Although lung cancer is not the most common cancer, it is still the leading cause of cancer death in men throughout the world, accounting for 29% of all cancer deaths in men in the European Community countries. The corresponding figure for women is 9%.[1,2] Closer to our home in Spain, data from the Tarragona Cancer Registry and the Catalonia Mortality Registry indicate that one in 14 men will develop lung cancer and nearly all of them will die of the disease. However, survival time can be improved. A meta-analysis of cisplatin(Drug information on cisplatin) (Platinol)-based chemotherapy showed an increase of 1.5 months in median survival, with a 10% absolute increase of survival at 1 year.
A recent randomized trial indicates that the addition of paclitaxel(Drug information on paclitaxel) (Taxol) to cisplatin may lead to an additional 2-month improvement in survival. Interestingly, single-agent paclitaxel has attained a promising median survival time of 40 weeks in patients with advanced nonsmall-cell lung cancer. Prompted by the promising activity of paclitaxel, several groups are currently testing paclitaxel combinations to find the best chemotherapy regimen.
Logically, the first step is to combine paclitaxel with a platinum compoundeither cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin). The rationale for combining paclitaxel with carboplatin stems from the five-arm Eastern Cooperative Oncology Group (ECOG) study in which 400 mg/m² of single-agent carboplatin, followed by mitomycin(Drug information on mitomycin) (Mutamycin), vinblastine(Drug information on vinblastine) (Velban), and cisplatin at the time of progression produced the best median survival (31.7 weeks) despite a 9% objective response rate. In addition, single-agent carboplatin turned out to be much less nephrotoxic and neurotoxic than the cisplatin combinations. The European Lung Cancer Working Party study also showed that toxicity with a carboplatin/etoposide combination was significantly less than with a cisplatin/etoposide combination, although there were no differences in response rate or survival between the two arms.
It can also be speculated that certain paclitaxel multiagent combinations may potentially overcome drug resistance, and that paclitaxel cytotoxicity may increase with prolonged exposure duration. For instance, recently, a unique resistance mechanism linked to molecular alterations in microtubules has been described in paclitaxel-resistant human ovarian cancer cells. Likewise, automatic DNA sequencing has been used to detect b-tubulin point mutations in five of 49 (10%) tumors of nonsmall-cell lung cancer patients who were treated with single-agent paclitaxel. None of those five patients whose tumors contained b-tubulin mutations obtained an objective response, whereas 12 of the remaining 44 patients without tubulin mutation (27%) had a partial or complete response. Moreover, median survival for patients without tubulin mutations was 8 months, with 1-year, 3-year, and 5-year survival rates of 22%, 10%, and 5%, respectively. In contrast, the median survival was only 2 months for the subset of patients with tubulin mutations (P = .029).
Recently, the paclitaxel/carboplatin combination for advanced nonsmall-cell lung cancer has been the focus of several phase II trials in Europe. Extensive experience has been reported by Greek,[12,13], Dutch, and Italian investigators. These and other investigated studies[16-19] are reviewed here (Table 1). Although only four of these studies have been fully reported, results are encouraging.
The Two Greek Phase II Studies
The first Greek study was a paclitaxel/carboplatin trial in previously untreated patients with locally advanced or metastatic (inoperable stage IIIA, IIIB, or IV) nonsmall-cell lung cancer. The primary objective was to assess response rate. The secondary objectives were to examine survival, time to progression, and toxicity. Patients received 175 mg/m² of paclitaxel by 3-hour infusion and carboplatin at an area under the concentration-time curve of 7 (AUC in mg/mL · min) in each 21-day cycle. Grade 3 neutropenia occurred in 7% of the patients, and grades 3 and 4 thrombocytopenia were observed in only 2%. Results have been published elsewhere.
Inclusion criteria limited entry into the trial to chemotherapy-naive patients with histologically confirmed inoperable stage IIIA, IIIB, or IV nonsmall-cell lung cancer. All participants were required to have an ECOG performance status equal to or lower than 2, adequate hematological function (white blood cell count > 4.0 × 109/L and platelet count > 100 × 109/L), and an estimated life expectancy of more than 12 weeks. All patients gave their informed consent. Sixty patients were entered: 56 were male and four female; median age was 57; six patients were stage IIIA (10%), 20 patients were stage IIIB (33.3%), and 34 patients were stage IV (56.7%). This study found a 27.3% overall tumor response rate, progression-free survival of 6.85 months, and a median survival of 8.95 months with a 21.6% 1-year survival probability.
Based on the safety profile of paclitaxel/carboplatin, Kosmidis et al carried out a randomized study of two dose levels of paclitaxel plus a fixed dose of carboplatin in previously untreated patients with locally advanced or metastatic nonsmall-cell lung cancer. The primary objective of this study was to compare the objective response rate of patients treated with one of two doses of paclitaxel. The secondary aims were to compare time to disease progression, survival, toxicity, and quality of life. Patients were randomized to receive either 175 mg/m² or 225 mg/m² of paclitaxel (3-hour infusion) plus a fixed dose of carboplatin at an AUC of 6 in each 21-day cycle.
Ninety-nine patients were randomized to paclitaxel at 175 mg/m² (Group A) and 99 to paclitaxel at 225 mg/m² (Group B). The response rate among 90 evaluable patients in Group A was 25.6% (6 CR, 17 PR), whereas in Group B, the response rate among 88 evaluable patients was 31.8% (3 CR, 25 PR) (P = .733). Median time to progression favored the high-dose paclitaxel arm (4.3 months vs 6.4 months, P = .044). The median survival was 9.5 months for Group A vs 11.4 months for Group B (P = .16). The 1-year survival was 37% for Group A and 44% for Group B (P = .35). With a relative dose intensity of P = .94 in both groups, neurotoxicity (P = .025) and leukopenia (P = .038) were more pronounced in the high-dose paclitaxel arm. No toxic death was noticed. The authors concluded that higher dose paclitaxel prolongs the median time to progression but causes more neurotoxicity and leukopenia.
The Dutch Dose-Evaluation and Dose-Sequencing Phase I Study
The background of this study derives from preclinical studies that had demonstrated a sequence-dependent cytotoxic effect for the cisplatin/paclitaxel combination in vitro. The paclitaxel/cisplatin sequence was shown to be more cytotoxic than the reverse sequence. Other sequence-dependent interactions had been reported for paclitaxel combined with doxorubicin (Adriamycin), cyclophosphamide(Drug information on cyclophosphamide), or etoposide(Drug information on etoposide). Hence, the primary objective of this phase I trial was to evaluate a potential sequence-dependent interaction between paclitaxel and carboplatin. Secondary objectives were to examine survival, response rate, and toxicity. Six patients were allocated to each dose level and randomized to receive either paclitaxel followed by carboplatin or carboplatin followed by paclitaxel. The original dose levels were 100 mg/m² of paclitaxel and 300 mg/m² of carboplatin every 28 days.
Inclusion criteria limited entry in the trial to chemotherapy-naive patients with histologically confirmed stage IIIB or IV nonsmall-cell lung cancer. All participants were required to have an ECOG performance status less than or equal to 2 and adequate hematological function (absolute granulocyte count > 2.5 ×109/L, platelet count > 100 × 109/L). All patients gave their informed consent. Nine dose levels were tested; at the ninth dose level, paclitaxel was administered at 250 mg/m² and carboplatin at 350 mg/m² in three patients. This study found an overall response rate of 11% (three complete responses and two partial responses) with a 6-month median survival time and a 20% 1-year survival probability. When the response rate was broken down by paclitaxel dose with a cutoff level of 175 mg/m², a higher objective response rate was observed with paclitaxel doses above this level.
From this Dutch study, we can draw five conclusions. First, a 28-day paclitaxel/carboplatin cycle induces a higher response rate and survival as a function of the paclitaxel dose. Second, a minimum paclitaxel dose (175 mg/m²) in a 3-hour infusion is required for activity in advanced nonsmall-cell lung cancer. Third, no sequence-dependent toxicities or sequence-dependent pharmacokinetic interactions occur with a paclitaxel/carboplatin combination. Fourth, the paclitaxel/carboplatin regimen is well tolerated (grade 4 neutropenia occurred in only 15% of the patients). Finally, less thrombocytopenia was observed with paclitaxel/carboplatin than with single-agent carboplatin.