of cisplatin (80 mg/m²) / oral vinorelbine (60 mg/m²) were administered as induction therapy followed, in the case of no progression, by 2 cycles of cisplatin (80 mg/m²) / oral vinorelbine (40 mg/m²) concomitant with radiotherapy (66 Gy). A 54% response was obtained, evaluated by external committee, with progression-free survival of 12.5 months, overall survival of 23.4 months and 2-year survival of 48%, with a better safety profile (4% grade 3 esophagitis). It should also be noted that 76% of patients received the maximum treatment dose established by the protocol, and 87% completed the chemo-radiotherapy as planned. The study found that the main toxicity was hematological: 28% grade 3-4 neutropenia during induction and 9% during combined therapy. Of non-hematological toxicity, grade-3 dysphagia secondary to radiation was the most common, occurring in 4.3% of patients. Late pulmonary fibrosis was only seen in one patient (Table6).