Small-cell carcinoma of the lung represents approximately 18% of all lung cancers that occur in the United States yearly. It has long been recognized as one of the most virulent forms of lung cancer, and left untreated it kills within 6 to 12 weeks. Until about 20 years ago, surgery and radiotherapy were the major treatment modalities available for patients with this disease, but there were few long-term survivors. The introduction of combination chemotherapy in the 1970s drastically altered the clinical outlook for patients with small-cell lung cancer (SCLC) and became the mainstay of treatment. Palliation for extensive-stage small-cell lung cancer is now routine, and, most important, an increasing proportion of patients with limited-stage disease can be cured.
Combination-chemotherapy programs evolved from first-generation therapies based on alkylating agents; next the anthracycline doxorubicin (Adriamycin, Doxil, Rubex) was integrated; and most recently, the etoposide (VePesid)/cisplatin (Platinol) regimen has predominated. Unfortunately, these changes brought little overall gain. In the past decade, the cure rate for small-cell lung cancer has remained at approximately 3%, and survival rates are essentially the same as they have been for 15 years, or about 7% in limited disease and about 1% in extensive disease.
One bright spot has been the development of more effective therapy for patients with limited disease. The use of etoposide and cisplatin with concurrent radiation, a therapeutic regimen first tested in small-cell lung cancer in the late 1980s and confirmed in the present decade,[6-8] has extended substantially the 2- to 3-year survival rate. In addition, new chemotherapeutic agents and combinations of agents currently under investigation offer the potential for more successful treatment. At the same time, tremendous strides have been made in understanding the biology of lung cancer in general and of small-cell lung cancer in particular.[3,9]
In this article, we offer a brief review of work performed in small-cell lung cancer to date and discuss some of the current research taking place in the search for new therapies for this disease.
Table 1 provides an overview of some of the concepts shown to have a positive or negative overall impact on the treatment of extensive small-cell lung cancer. A review by Morstyn et al summarizing work carried out in the 1970s emphasized that combination chemotherapy had increased overall complete response rates to approximately 25% and median survival to over 6 months. Unfortunately, this rate has not increased significantly in the intervening 20 years.
Combination therapy incorporating agents such as etoposide and cisplatin (or carboplatin [Paraplatin]) has provided a reliable and tolerable standard of care for patients with extensive disease. Alternating combinations of drugs (according to the Goldie/Coldman concept or by rapid sequencing of agents) has not yielded consistent increases in either response or survival. A number of studies have evaluated dose-intensive therapy for extensive small-cell lung cancer and have demonstrated that, although there is a clear threshold effect with dose escalation, raising doses to maximally tolerated levels with or without growth factors or bone marrow/stem cell support yields no consistent or even incremental advantage in terms of survival. To date, only a few studies have evaluated modulators of drug resistance[11,12] but, in general, these have shown no consistent benefit.
The combination of etoposide and cisplatin was first used in clinical cancer trials in the early 1980s. Randomized clinical trials in patients with extensive disease had shown that this combination produced results at least as good as those associated with approaches based on cyclophosphamide (Cytoxan)/doxorubicin/vincristine (Oncovin) (CAV), and with less toxicity. McCracken et al were the first to combine etoposide and cisplatin with concurrent radiation therapy, resulting in a striking advantage over previously existing therapies. Subsequent studies by Turrisi et al[6,8] reporting similar results were ultimately verified in a large randomized trial carried out by the Eastern Cooperative Oncology Group.
The combination of etoposide and cisplatin plus concurrent radiation therapy was shown to increase the 2- to 3-year survival rates for patients with limited disease from approximately 20% to 40%. The fact that this doubling of survival in patients with limited disease was not replicated in those with extensive disease has had a significant impact on the design of further studies using newer agents, as will be discussed.
Two concepts tested in limited small-cell lung cancersequential combination chemotherapy and radiation and combination chemotherapy with concurrent radiation therapyhave been shown to be consistently beneficial in studies throughout the world (Table 2). A number of studies have now verified that radiation therapy should be used early in the course of the treatment regimen.[14-16]
Interestingly, only a few studies have evaluated the effect of dose intensification on response in patients with limited disease in a randomized clinical trial setting, although such trials are now being designed. As in extensive disease, the mechanisms of drug resistance and their modulation in limited disease have not yet been extensively explored. The few studies that have looked at these concepts have evaluated the modulation of the multidrug-resistance phenotype, which tends not to be an important mechanism of resistance in this disease.
At least three areas of investigation are expected to drive clinical research in small-cell lung cancer over the next several years: the development of prevention strategies in long-term survivors with limited disease, new therapies based on combinations of newer agents, and the development of entirely new treatment strategies based on an understanding of small-cell lung cancer biology.
Prevention Strategies in Long-Term Survivors with Limited Disease
As mentioned, the anticipated 2- to 3-year disease-free survival of patients with limited small-cell lung cancer has doubled in recent years. Investigators from the National Cancer Institute Navy Branch were the first to emphasize that long-term survivors with small-cell lung cancer were at significant risk of developing second primary lung cancers, usually of the non-small-cell type, in the first 5 years after diagnosis of small-cell lung cancer.[17-19] As treatments advance, allowing more patients to achieve long-term remission, this problem will increase.
Prevention strategies in lung cancer generally have been directed to patients who have received curative therapy for stage I non-small-cell lung cancer, a population with a 3% to 5% annual risk of developing a second primary lung cancer.[9,20] The increased risk for developing a second primary tumor is at least as great for patients with small-cell lung cancer; in fact, the upper limit of the estimate is much higher32-foldthan for those with non-small-cell lung cancer.
The field of chemoprevention in lung cancer is based on the concept that cigarette smoke leads to a field-cancerization effect, so that the entire bronchial mucosa is at risk. In susceptible individuals, there may be a general spectrum of disease ranging from frank invasive cancer to varying stages of noninvasive neoplastic transformation. Second, pioneering work by Hong et al in head and neck cancer has shown that retinoids are capable of both reversing the progression from preneoplasia to invasive cancer and preventing the development of second primary tumors associated with the carcinogens in cigarette smoke. In a randomized clinical trial, Pastorino et al reported a similar effect in lung cancer. Most recently, a large study in the United States comparing cis-retinoic acid with placebo in patients with completely resected stage I non-small-cell lung cancer has completed accrual.
Similar studies need to be performed in patients who have survived 2 to 3 years after treatment of small-cell lung cancer. In the United States, this group would consist of about 7,000 cases annually, a population for which a definitive national trial could be designed and completed in a timely fashion.
New Therapies Based on Combinations of Newer Agents
A wide variety of new agents with differing mechanisms of action and reasonably high levels of activity has recently been researched for the treatment of small-cell lung cancer (Table 3). The most extensively studied member of this group is paclitaxel (Taxol). The use of paclitaxel in the treatment of small-cell lung cancer was first described in studies by the Eastern Cooperative Oncology Group and subsequently in work performed by the North Central Cancer Treatment Group. The overall response rate in the combined experience of these two groups was 52%, defining paclitaxel as one of the most active drugs for the treatment of this disease. Due probably to its premier position in United States-based clinical trials in recent years, paclitaxel is the agent that has been evaluated most extensively in combination-chemotherapy studies.
The results of three trials recently presented or updated at the 1997 Annual Meeting of the American Society of Clinical Oncology are shown in Table 4.[26-28] In each instance, paclitaxel was combined with a platinum analogue, either carboplatin or cisplatin, with or without etoposide. The most extensive evaluation of this regimen was performed by Hainsworth and Greco at the Minnie Pearl Cancer Center in Nashville. In that study, paclitaxel was administered as a 1-hour infusion in conjunction with both carboplatin and etoposide. The data shown in Table 4 relate to patients with extensive disease only. Paclitaxel-based therapy showed a high level of activity, and there was some indication of a dose-response effect. This effect also was suggested by results of the North Central Cancer Treatment Group study incorporating cisplatin, and, while such a finding cannot be confirmed in a phase II setting, it is worthy of study in future clinical trials.
The Eastern Cooperative Oncology Group was unable to show a dose-response relationship when patients with metastatic non-small-cell lung cancer were treated with either paclitaxel 250 mg/m² or 135 mg/m² via 24-hour infusion schedule. This lack of effect may reflect a different dose-response relationship for this agent in small-cell lung cancer, or the dose threshold to obtain the maximal response may relate to treatment schedule. From the preliminary results presented in Table 4, it is clear that paclitaxel has a high level of activity in the extensive-disease setting, but it is not clear whether the survival associated with treatment differs remarkably from that noted with existing therapies.
In any case, the level of activity seen with the platinum- and paclitaxel-based combinations is clearly sufficient to justify the initiation of combined-modality studies in patients with limited disease and the quick design and execution of phase III trials. In fact, the group in Nashville has completed phase I-II evaluations of the three-drug combination of paclitaxel, carboplatin, and etoposide plus radiation therapy in patients with limited disease, and a phase III study is under way. To establish the optimal regimen, additional studies are needed to compare paclitaxel-based therapy with standard etoposide/cisplatin and radiation therapy.
The development of new combinations of agents that might or might not be based on a foundation of etoposide/cisplatin is also important. Such trials would include combinations such as paclitaxel and topotecan (Hycamtin), paclitaxel plus gemcitabine (Gemzar) and cisplatin (or carboplatin), or a host of combinations employing the newer compounds noted in Table 3.
A potential flow of trials from phase I-II to phase III is shown in Figure 1. Experience has shown that a substantial increase in activity in the extensive disease setting is not a prerequisite for a therapeutic advance in the limited-disease setting. For instance, two of the three studies that have evaluated the combination of etoposide and platinum in patients with extensive disease have failed to show that the regimen is superior to CAV or alternating programs. Yet in patients with limited disease, a consistent increase in 2- to 3-year disease-free survival has been noted with the cisplatin combination plus radiation therapy. Thus, the extensive-disease setting should be viewed as a testing ground for phase
I-II experience with new combinations. Once the appropriate dose, schedule, and preliminary indications of activity are obtained, active new regimens should be combined with local radiation therapy as a lead-in to the required definitive study. Randomized phase III trials of new combinations should only be conducted in patients with extensive disease once phase II trials provide a clear signal that the new combination offers a significant level of activity.
1. Ries LAG, Hankey BF, Miller BA, et al: Cancer Statistics Review 1973-1988. Bethesda, Maryland, National Cancer Institute, NIH publication no. 91:2189, 1991.
2. Ihde DC, Pass HI, Glatstein E: Cancer of the lung: Small-cell lung cancer. In DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th ed, pp 911-949. Philadelphia, Lippincott-Raven, 1997.
3. Fukuoka M, Masuda N, Ariyoshi Y: Therapeutic approach to disseminated small-cell lung cancer, in Aisner J, Arriagada R, Green MR, et al (eds): Comprehensive Textbook of Thoracic Oncology, pp 496-511. Baltimore, Williams & Wilkins, 1996.
4. Martin VR, Comis RL: Small-cell carcinoma of the lung: An updated overview. Semin Oncol Nurs 12:295-303, 1996.
5. Klastersky J: Small-cell lung cancer: Can treatment results be improved further? (suppl 2). Semin Oncol 21:1-2, 1995.
6. Turrisi AT, Glover DJ, Mason BA: Concurrent twice daily radiotherapy plus platinum-etoposide chemotherapy for limited small-cell lung cancer: A preliminary report. Antibiot Chemother 41:109-114, 1988.
7. Bunn PA, Crowley J, Kelly K, et al: Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 13:1632-1641, 1995.
8. Turrisi AT, Wagner H, Glover D, et al: Limited small-cell lung cancer: Concurrent bid thoracic radiotherapy with platinum-etoposide: An ECOG study (abstract). Proc Am Soc Clin Oncol 9:230, 1990.
9. Perry MC: Future directions in the therapy of small-cell lung cancer, in Kohman LJ (ed): Chest Surgery Clinics of North America: Small-Cell Carcinoma, 7:183-194. Philadelphia, WB Saunders, 1997.
10. Morstyn G, Ihde DC, Lichter AS, et al: Small-cell lung cancer 1973-1983: Early progress and recent obstacles. Int J Radiat Oncol Biol Phys 10:515-539, 1984.
11. Murray N: Treatment of small-cell lung cancer: The state of the art. Lung Cancer 17:S75-S89, 1997.
12. Fisher GA, Sikic BI: Clinical studies with modulators of multidrug resistance. Hematol Oncol Clin North Am 9:363-382, 1995.
13. McCracken JD, Janaki LM, Crowley JJ, et al: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: A Southwest Oncology Group study. J Clin Oncol 8:892-898, 1990.
14. Payne DG, Murray N, Warde P: Small-cell lung carcinoma: Role of thoracic radiation and its timing in relation to chemotherapy. Bull Cancer (Paris) 81:119-128, 1994.
15. Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11:336-344, 1993.
16. Jeremic B, Shibamoto Y, Acimovic L, et al: Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: A randomized study. J Clin Oncol 15:893-900, 1997.
17. Johnson BE, Ihde DC, Matthews MJ, et al: Non-small-cell lung cancer: Major cause of late mortality in patients with small cell lung cancer. Am J Med 80:1103-1110, 1986.
18. Ihde DC, Tucker MA: Second primary malignancies in small-cell lung cancer: A major consequence of modest success. J Clin Oncol 10:1511-1513, 1992.
19. Sagman U, Lishner M, Maki E, et al: Second primary malignancies following diagnosis of small-cell lung cancer. J Clin Oncol 10:1525-1533, 1992.
20. Benner SE, Lippman SM, Hong WK: Chemoprevention of lung cancer. Chest 107:316S-321S, 1995.
21. Richardson GE, Tucker MA, Venzon DJ, et al: Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking-related second primary tumors. Ann Intern Med 119:383-390, 1993.
22. Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323:795-801, 1990.
23. Pastorino U, Infante M, Maioli M, et al: Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 11:1216-1222, 1993.
24. Ettinger DS: Overview of paclitaxel (Taxol) in advanced lung cancer. Semin Oncol 20:46-49, 1993.
25. Kirschling RJ, Jung SH, Jett JR, et al: A phase II trial of Taxol and G-CSF in previously untreated patients with extensive stage small-cell lung cancer (SCLC) (abstract). Proc Am Soc Clin Oncol 13:326, 1994.
26. Meluch AA, Hainsworth JD, Thomas M, et al: Preoperative therapy with paclitaxel, carboplatin, 5-FU, and radiation yields 69% pathologic complete response (CR) rate in the treatment of local esophageal carcinoma (Abstract 927). Proc Am Soc Clin Oncol 16:261a, 1997.
27. Nair S, Marschke R, Grill J, et al: A phase II study of paclitaxel (Taxol) and cisplatin (CDDP) in the treatment of extensive stage small-cell lung cancer (ESSCLC) (abstract 1629). Proc Am Soc Clin Oncol 16:454a, 1997.
28. Glisson BS, Kurie JM, Fox NJ, et al: Phase I-II study of cisplatin, etoposide, and paclitaxel (PET) in patients with extensive small-cell lung cancer (Abstract 1635). Proc Am Soc Clin Oncol 16:455a, 1997.
29. Hainsworth JD, Gray JR, Hopkins LG, et al: Paclitaxel (1-hour infusion), carboplatin, and extended schedule etoposide in small-cell lung cancer (SCLC): A report on 117 patients (pts) treated by the Minnie Pearl Cancer Research Network (abstract 1622). Proc Am Soc Clin Oncol 16:451a, 1997.
30. Bonomi P, Kim K, Chang A, et al: Phase III trial comparing etoposide (E)-cisplatin (C) versus Taxol-cisplatin in advanced non-small-cell lung cancer. An Eastern Cooperative Oncology Group (ECOG) trial (abstract). Proc Am Soc Clin Oncol 15:A1145, 1996.
31. Minna JD, Sekido Y, Fong KM, et al: Cancer of the lung: Molecular biology of lung cancer, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th ed, pp 849-857. Philadelphia, Lippincott-Raven, 1997.
32. Williams CL: Basic science of small-cell lung cancer, in Kohman LJ (ed): Chest Surgery Clinics of North America: Small-Cell Carcinoma, 7:1-20. Philadelphia, WB Saunders, 1997.
33. Vutich F, Yoshitaka S, Fong K, et al: Neuroendocrine tumors of the lung: Pathology and molecular biology, in Kohman LJ (ed): Chest Surgery Clinics of North America: Small-Cell Carcinoma, pp 7:21-48. Philadelphia, WB Saunders, 1997.
34. Anderson MLM, Spandidos DA: Oncogenes and onco-suppressor genes in lung cancer. Respir Med 87:413-420, 1993.
35. Skarin AT, Blanco R: Lung cancer and tumors of the heart and mediastinum, in Skarin AT (ed): Atlas of Diagnostic Oncology, 2nd ed, pp 63-109. London, Mosby-Wolfe, 1996.
36. Ben-Ezra JM, Kornstein MJ, Grimes MM, et al: Small-cell carcinomas of the lung express Bcl-2 protein. Am J Pathol 145:1036-1040, 1994.
37. Higashiyama M, Doi O, Kodam K, et al: High prevalence of bcl-2 oncoprotein expression in small-cell lung cancer. Anticancer Res 15:503-505, 1995.