Small-Cell Lung Cancer: A Perspective on the Past and a Preview of the future

ABSTRACT: Despite advances in the treatment of small-cell lung cancer during the 1970s, with the use of combination chemotherapy, and in the 1980s, with the combination of etoposide and cisplatin plus concurrent radiation therapy, treatment success seems to have reached a plateau in the current decade. Research should now be directed into three areas: (1) strategies to prevent the development of second cancers, one of the major causes of death in people “cured” of their first primary cancer; (2) introduction of new agents such as paclitaxel (Taxol) and other newer chemotherapeutic drugs into clinical trials, particularly in conjunction with radiation therapy in limited disease; and (3) development of new therapeutic approaches, such as the modulation of drug resistance, molecular biology interventions, and monoclonal antibody therapy, strategies that are based on increased understanding of small-cell lung cancer biology. Although it is doubtful that any single strategy will be curative, selective approaches that exploit new research findings in conjunction with moderately effective, more conventional treatments might allow us to raise remission and survival rates significantly.[ONCOLOGY12(Suppl 2):44-50, 1998]

Small-cell carcinoma of the lung represents approximately 18% of all lung cancers that occur in the United States yearly.[1] 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.[2] 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.[3] 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.[4] 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%,[5] 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.[2]

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.[2] In addition, new chemotherapeutic agents and combinations of agents currently under investigation offer the potential for more successful treatment.[3] 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.

A Brief History of Research in SCLC

Extensive 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[10] 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.

Limited Disease

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.[3] McCracken et al[13] 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 cancer—sequential combination chemotherapy and radiation and combination chemotherapy with concurrent radiation therapy—have been shown to be consistently beneficial in studies throughout the world (Table 2).[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.

Future Directions in the Treatment of SCLC

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 higher—32-fold—than 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.[21] 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[22] 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[23] 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[24] and subsequently in work performed by the North Central Cancer Treatment Group[25]. 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[29] 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[27] 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.[30] 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.

Development of Entirely New Treatment Strategies Based on an Understanding of SCLC Biology

In the past 20 years there has been tremendous progress toward understanding the biology of small-cell lung cancer. This information is leading to therapeutic strategies that will be tested increasingly over the next several years. It is clear that the classic chemotherapeutic approach to management of this disease has its limitations. It is hoped that interdicting selected critical pathways that control the malignant cellular process in small-cell lung cancer will provide the additional therapeutic boost that will benefit the thousands of patients afflicted with this disease.[31-33]

Careful evaluation of preneoplastic pulmonary lesions has shown that certain abnormalities occur early in the development of lung cancer. In particular, the genes that are deleted in the 3p14-23 region of chromosome 3 are injured early in the dysplastic/neoplastic process. Although there are several candidate genes,[34] the critical gene or genes that relate specifically to lung cancer development have not yet been identified.

Figure 2 shows a schema of the lesions known to dysregulate apoptosis and cell-cycle control in small-cell lung cancer. The overwhelming majority of small-cell lung cancer cells have abnormalities in three critical genes.

First, approximately 80% of small-cell lung cancer cells have p53 abnormalities,[35] which interfere with the ability of cells to undergo apoptosis and provide the time required to hold the G₁/S boundary necessary for DNA repair.

Second, this abnormality is compounded by additional, essentially universal lesions such as functional abnormalities of the retinoblastoma (Rb) gene, which have been noted in nearly all cases of small-cell lung cancer. Normally, this gene has a suppressor effect, keeping the G₁/S boundary in check, and thereby dampening the proliferation of small-cell lung cancer. Interestingly, in non-small-cell lung cancer, abnormalities in this gene itself are much less common (20% to 30%), but a similar effect is produced by the alteration of genes involved upstream of Rb, such as cyclin D1 and the cyclin-dependent kinases.

Third, the abnormalities relating to apoptosis introduced by mutated p53 are frequently magnified by the dysregulation of bcl-2, a process that occurs in between 65% and 70% of patients with small-cell lung cancer.[36,37] Bcl-2 is the major regulator of apoptosis. Overexpression of this gene, as found in small-cell lung cancer, prevents cells from undergoing apoptosis, a critical pathway in the response to injury introduced by existing cytotoxic therapies.

Figure 2 shows a number of strategies under development that could address the problems associated with these fundamental biologic lesions. For instance, it has been shown that certain individuals have antibodies that are directed against their own mutant p53 gene, suggesting that immunization strategies using this target may be possible. The taxanes, paclitaxel and docetaxel (Taxotere), have been shown to be potent phosphorylators of bcl-2, a process that leads to functional inactivation of bcl-2 and triggers apoptosis. Finally, a strategy of gene replacement might be considered, whereby the consistent abnormality in Rb function could be reconstituted.

Thus, the abnormalities in p53, bcl-2, and Rb break down the cell-cycle checkpoint at the G₁/S boundary, as well as dampen the ability of cells to undergo apoptosis, in essence aborting the “brake” for the system. The lesions shown in Figure 3 represent the next level of dysregulation—and potential therapeutic targeting. These lesions provide a positive drive for proliferation in this “debraked” mechanism.

Two general categories are shown in Figure 3. First, a consistent body of work has shown that numerous growth factors are elaborated by small-cell lung cancer cells. These include peptides such as gastrin-releasing peptide (GRP), a host of neuropeptides, and the insulin-like growth factor IGF-1. In each instance, an autocrine effect is introduced in which the cells are capable of both producing and responding to the growth factor in an abnormal and unregulated manner. In effect, this leads to a continual, positive thrust toward cell division. To compound this proliferative thrust, certain oncogenes are mutated. In particular, small-cell lung cancer cells often have abnormalities in the c-myc and related genes n-myc and l-myc. This group of genes is important in cell regulation, as evidenced by the critical role of c-myc in the pathogenesis of Burkitt’s lymphoma, one of the most virulent and rapidly dividing of human cancers. Both the positively acting oncogenes and the growth factors act to accelerate this brakeless mechanism. Trials are already underway to attempt to interrupt certain growth factor/receptor interactions with anti-gastrin-releasing peptide antibodies.

Pharmaceutical firms are intensively developing specific inhibitors of downstream signal-transduction pathways, upon which the growth factor effect depends. Research into alkaloid receptors, including the nicotine receptor and the muscarinic acid receptor, is providing leads on how to bypass this growth-factor effect and, in fact, increase the ability of cells to undergo apoptosis. Antisense molecules directed against the myc series of genes are becoming available, and long-term drug-development programs are being designed that will attempt to “freeze” abnormal genes by developing DNA triplexes tailored specifically to the desired gene abnormality.

Figure 4 briefly describes the third category of abnormality critical to the development of the lethal phenotype in small-cell lung cancer. The two most striking clinical characteristics of small-cell lung cancer are its rapid proliferative rate and its propensity to metastasize. Figures 2 and 3 relate to the former characteristics, Figure 4 to the latter. Cellular aggregation and adhesion are requirements of normal organ function and, as a corollary, their deregulation is a prerequisite for metastases, the essence of cancer’s lethality. A large body of developing work indicates that critical abnormalities exist in small-cell lung cancer relating to adhesion and cell motility.

Nerve cell adhesion molecule (N-CAM) and E-cahedrin are potent molecules that regulate cell adhesion. In small-cell lung cancer, N-CAM exists predominantly in its sialylated state. Sialylation decreases the ability of N-CAM to induce cell adhesion. In small-cell lung cancer, E-cahedrin levels are low, providing a push toward disaggregation. Interestingly, manipulation of the previously mentioned alkaloid receptors such as the muscarinic acid receptor and reintroduction of E-cahedrin mediates adhesion, which, in vivo, would presumably provide an inhibitory effect on the ability of a localized lesion to metastasize.

Another interesting system related to the metastatic potential of these tumors is the C-kit transmembrane tyrosine kinase complex. Specific receptors for this protein are expressed in small-cell lung cancer cells. The ligand for this receptor, stem-cell factor, is a potent chemotactic agent and inducer of cellular migration. Interestingly, neuropeptides, which have been noted to be potential autocrine growth factors, have chemoattractant and cell-migratory effects as well. Thus, a number of targeted strategies could be employed to counteract these effects, including monoclonal antibodies directed against sialylated N-CAM or vaccine strategies directed against GD3 ganglioside. Lastly, there are several antiangiogenesis agents, such as marimastat, TNP-470, and low-dose paclitaxel, that might interfere with the metastatic potential of small-cell lung cancer by disabling the mechanism by which satellite lesions attempt to establish a local blood supply. These agents are now being examined in clinical trials and should be tested in small-cell lung cancer.

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