In the late 1960s, it became clear that small-cell lung cancer (SCLC) is distinct from other histologic types of lung cancer and could be differentiated in a number of ways. At the time of diagnosis, for example, small-cell lung cancer usually manifests as a central tumor, with dissemination to the locoregional lymph nodes and signs of dissemination to distant sites in the vast majority of patients. Further, it is often associated with paraneoplastic signs like inappropriate antidiuretic hormone production, Cushings syndrome, and Eaton-Lambert syndrome.
The general consensus about the approach to treating this tumor changed considerably after it became clear that despite any apparent success of local treatment, ie, radiotherapy or surgery in selected patients, the short- and long-term prognosis for patients with small-cell lung cancer was very poor. In fact it was questionable whether therapy offered any benefit over no treatment, which resulted in a median survival of 6 weeks for patients with extensive disease and 3 months for those with limited disease. Despite the questionable success of radiotherapy as a single-treatment modality for limited-disease patients, the staging system for this tumor is still based on the potential to create a radiotherapy field that will encompass all known tumor sites.
The first small step forward in the treatment of small-cell lung cancer came after some effect was seen with the alkylating agent cyclophosphamide (Cytoxan, Neosar), one of the cytotoxic drugs available at that time. Since then, small-cell lung cancer has been considered to be a systemic disease that requires systemic therapy.
Following the first clinical trial using cyclophosphamide, several other drugs were tested (Table 1). Of the chemotherapeutic drugs available in the 1970smethotrexate, doxorubicin (Adriamycin), vincristine (Oncovin), procarbazine (Matulane), and the nitrosoureas (lomustine [CCNU], carmustine [BiCNU])only doxorubicin and vincristine are still in use for small-cell lung cancer, and both are near the point of being replaced by more active and/or less toxic drugs. Several drugs that remain important in the treatment of small-cell lung cancer first became available for clinical use in the 1980s. This list includes etoposide (VePesid), teniposide (Vumon), ifosfamide (Ifex), epirubicin, cisplatin (Platinol), and carboplatin (Paraplatin).
During the first half of the 1990s, still other drugs were tested and found to be active in this tumor. These include docetaxel (Taxotere), paclitaxel (Taxol), topotecan (Hycamtin), irinotecan (Camptosar), and gemcitabine (Gemzar). The ultimate roles of these drugsif they have anydepend on several factors, as will be discussed.
With all drugs listed in the second and third columns of Table 1, it is possible to form many different combination chemotherapy regimens. In general, combinations are more active than their individual components. Hundreds of publications have focused on many of these regimens without demonstrating any major differences in activity. Nevertheless, during the last decade, the combinations described in Table 2 have been used widely in clinical trials and may be considered standard combination chemotherapy for small-cell lung cancer.
During the last 25 years, chemotherapy has been the cornerstone of treatment for small-cell lung cancer. That some degree of myelotoxicity had to be accepted to obtain sufficient antitumor activity was recognized quite early. Based on this assumption, several regimens were evaluated and then given until tumor progression or intolerability. This approach often resulted in chemotherapy being administered for the remaining lifetime of the patient with small-cell lung cancer or for 18 months for the rare patient who achieved a long-term response. Whether this management course resulted in optimal quality of life, especially for patients facing a limited survival time, was questionable.
The Role of Maintenance Chemotherapy
The role of maintenance treatment was therefore addressed in a number of large, randomized trials. Although the design of these studies differed somewhat, the overall consensus was that maintenance chemotherapy prolongs the disease-free period without significantly affecting overall survival. Currently, short-term chemotherapy is considered standard, and in most trials four to six courses are given over a period of 3 to 6 months. Reducing this period any further would probably not improve quality of life for the patients and might impair it. Apparently, patients with small-cell lung cancer benefit most from maximal tumor reduction, which usually corresponds to two to four courses of chemotherapy.
Another management approach evolved from experiments with tumor xenografts and resulted in the Goldie-Coldman hypothesis of the potential benefit of alternating non-cross-resistant chemotherapy. Theoretically, this hypothesis is very attractive, and initial results of clinical trials involving the alternating use of two active chemotherapy regimens seemed to support its validity in the treatment of solid tumors and lymphomas. However, it soon became clear that translating this laboratory concept to the clinical environment is not that simple. Basic information was needed concerning the individual regimens to be alternated before it could be decided whether the regimens were suitable for alternation.
Comparable Activity and Non-Cross-ResistanceTwo important points have to be considered before embarking on a randomized trial: First, the activity of both regimens has to be comparable, and second, the regimens must have some degree of non-cross-resistance. In practice, this means that regimen A should be active in patients who were initially treated with regimen B, but whose disease subsequently progressed during or shortly after treatment, and vice versa.
If all regimens used in the different trials had been evaluated in this way before large randomized trials were initiated, many patients would have been treated otherwise. The apparent degree of non-cross-resistance between the two most frequently used combinationsCAV (cyclophosphamide/Adriamycin/ vincristine) and EP (etoposide/Platinol)in these trials was so small that no clinically valuable difference could be demonstrated between the alternating arm and the standard arm using one of the two combinations. Further, the activity of the two regimens differs somewhat, in favor of the EP schedule. Only two combinationsCDE (cyclophosphamide, doxorubicin, and etoposide) and VIMP (vincristine, ifosfamide, mesna, and Paraplatin)with comparable first-line activity and a sufficient degree of non-cross-resistance have been evaluated, and these combinations failed as well.[3,4]
Unless new drugs or combinations are developed that are truly non-cross-resistant with currently available agents, the idea of alternating chemotherapy will be no more than a concept without any clinical value.
Weekly Chemotherapy With Dose Intensification
Using the drugs listed in the second and third columns of Table 1, it was possible to design multiple-drug regimens given by alternating schedules every week to increase the dose-intensity of chemotherapy. In a number of randomized trials, this approach was shown to be feasible, although the dose-intensity achievable was not much higher than was possible with standard administration. With regard to efficacy, all trials failed to show any improvement in survival.
Radiotherapy to the Primary Tumor
The problem of demonstrating sufficient gain from the addition of a local therapy to chemotherapy has been the topic of many randomized trials, which showed only marginal or no clear benefit for combined-modality therapy. In a meta-analysis of 13 trials, combined modalities proved somewhat more effective than chemotherapy alone in patients with limited disease. At 3 years, a survival rate of 14% after combined-modality therapy compared favorably with the 9% rate associated with chemotherapy alone. Currently, radiotherapy to the primary tumor should be considered standard, although many questions concerning timing, schedule, fractionation, field size, and interaction with chemotherapy have not been answered sufficientlyor at all.
Treatment of Brain Metastases
For decades, brain metastasis has been treated with radiotherapy, based probably on the assumption that it signals tumor progression in an area inaccessible to chemotherapy because of the blood-brain barrier. From several studies, however, it has now become clear that brain metastases respond to chemotherapy in the same way as do all other metastases of lung cancer.
The choice of treatment for this type of metastasis should therefore be based not on misleading assumptions but on the goal of improving the quality of life for the individual patient. It is, therefore, possible to start with chemotherapy as well as with radiotherapy, or even a combination of the two. The main advantage of chemotherapy in this situation is the possibility of starting treatment immediately, without concerns over the possibility of a waiting time until the start of radiotherapy.
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