Lung cancer is by far the leading cause of cancer-related death. In 2002, an estimated 183,200 patients will be diagnosed with lung cancer, and an estimated 161,400 deaths will occur.[1] Much work remains to be done in this disease, which is associated with a 5-year survival of only 15.8%, and a median survival for stage IV disease (even with enhanced cytotoxic therapies used in combination) ranging from 7.4 to 9.2 months.[1-6] However, it should be noted that over the past 15 years, combination platinum-based cytotoxic chemotherapy has resulted in a doubling of the median survival rate among stage IV NSCLC patients, from approximately 4 to 8 months. Furthermore, an almost threefold increase in the 1-year survival rate (from 11% to 14% up to 30% to 35%) and meaningful 2-year survival rates have been demonstrated in several randomized trials.[7]
Docetaxel (Taxotere) has demonstrated modest but very real survival and quality-of-life advantages when used in the second-line NSCLC setting; it could ultimately produce a more meaningful survival advantage in early- to intermediate-stage disease.[8,9] This theory was evaluated in a phase II trial conducted by the Southwestern Oncology Group (SWOG) in which patients received docetaxel(Drug information on docetaxel) after completing concurrent chemoradiation therapy with cisplatin(Drug information on cisplatin) and etoposide(Drug information on etoposide). The patients, all of whom had stage IIIB NSCLC without a malignant pleural effusion, demonstrated a median overall survival of 27 months and a 3-year survival of 37%.[10] The results of this phase II multi-institutional, cooperative group study highlight the fact that agents that have activity in advanced, refractory cancers often show significantly more activity in earlier stages of disease. Therefore, docetaxel should be investigated as a single agent and in combination with other cytotoxic agents, as a building block to improve upon the results now possible in the treatment of patients with NSCLC.
Front-Line Therapy of NSCLC: Single-Agent Docetaxel
Every-3-Week Regimen
Numerous phase I and II trials have shown that single-agent docetaxel is active in the treatment of incurable or metastatic NSCLC in chemotherapy-naive patients. A combined overall response rate of 27% was documented in six phase II trials of docetaxel, 100 mg/m² every 3 weeks, in this patient population, with a median response duration of 6 months, a median overall survival of 9.2 months, and a 1-year survival of 39%.[11] Lower doses of docetaxel have also been investigated in phase II trials in the front-line therapy of NSCLC. Docetaxel at 75 mg/m² and 60 mg/m² every 3 weeks resulted in overall response rates of 25% and 19%, respectively, and median survivals of 10 and 9.2 months.[12,13]
Based on these findings, Roszkowski et al conducted a randomized, open-label phase III trial in 207 patients with either unresectable or metastatic NSCLC who were treated with docetaxel plus best supportive care (BSC) or BSC alone.[14] Patients in the chemotherapy arm received docetaxel at 100 mg/m² as a 1-hour intravenous infusion every 21 days until evidence of disease progression, the estimated maximal benefits from treatment were obtained, or unacceptable toxicity. The study was conducted with 2-to-1 randomization; 137 patients received docetaxel and 73 received BSC.
Overall survival was significantly longer for the docetaxel plus BSC arm as compared to the BSC alone arm (P = .026). The 2-year survival in the docetaxel plus BSC arm was 12%, whereas none of the patients in the BSC arm survived longer than 20 months. The overall response rate in the patients who received a minimum of two cycles of docetaxel was 19.7%. Time to disease progression was significantly better in the docetaxel plus BSC arm vs the BSC alone arm at 12.6 weeks vs 8.9 weeks, respectively (P < .001). Quality-of-life tests revealed the superiority of the docetaxel arm (P = .0401). Additionally, requirements for narcotic analgesics and palliative radiation therapy were significantly lower in the docetaxel plus BSC arm vs the BSC alone arm, in spite of the fact that 16% of the BSC arm went on to receive chemotherapy.
Weekly Docetaxel Regimen
A trial of single-agent docetaxel as a weekly regimen in the treatment of patients with NSCLC has been reported by Hainsworth et al.[15] Docetaxel was administered at 36 mg/m²/wk for 6 consecutive weeks of an 8-week cycle to 39 elderly or poor performance status patients with chemotherapy-naive NSCLC. An overall response rate of 18% was demonstrated, with one complete response and six partial responses. The median survival was 5 months, with an estimated 1 year survival rate of 27% in this group of elderly patients. Similar to findings from other studies of weekly docetaxel administration, hematologic toxicities were greatly reduced. Grade 3 leukopenia was noted in only three patients, with none developing grade 4 myelosuppression.
As a result of these findings, and in particular in light of the absence of grade 3/4 neutropenia or neuropathy, many community physicians favor using a weekly schedule of docetaxel administration. Further testing remains to be completed to determine whether response rates and survival are equivalent to the every-3-week regimen. As will be discussed below, the use of docetaxel on a weekly schedule also offers attractive options for the development of combination regimens.
Combination Regimens of Docetaxel With the Platinum Agents
Docetaxel and Cisplatin
Based on docetaxel’s single-agent activity as first- and second-line therapy of NSCLC, and because the platinum compounds have long been a staple of front-line therapy for NSCLC, the next logical step was to combine docetaxel with cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin). The lack of cross-resistance and the largely nonoverlapping toxicity profile of docetaxel and the platinum agents provided additional rationale to investigate the combinations.
Several phase I trials of docetaxel and cisplatin have established the toxicity profile and activity of the combination in advanced NSCLC.[16-18] The two maximum tolerated doses achieved were either docetaxel at 100 mg/m² administered as a 1-hour infusion followed by cisplatin at 75 mg/m² 3-hour infusion or docetaxel at 75 mg/m² as a 1-hour infusion followed by cisplatin at 100 mg/m² as a 3-hour infusion with cycles repeated every 3 weeks. Many phase II trials have used doses of 75 mg/m² of each of the two compounds administered at 3-week intervals; however, other regimens have also been explored, as discussed below.
· The Zalcberg et al Trial—Zalcberg treated a total of 47 chemo-naive patients with the combination of docetaxel at 75 mg/m² followed by cisplatin at 75 mg/m².[19] Premedications included ondansetron (Zofran), dexamethasone(Drug information on dexamethasone), promethazine(Drug information on promethazine), and standard hyperhydration with magnesium supplementation. Of the 47 patients (72% male) enrolled, two-thirds had metastatic disease and 85% had a good performance status (World Health Organization [WHO] 0 or 1). All 47 patients were assessable for toxicity and 37 were evaluable for response, with 3 patients ineligible for enrollment and 8 discontinuing treatment due to significant toxicity.
Among assessable patients, the overall response rate was 38.9% (95% confidence interval [CI]: 23.1% to 56.5%). An additional 36.1% had stable disease and 25% had disease progression. Based on an intent-to-treat analysis, the objective response rate was 29.8%, with a median survival of 9.6 months and an estimated 1-year survival of 33%. The most significant toxicities seen included grade 3/4 nausea (26%), hypertension (15%), diarrhea (15%), and dyspnea (13%). However, only one patient (1.2%) experienced grade 3 neurosensory toxicity after completing eight cycles of therapy. Other grade 3/4 toxicities included hypomagnesemia (24%), febrile neutropenia (13%), and neutropenic infections (11%), leading to two treatment-related deaths. The authors concluded that docetaxel/cisplatin is active and feasible as a front-line therapy for NSCLC, with a favorable response rate, an acceptable toxicity profile, and good median and 1-year survivals.
The Le Chevalier et al Trial
Le Chevalier et al evaluated docetaxel, 75 mg/m², plus cisplatin, 100 mg/m², administered every 3 weeks for three cycles and then every 6 weeks in 51 chemotherapy-naive patients with locally advanced or metastatic (80%) NSCLC, including 37% with bone involvement.[20] The patient population was largely male (92%), with a median age of 54 years, and a median WHO performance status of 1. Patients received a median of four treatment cycles (range: 1 to 9), with more than 90% receiving full doses of both drugs as planned per protocol.
An overall response rate of 33% (95% CI: 19.6%-49.6%), was demonstrated among the 42 evaluable patients, 14 of whom responded. The median response duration was 7.3 months, with a median survival of 8.4 months and a 1-year survival of 35%. Neutropenia was the predominant toxicity, occurring in approximately two-thirds of patients, with febrile neutropenia reported in seven patients (14%) and sepsis in one. Nonhematologic toxicities included grade 3 vomiting (14%), although neuromotor and neurosensory deficits were infrequent, with grade 3 neuromotor and neurosensory toxicities occurring in one patient each (2%).
The authors concluded that the results were encouraging, given the poor prognostic factors of the patient population, but questioned whether cisplatin added to the efficacy of single-agent docetaxel, given its impressive cumulative phase II response rate of 27% in a similar patient population.
The Belani et al Trial
The third multicenter trial was conducted by Belani et al, who tested a combination of docetaxel at 75 mg/m² and cisplatin at 75 mg/m² every 3 weeks in 47 patients with stage IIIB or IV NSCLC.[21] Among the 40 patients evaluable for response, 1 achieved a complete response and 14 achieved a partial response, for an overall response rate of 37.5% (intent-to-treat response rate: 32%). The median duration of response was 34.6 weeks. The median duration of survival was 11.3 months, and the median time to progression was 18.9 weeks. As demonstrated previously, grade 3/4 neutropenia was predominant, reported in 74.4% of patients and in 55.4% of cycles. The incidence of febrile neutropenia was 12.8%. Nonhematologic toxicities included asthenia in 14.9% of patients. Other grade 3/4 toxicities included nausea (20%), vomiting (12.5%), neurosensory effects (15%), neuromotor effects (12.5%), diarrhea (10%), and infection (7.5%). The Belani trial was the third phase II trial to demonstrate the substantial activity of the docetaxel/cisplatin combination.
The Georgoulias et al Trial
The fourth phase II trial of the docetaxel/cisplatin combination was conducted by Georgoulias et al, who performed a multicenter investigation of the regimen in 53 chemotherapy-naive patients with stage IIIB/IV NSCLC. Eligible patients received docetaxel at 100 mg/m² on day 1 and cisplatin at 80 mg/m² on day 2 every 21 days. Prophylactic granulocyte colony-stimulating factor (G-CSF, Neupogen), 150 µg/m², was administered on days 3 to 13.[22] An overall response rate of 45% was documented, with 1 complete response and 23 partial responses. The median time to progression was 36 weeks, and the median survival was 48 weeks. The 1-year survival rate of 48% was notable.
Despite the use of prophylactic G-CSF, grade 3/4 neutropenia developed in 43% of patients and resulted in febrile neutropenia in 28%. There were two septic deaths reported in this study. Nonhematologic toxicities included grade 3 fatigue (13%), grade 3/4 diarrhea (11%), grade 3 neurotoxicity (9%), and grade 3/4 mucositis (7.5%). The authors concluded that although the docetaxel/cisplatin combination was highly active at the doses used in this study, the incidence of hematologic toxicity was high despite the prophylactic use of G-CSF.
Several other trials of the docetaxel/cisplatin combination have been reported in abstract form, with overall response rates ranging from 47% to 52%.[23-25] As a result of the encouraging response rates, time to progression, and median survival rates consistently demonstrated in phase II studies, the docetaxel/cisplatin combination has been investigated in large, phase III randomized trials, the results of which will be discussed below.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
