Vepesid

Lung cancer is currently the leading cause of cancer death in both men and women in the United States and accounts for approximately 150,000 deaths per year.[1] For purposes of treatment planning, several histologies, including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, as well as mixtures of these histologies, can be grouped together under the heading "non-small cell" lung cancer. These histologies account for approximately 75 percent of all lung cancers,[2] and treatment considerations and results do not differ appreciably between these histologies. Small cell lung cancer, which behaves and responds much differently from non small cell lung cancer, is not discussed in this article.

Surgical resection remains the most effective treatment modality for non-small cell lung cancer. Almost all patients who are cured of this disease are those whose cancer is operable and who undergo resection. Unfortunately, definitive surgical resection can be accomplished in only 30 percent of affected patients. The remaining 70 percent are unresectable because of overt distant metastases (40 percent) or locally advanced, unresectable disease within the chest (30 percent). Even after definitive resection, 50 percent of patients relapse, resulting in a rather dismal cure rate of 15 percent. The surgical cure rate is closely correlated with the stage of disease; Table 1 reviews the staging system for non-small cell lung cancer and shows the rapidly declining surgical cure rate in patients with more advanced stages of disease.[3]

TABLE 1

Staging System and Surgical Cure Rates in Non-Small Cell Lung Cancer

Adapted from Mountain CF. A new international staging system for lung cancer. Cancer 1986;89(4 Suppl):2238-50.

The success of surgical resection is limited because non-small cell lung cancer has usually spread by the time the first symptoms become manifest. Radiation therapy, the treatment traditionally used in patients with locally unresectable (stage IIIA and stage IIIB) non-small cell lung cancer, is also limited in most cases because of the systemic nature of the disease at presentation. Non-small cell lung cancer also tends to be resistant to traditional chemotherapeutic agents, with response rates of less than 15 percent with most standard drugs.[4] Because of this low level of activity, systemic therapy using traditional agents has had little impact on the survival of patients with non-small cell lung cancer and has not been considered a part of standard therapy.

During the past several years, hope has finally grown that improved systemic therapy may result in improved survival in advanced non-small cell lung cancer. Several new agents, with single-agent response rates in the 20 to 30 percent range, are either newly available or in clinical development. Combination regimens with response rates as high as 60 percent in stage IV non-small cell lung cancer have recently been reported.[5] Several randomized studies have shown improved survival in patients with locally advanced, unresectable non-small cell lung cancer who are receiving a combination of radiation plus chemotheraphy compared with patients receiving radiation therapy alone.[6-10] Randomized trials have also demonstrated improved survival in surgically resectable patients who received preoperative chemotherapy compared with those who underwent surgery.[11,12] This review briefly examines the most recent developments in the systemic therapy of non-small cell lung cancer. The review is divided into three sections: treatment of patients with metastatic (stage IV) disease; treatment of patients with locally advanced unresectable (stage IIIA and stage IIIB) disease and treatment of patients with potentially resectable (stage II and stage IIIA) disease.

Metastatic (Stage IV)

Non-Small Cell Lung Cancer

Effective treatment of metastatic non-small cell lung cancer has not been possible because of the limited activity of most standard chemotherapeutic agents. The most commonly used drugs include cisplatin (Platinol), carboplatin (Paraplatin, vinblastine (Velban), mitomycin-C (mutamycin) and etoposide (VePesid); they have response rates of only 10 to 20 percent against non-small cell lung cancer.[4] Many different combination regimens have been tested, including use of two or more agents; most "standard" regimens have included one of the platinum analogs. Using combination chemotherapy, response rates as high as 40 to 50 percent have been reported in highly selected groups of patients, but in cooperative group studies, most response rates are no higher than 25 percent.[13-15]

Because of these relatively low response rates, which were achieved at the price of treatment-related toxicity, several randomized trials[16-19] comparing chemotherapy to "best supportive care" were completed during the 1980s. The definition of "best supportive care" differed somewhat among these studies but, in most cases, included symptomatic treatment with palliative radiation therapy for local symptoms. The results of these trials are summarized in Table 2. Although the group of patients receiving chemotherapy had modest prolongation of median survival, the benefits of this therapy in most patients were minimal. Consequently, none of these regimens has been adopted for standard use.

TABLE 2

Results of Randomized Trials Comparing Chemotherapy with Supportive Care in Patients with Non-Small Cell Lung Cancer

Derived from references 16 through 19.

It should be further noted that even these rather unimpressive results may overestimate the overall impact of chemotherapy in this disease. In all of these randomized trials, patients with poor performance status were excluded, since these patients tolerate chemotherapy poorly and rarely respond to it. Other unfavorable prognostic factors in patients with non-small cell lung cancer include weight loss greater than 10 percent, hypercalcemia and tumor involvement in certain visceral sites (e.g., liver, brain). At present, systemic therapy should not be considered in patients with metastatic non-small cell lung cancer and poor prognostic features; symptomatic care is considered the optimal approach in these patients.

Fortunately, several new chemotherapeutic agents, either recently available or in advanced stages of clinical development, appear to have improved efficacy in the treatment of non-small cell lung cancer. Several new drugs, including paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), irinotecan (Camptosar) tecan (Camptosar) and topotecan (Hycamtin), have shown single-agent response rates of 20 to 30 percent. Most of these drugs have unique mechanisms of action and, therefore, it is likely that using them in combination will increase response rates substantially compared with single-agent response rates.

Since its introduction in 1993, paclitaxel has proved to be highly active in the treatment of several cancer types, including ovarian, breast, esophageal, head and neck, and lung cancers. Single-agent studies have consistently shown a 25 to 30 percent response rate in stage IV non-small cell lung cancer; all of the early trials also showed a one-year survival rate of approximately 40 percent, better than the 20 percent or less achieved using other drugs.[20-22]

Combination regimens including paclitaxel have also been developed and are undergoing further study. At present, the combination of paclitaxel and carboplatin looks most promising, with several investigators reporting response rates in the 50 to 60 percent range and median survival rates of approximately 12 months.[5,23,24] In addition to the favorable response rates, this regimen was well tolerated by most patients, and responding patients experienced consistent, subjective improvement, including weight gain and improved performance status. If these encouraging response rates and survival results are confirmed, this regimen will emerge as the first standard therapy for advanced non-small cell lung cancer, since median survival with other combination regimens has consistently been between 20 and 30 weeks (Table 2).

Vinorelbine was recently approved by the U.S. Food and Drug Administration for use in combination with cisplatin for the treatment of advanced non-small cell lung cancer. This approval was based on demonstrated single-agent activity, as well as improvement in survival and quality of life when patients receiving this combination were compared with patients receiving either cisplatin plus vindesine (Eldisine) or vinorelbine alone.[25] Several randomized studies are currently comparing the efficacy of these regimens, and results should be available in the near future.

Patients with good performance status should be considered for a trial of systemic chemotherapy; the combination of paclitaxel and carboplatin appears to be the most active regimen at present. Enrollment in a clinical trial, if available, should be considered, since many important research questions regarding optimal use of the newer agents remain unanswered. In spite of the increased activity of these regimens, nothing yet clearly indicates that chemotherapy benefits patients with very poor performance status, and symptomatic treatment of these patients is still appropriate.

Locally Advanced, Unresectable Cancer

Approximately 30 percent of patients with non-small cell lung cancer are found to have unresectable disease at presentation because of the extent of intrathoracic involvement, even though no obvious distant metastasis is evident. Involvement of mediastinal lymph nodes is the most common cause of inoperability; direct extension to the pleura, the pericardium or the mediastinum also precludes resection in some patients. Radiation therapy to the primary lesion and to the mediastinum has been the traditional treatment of choice in these patients and often achieves some palliation. However, in these patients, curative therapy with radiation alone is rare (less than 5 percent), and median survival is only nine to 12 months.[26] The efficacy of radiation therapy in these patients is limited both by the relative radioresistance of this type of cancer and by the frequent occurrence of distant metastases.

The use of combination chemotherapy in conjunction with radiation therapy in the treatment of locally advanced unresectable non-small cell lung cancer has been evaluated extensively during the past several years. Several randomized trials have compared results of combined modality therapy versus results of radiation therapy alone. Interest in this approach was heightened by the observation that response rates to standard chemotherapeutic combinations were higher in patients with no evidence of distant metastases (40 to 50 percent versus 20 to 25 percent with distant metastases).[10-12,27] Results of randomized trials evaluating this treatment approach are summarized in Table 3.[6-10] Although the exact treatment regimens differed among these trials, patients who received chemotherapy in addition to radiation therapy did better in most of the trials. In some trials, the differences reached statistical significance. In no trial did the combined modality group have a worse outcome than the group receiving radiation therapy alone.

TABLE 3

Summary of Randomized Trials Comparing Radiation Alone Versus Chemotherapy Plus Radiation in Locally Advanced Non-Small Cell Lung Cancer

NS = not significant.

(*)--Chemotherapy regimens varied, but most used cisplatin-based combination regimens.

Derived from references 6 through 10.

The trial showing the greatest differences between combined modality therapy and radiation alone was reported by Cancer and Leukemia Group B (CALGB) and now has follow-up results covering several years.[10] In this trial, median survival in the combined-modality group was 14 months, compared with 10 months in the radiation-therapy-only group. Survival differences have persisted, with 23 percent of the combined modality group alive at three years, versus 11 percent alive who were treated with radiation alone. Patients entering this trial, however, were a rather select group. Performance status was excellent in most patients; those with weight loss were excluded. In addition, patients with stage IIIB disease were excluded, so it may not be possible to generalize the favorable results from this trial to all patients with locally advanced non-small cell lung cancer. Other randomized trials also included mostly stage IIIA patients with good performance status.[6-9]

As more active chemotherapy regimens are developed for the treatment of advanced disease, it is likely that their impact will be even greater in patients with more limited stages of non-small cell lung cancer. At present, information concerning treatment of patients who have locally advanced disease with newer chemotherapy regimens in combination with radiation therapy is extremely limited. Our initial results using a paclitaxel-based regimen in conjunction with radiation therapy in patients with stage IIIA and stage IIIB disease are encouraging, with a 36 percent complete response rate and a median survival that will exceed 16 months.[28] Although such treatment cannot yet be recommended as standard, this is an area of intense clinical investigation, and patients should be considered for inclusion in clinical trials if they are available.

The benefits of this approach are probably limited to patients with good performance status, whose intrathoracic disease can be incorporated within a radiation-therapy portal. It is likely that the benefits of such an approach will become greater as newer, more active chemotherapeutic regimens are introduced. At present, patients with very poor performance status should be considered for either palliative radiation therapy alone or symptomatic treatment.

Preoperative (Neoadjuvant)

Chemotherapy for Resectable Cancer

The use of preoperative chemotherapy (with or without radiation therapy) in patients with potentially resectable non-small cell lung cancer is currently undergoing investigation by several groups. Patients who undergo resection for stage II or stage IIIA non-small cell lung cancer have a high risk of recurrence. Similar use of systemic therapy in conjunction with surgical resection for high-risk patients has proved effective in several other types of cancer, including breast cancer and colon cancer. Several small studies[29-31] show high response rates to initial chemotherapy (40 to 60 percent), as well as encouraging survival of patients following resection. In addition, no increase in post-surgical complications was encountered.

Two randomized studies[11,12] compared surgical resection with or without preoperative chemotherapy in patients with stage IIIA non-small cell lung cancer. In one study,[12] both groups of patients also received mediastinal irradiation. In spite of slight differences in the patient population and also in the chemotherapy regimens employed, both randomized trials showed improved survival in patients receiving preoperative chemotherapy. Table 4[11,12] summarizes the results of these two studies.

TABLE 4

Summary of Randomized Trials Comparing Preoperative Chemotherapy Plus Resection with Resection Alone in Operable Stage IIIA Non-Small Cell Lung Cancer

NS = not significant.

Derived from references 11 and 12.

Despite the results of these two randomized studies demonstrating the advantage of preoperative chemotherapy, this approach has not yet become standard in the management of patients with non-small cell lung cancer. Further studies are ongoing, and it is hopeful that the positive results of the two studies can be confirmed in larger numbers of patients. It seems likely that chemotherapy regimens with improved activity will accentuate the benefits of this approach even further. Ongoing studies are also seeking to extend the benefits of this approach to stage II patients, a group with a cure rate of less than 50 percent with surgical treatment.

At present, it seems reasonable to consider preoperative chemotherapy in patients whose disease is potentially resectable but who can be predicted to have low cure rates with surgical resection. This group of patients would include those with very large lung masses, patients with any mediastinal adenopathy on computed tomographic scanning, and those with primary tumor involving the pleura locally. It is likely that preoperative chemotherapy will be considered standard treatment in high-risk patients in the near future.

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[25.] Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer results of a European multicenter trial including 612 patients. J Clin Oncol 1994;12:360-7.

[26.] Curran WJ Jr, Stafford PM. Lack of apparent difference in outcome between clinically staged IIIA and IIIB non-small-cell lung cancer treated with radiation therapy. J Clin Oncol 1990;8:409-15.

[27.] Pisters K, Kris M, Gralla R, et al. Preoperative chemotherapy in stage III non-small cell lung cancer: an analysis of a trial in patients with clinically apparent mediastinal node involvement. In: Salmon SE, ed. Adjuvant Hherapy of cancer VII: proceedings of the Sixth International Conference on the Adjuvant Therapy of Cancer, Tucson, Arizona, March 7-10, 1990. Philadelphia: Saunders, 1990:133-43.

[28.] Greco FA, Stroup SL, Gray JR, Hainsworth JD. Paclitaxel in combination chemotherapy wiHh radiotherapy in patients with unresectable stage III non-small-cell lung cancer. J Clin Oncol 1996;14:1642-8.

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[30.] Strauss GM, Herndon JE, Sherman DD, Mathisen DJ, Carey RW, Choi NC, et al. Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study J Clin Oncol 1992;10:1237-44.

[31.] Martini N, Kris MG, Flehinger BJ, Gralla RJ, Bains MS, Burt ME, et al. Preoperative chemotherapy for stage IIIA (N2) lung cancer the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993;55:1365-74.

JOHN D. HAINSWORTH, M.D. is director of clinical research at the Sarah Cannon Cancer Center, Nashville, Tenn. Dr. Hainsworth graduated from Vanderbilt University School of Medicine, Nashville, where he completed a residency in internal medicine and a fellowship in medical oncology.

Address correspondence to John D. Hainsworth, M.D., Sarah Cannon Cancer Center, Centennial Medical Center, 250 25th Ave. North, Suite 412, Nashville, TN 37203.

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