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Lung cancer is among the most commonly occurring malignancies in the world and is one of the few that continues to show an increasing incidence. In the United States, lung cancer is the leading cause of cancer death in men, and it surpassed breast cancer as the leading cause of cancer death in women in the latter part of the 1980s. In 2006, there will be about 177,000 new cases and about 159,000 deaths from this disease.
Excluding this malignancy, most developed countries have shown declines in death rates from cancer in the past 20 years. During the same time period in countries such as the United States and Canada.
The incidence of lung cancer now exceeds 70 per 100,000 men in the United States. As we enter the 21st century, it is expected that the altered smoking habits of the past two decades and the decreased tar content of cigarettes consumed in the United States will lead to a leveling and finally a decline in lung canser incidence.
In the United States, only 13% of patients who develop lung cancer survive 5 years. These mortality rates far exceed those of the acquired immunodeficiency syndrome epidemic.
The epidemiologic data on smoking and lung cancer fulfill the following criteria for causal association.
International data demonstrate that lung cancer death rates parallel cigarette smoking prevalence rates in both men and women. Cigarette consumption per capita in people aged 18 years or older measures the total number of cigarettes smoked per year divided by the estimated population and includes smokers.
There is no apparent threshold in the dose--response relation between the degree of smoking and the incidence of lung cancer. Consequently, the potential of smoke in the environment of nonsmokers to induce lung cancer has become an important issue. The smoke inhaled by nonsmokers has a similar chemical composition to that inhaled by smokers but has higher N-nitrosamine levels and smaller size.
Increases in lung cancer risk accompany exposure to carcinogens, such as asbestos, radon, bis (chloromethyl) ether, polycyclic aromatic hydrocarbons, chromium, nickel, and inorganic arsenic.
The component fibers of asbestos, particularly crocidolite, are known carcinogens with a proven ability to cause lung cancer as observed in shipyard workers, insulation workers, cement workers, boiler workers, and probably in people with nonoccupational exposures. Asbestos exposure has a
Radon is a naturally occurring chemically inert gas that is a decay product of uranium-238. Radon
The treatment of occult lung cancer depends on the stage of disease at diagnosis. Because most of these tumors are early but invasive T1, N0 carcinomas, many are treated by surgical excision. Whenever surgery is contraindicated, curative radiotherapy is indicated. With proximal early-stage tumors, the role of brachytherapy to augment the total dose is unknown, but curative treatment can be applied in this fashion.
In patients who have carcinoma in situ, hematoporphyrin or Nd:YAG laser destruction of lesions can been attempted. Hayata and colleagues found that that early lesions should be less than 1 cm2 in total
Surgery and radiotherapy have been used independently to obtain local control of the primary tumor and regional lymphatic drainage. Until recently, chemotherapy had been used in an attempt to prolong
In NSCLC, when the tumor is limited to a hemithorax and can be totally encompassed by excision, surgery provides the best chance for cure. In stage I and II disease, when the tumor has not extended beyond the bronchopulmonary lymph nodes, a complete excision is
Radiotherapy for the treatment of NSCLC has experienced significant changes in a short time with respect to the evolution
| Mortality Rate (%) |
Complication Rate (%) |
|
|---|---|---|
| TYPE OF RESECTION | ||
| Segment or wedge | 1.3 | 10.4 |
| Lobectomy | 2.9 | 15 |
| Pneumonectomy | 6.2 | 15 |
| AGE (Y) | ||
| <50 | 1.3 | 3 |
| 50--59 | 1.3 | 10.7 |
| 60--69 | 4.1 | 13.0 |
| 70--79 | 7 | 24.5 |
| >80 | 8.1 | 20 |
| PULMONARY FUNCTION | ||
| FEV1 <1.2 | NS | 22 |
| FEV1 1.2--2.0 | NS | 14 |
| FEV1 >2 | NS | 14 |
| DISEASE STAGE | ||
| I | NS | 10.6 |
| II | NS | 11.2 |
| III | NS | 18.6 |
The use of chemotherapy in patients with NSCLC has been under investigation for several decades. Conceptually, it has evolved from administration in the palliative care setting to integration into combined-modality curative therapy settings in patients with locoregionally advanced disease.
Chemotherapy can be considered standard therapy for patients with stage IV disease or stage IIIB disease due to pleural effusion or positive scalene lymph nodes. In these settings, prolongation of survival time and amelioration of clinical symptoms are the goals of therapy.
In patients with locoregionally advanced disease (stage IIIA or IIIB), traditional therapy has consisted of surgery and postoperative radiotherapy or radiotherapy alone for patients with unresectable disease. In these patients, chemotherapy is now used as a component of multimodality therapy. Therapy is given
Most drugs have at best moderate activity in NSCLC. It has been generally accepted that a single agent should have a response rate of about 15% for the drug to be considered active. This guideline is compromised by the fact that not all drugs have been studied in rigorously designed and conducted phase II trials.
Nevertheless, throughout the 1970s and 1980s, only six drugs were thought to have sufficient single-agent activity in NSCLC. Complete responses to single-agent therapy were exceedingly rare. Furthermore, the response duration was short, on average 2 to 3 months. Median survival was 6 to 8 months, with no long-term survivors.
Combination chemotherapy was investigated in an attempt to increase response rates. Generally, higher responses were reported, but it remained unclear whether a more pronounced impact on survival was also achieved.
One of the earliest combination chemotherapy regimens was the CAMP regimen, consisting of cyclophosphamide, doxorubicin, methotrexate, and procarbazine. In a single institution study, a response rate of 26% was noted.
Most subsequent clinical trials have incorporated cisplatin, which has been thought by many investigators to be the most active single agent in NSCLC. Among the most frequently used combinations were the popular regimens of cisplatin and etoposide, cisplatin and vinblastine, or in Europe, cisplatin and vindesine or teniposide. Three drug combinations incorporating ifosfamide, mitomycin-C, or leucovorin, were also investigated
Most of these regimens have in common the combination of cisplatin with a vinca alkaloid or etoposide. They were based on the incorporation of drugs with known single-agent activity, unlike earlier combinations such as CAMP. Phase II studies of these regimens frequently resulted in response rates of
Because cisplatin is logistically difficult to administer and results in more severe toxicity, the suggestion of increased activity called for a direct comparison of cisplatin-based regimens with non--cisplatin-containing combinations. Although some studies reported increased response rates with a cisplatin-containing regimen, there was no consistent increase in survival. Only three studies reported
Another question of interest has been whether there exists a dose--response curve for cisplatin's activity in NSCLC. One early study suggested an increase in response rate when increasing the cisplatin dose from 60 to 120 mg/m2 . A second study, however, did not support this observation. Gandara and colleagues escalated the dose of cisplatin further to 200 mg/m2 (administered as 100 mg/m2 doses on
Randomized phase III trials investigating a new drug in stage IV NSCLC are aimed at demonstrating improved survival when compared with standard therapy. Although it can be argued that the randomized
Vinorelbine has undergone the most thorough testing in NSCLC . A randomized study conducted in Europe compared a standard of cisplatin and vindesine with cisplatin and vinorelbine and with
A second study in the United States compared the combination of cisplatin and vinorelbine with single-agent cisplatin. Again, the combination of cisplatin and vinorelbine proved superior to the single agent. Finally, single-agent vinorelbine resulted in superior survival times compared with 5-fluorouracil
These randomized trials show that vinorelbine plus cisplatin results in superior survival times than
Paclitaxel also has shown encouraging single-agent activity. The ECOG has completed a three-arm randomized study comparing cisplatin plus etoposide with cisplatin plus paclitaxel, with paclitaxel given
The combination of carboplatin and paclitaxel is also of interest. Both drugs have single-agent activity in NSCLC. Since neutropenia is dose-limiting for both drugs, the addition of granulocyte colony-stimulating factor might allow for dose intensification. Several phase II trials have been
Preliminary data for docetaxel, gemcitabine, and irinotecan also exist. Docetaxel has also been shown to have activity as second-line therapy in patients with cisplatin-refractory disease. This is encouraging