Overview and State of the Art in the Management of Lung Cancer

Worldwide, more than 1.2 million people are diagnosed each year with lung cancer, and approximately 1.1 million will die from the disease. In the United States, it is estimated that in 2004, 173,770 individuals will be diagnosed and 160,440 will die from lung cancer.[1] Non-small-cell lung cancer (NSCLC) accounts for approximately 80% to 85% of all cases of diagnosed lung cancer, while smallcell lung cancer (SCLC) accounts for the remainder of cases. This paper will highlight recent advances in the treatment of both NSCLC and SCLC. Stages of Lung Cancer Staging of NSCLC is based on the TNM classification. For SCLC, staging it is divided into limited disease (LD) or extensive disease (ED). Table 1 provides the staging of lung cancer as well as 1-and 5-year survival rates for each stage of disease.[2] Non-Small-Cell Lung Cancer Adjuvant Therapy
Radiation therapy (RT) and chemotherapy have been utilized as ad- juvant therapy following surgical resection of NSCLC (see Table 2 for an overview). A meta-analysis of postoperative RT from nine phase III trials compared postoperative RT to no postoperative therapy in stage I to III disease. The results demonstrated an adverse effect of RT on survival,[3] which was statistically significant; 55% of surgery-alone patients survived 2 years compared with 48% of those patients receiving postoperative radiation therapy. The dose of RT varied from 30 to 65 Gy. In 1995, a meta-analysis evaluating chemotherapy as postoperative adjuvant chemotherapy reported that alkylating agents were detrimental to patients while cisplatin(Drug information on cisplatin)-based chemo- therapy produced a 13% decrease in the risk of death (hazard ratio, 0.87; P = .08).[4] In 2000, the Eastern Cooperative Oncology Group (ECOG) compared radiation therapy (50.4 Gy) to RT plus etoposide(Drug information on etoposide) and cisplatin given postoperatively to patients with stage II and IIIA disease.[5] In both stages, there was no difference in survival or local recurrences whether the patient received postoperative RT or postoperative RT/chemotherapy. The study did not include a surgery-alone arm. In the randomized International Adjuvant Lung Cancer Trial (IALT),[6] 1,867 patients with stage I to III NSCLC received either adjuvant cisplatin-based CT or no therapy postoperatively. There was an absolute 4% 5-year survival (P < .03) advantage for those receiving chemotherapy (44.5% vs 40.4%). Disease-free survival (39% vs 34%) was also significantly different at 5 years (P < .003). Age, gender, performance status, type of surgery, or use of RT had no effect on survival. Neoadjuvant Therapy
Neoadjuvant CT in resectable NSCLC appears to improve survival rates (Table 3).[7-10] In three small studies involving 60 stage IIIA or less patients, there was a statistical surviv al advantage in patients receiving preoperative chemotherapy.[7-9] Pass et al reported a 3-year survival advantage of 40% vs 12% and median survival of 28.7 vs 15.6 months (P = .095). Roth et al[8] demonstrated a 3-year survival of 56% vs 15% and median survival of 64 months vs 11 months (P = .008). Rosell et al[9] reported a 3-year survival of 23% vs 0% and median survival of 26 vs 8 months (P < .001). In a large neoadjuvant chemotherapy study of 355 stage IB and IIIA patients, Depierre et al reported a statistically significant survival advantage for patients with stage I and II disease receiving neoadjuvant chemotherapy (2-year survival, 52% vs 41%; P = .04).[10] For stage III disease, there was no statistically significant difference. Chemotherapy/RT for Unresectable Stage III Disease
Neoadjuvant chemotherapy followed by RT for stage III NSCLC has been shown to be superior to RT given alone.[11,12] Dillman et al reported that two cycles of cisplatin plus vinblastine(Drug information on vinblastine) followed by RT (60 Gy) vs RT (60 Gy) alone produced a median survival of 13.8 vs 9.7 months with a 7-year survival of 13% vs 6%. A phase III Intergroup study utilizing the regimens in the Dillman et al study plus a third arm involving hyperfractionated RT demonstrated a statistically significant advantage of chemotherapy/RT over RT alone (1-year survival, 59% vs 46%; 5-year survival, 8% vs 5%).[13] It appears that concurrent chemoradiation therapy is more effective than sequential therapy in the treatment of unresectable stage III NSCLC (Table 4).[14,15] Furuse et al reported that concurrent mitomycin(Drug information on mitomycin) (Mutamycin), vindesine(Drug information on vindesine), and cisplatin (MVP) × 2 + RT 28 Gy followed by 2 weeks rest and then RT 28 Gy is statistically significantly better than sequential MVP × 2 followed by RT (56 Gy) in unresectable stage III NSCLC.[14] The median survival was 16.5 vs 13.3 months; 5-year survival was 16% vs 8.9% (P = .01). The Radiation Therapy Oncology Group (RTOG) conducted a phase III study comparing concurrent with sequential chemotherapy/RT as well as concurrent chemotherapy with hyperfractionated RT.[15] For the concurrent chemotherapy/RT vs sequential therapy, median survival was 17.0 vs 14.6 months, and 4-year survival was 21% vs 12% (P = .046). However, grade 3/4 esophagitis was 25% with concurrent therapy but only 4% with sequential therapy. Stage IIIB/Stage IV Disease
Combination chemotherapy is currently the standard treatment for good performance patients with stage IIIB (pleural effusion)/stage IV NSCLC. A meta-analysis from 52 randomized clinical trials demonstrated a survival advantage for advanced NSCLC patients receiving chemotherapy.[4] The increase in median survival was 2 months, with a 10% increase in 1-year survival. A number of twoagent combinations are active against advanced NSCLC.[16-20] Active agents such as paclitaxel, docetaxel(Drug information on docetaxel) (Taxotere), gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), and irinotecan(Drug information on irinotecan) (Camptosar) have been combined with cisplatin or carboplatin(Drug information on carboplatin) to treat patients with advanced NSCLC (Table 5). In general, such two-agent combinations produce response rates of 20% to 50%, median survivals of 8 to 10 months, 1- and 2-year survival rates of 30% to 35% and 10% to 15%, respectively. The use of chemotherapy is effective in treating the elderly with NSCLC (Table 6).[21,22] In the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) trial,[21] untreated stage IIIB/IV patients ≥ 70 years of age were randomized to receive vinorelbine or no therapy. Median survival and 1-year survival in patients receiving chemotherapy compared with observation was 6.5 months and 32% vs 4.9 months and 14%, respectively (P = .03).[21] Other studies have shown that chemotherapy can be given to the elderly.[22] In the United States, docetaxel is approved for use as second-line therapy for patients with advanced NSCLC.[23] Hanna et al recently reported on pemetrexed(Drug information on pemetrexed) (Alimta) compared with docetaxel as second-line therapy.[24] The response rate and survival rates were similar; however, pemetrexed was less toxic (Table 7). To improve the therapy of patients with NSCLC, new agents with unique mechanisms of action are being evaluated. Targeted therapies are such agents.[25,26] Inhibitors of epidermal growth factor receptors (EGFR) such as gefitinib(Drug information on gefitinib) (Iressa) have been studied (Table 8).[26] While gefitinib has been shown to be effective in advanced NSCLC patients who previously failed one or more regimens,[27,28] when combined with chemotherapy, there was no advantage to those patients receiving chemotherapy alone.[29] As second- or third-line therapy, the response rate was 9% to 20%, with survival rates of 7 to 8 months. The major toxicity has been acneiform rash and diarrhea. Gefitinib was first approved for use in Japan. Less than 1% of patients receiving the drug developed pulmonary interstitial disease. Other molecular targeted therapies including bevacizumab(Drug information on bevacizumab) and cetuximab(Drug information on cetuximab) are being studied.[30,31] Small-Cell Lung Cancer Small-cell lung cancer accounts for 15% to 20% of lung cancer diagnosed in the United States. Small-cell lung cancer is divided into limited disease (LD) or extensive disease (ED). The cornerstone of treatment of SCLC is chemotherapy. LD SCLC is treated with chemotherapy and radiation therapy.[ 32] The 5-year survival rates with appropriate therapy are 15% to 25%. The use of hyperfractionated (twicedaily) radiation therapy with chemotherapy appears superior to that used with daily radiation therapy.[33] However, Schild et al reported results of a phase III study that showed splitcourse, twice-daily RT was not superior to once-a-day RT in LD SCLC (Table 9).[34] In ED SCLC, median survival is 8 to 10 months with chemotherapy. Etoposide/ carboplatin (Paraplatin) is as effective as etoposide/cisplatin in treating patients with ED SCLC.[35] More recently, irinotecan/cisplatin was shown to be superior to etoposide/ cisplatin in patients with ED SCLC (Table 10).[36] For relapsed SCLC, chemotherapy is more effective in patients who have sensitive rather than refractory disease (Table 10).[37] Conclusions Since 1990, progress, albeit modest, has been made in the treatment of lung cancer, especially NSCLC. Combined- modality therapy is now used in resectable (stage I to III) as well as locally advanced unresectable (stage III) disease. Adjuvant chemotherapy produced an absolute 5% survival advantage for patients with surgically resectable stage I to III disease. Chemotherapy plus RT is standard therapy for locally advanced unresectable NSCLC. Concurrent chemotherapy/RT appears more effective than sequential chemotherapy and RT in treating such disease. Newer agents used in combination chemotherapy have improved survival and quality of life in NSCLC patients with metastatic disease. With the availability of molecular targeted therapies, treatment of such patients appears promising. Some progress has been made in the treatment of SCLC. Chemotherapy remains the cornerstone of therapy. In LD SCLC, concurrent chemotherapy/RT is the treatment of choice. For ED SCLC patients, irinotecan plus cisplatin appears more effective than the standard therapy of etoposide plus cisplatin.