Commentary (Tahn/Khuri): Second-Line Treatment of Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) poses one of the greatest management challenges in clinical oncology, as the mortality rate approaches 95% within 2 years after presentation for patients with extensive disease, despite widespread use of combination chemotherapy.[1] Given a disease that is largely managed by the community physician and for which recent definitive clinical trials are relatively scarce,[2] it is incumbent upon the clinician to be cognizant of the critical factors innovolved in offering patients chemotherapy. The considerations that go into making this crucial decision are outlined clearly by Dr. Eckardt in his article.

The role of second-line therapy for SCLC is an important question that needs to be addressed on an individual basis and subcategorized according to performance status and disease status (recurrent or refractory). Only by defining these often loosely used parameters can factors such as patient survival, quality of life, and symptom palliation-the primary end points of SCLC treatment- be utilized in a scientific fashion. Again, Dr. Eckardt nicely portrays the difficult decisionmaking process. Understanding how these factors interact with each other is the key to identifying patients who will benefit from additional therapy.

Treatment of Relapsed SCLC

Although combination chemotherapy is the gold standard of front-line therapy for SCLC, and while full doses of drugs are superior to doses that produce only minimal or mild hematologic toxic effects,[3] this is clearly not the case in the second-line setting. Whether in recurrent or refractory SCLC, the data for secondline treatment have not been as compelling, and single-agent topotecan (Hycamtin) has proven as efficacious as CAV (cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine), a more intensive combination regimen with far greater chemotherapy-associated toxicity in the best described secondline trials.[4]

The appropriate duration of therapy is less apparent. The combination of etoposide and cisplatin/carboplatin (Paraplatin) chemotherapy for four to six cycles has been established as the mainstay of treatment for both limited and extensive SCLC in the front-line setting, due to both its tolerability and manageable side effects. Treatment beyond six cycles has not been shown to be beneficial, and at least one randomized clinical trial has shown a decrease in survival with maintenance therapy.[5,6] This area has been even less well-defined in the second-line setting, and the author suggests that in highly selected patients, continuing treatment until progression may be indicated.

The caveat emptor of therapy for SCLC has long been that it should prolong survival and cure selected patients with limited disease. In the second- line setting, an impact on survival is only one of several desirable goals, including symptom palliation and improvement in or maintenance of quality of life. With the objective of balancing treatment toxicity with reasonable efficacy, these aims are all as important as prolonging survival

Quality-of-Life Measures

Definitions of quality of life and symptom palliation are difficult to compare across studies, as there are multiple instruments used to quantify these personal assessments. A review of the available literature by Montazeri et al[7] cited over 50 different instruments, the most popular of which were the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires, Rotterdam Symptom Checklist (RSCL), Hospital Anxiety and Depression Scale (HADS), Functional Living Index for Cancer (FLI-C), and Daily Diary Card (DDC). Each instrument has its role and function, but some are less specific to the problems faced by lung cancer patients and may not fully assess their individual concerns.

For performance status, the Karnofsky score and Eastern Cooperative Oncology Group (ECOG) performance status scales have both been established as valid, reliable measures. The Karnofsky score is more detailed, whereas the ECOG status is easier to score and takes only seconds to rate. The authors of this extensive review of quality-oflife measurements concluded that, in the absence of objective measures of clinical benefit, the patient's perceptions and attitudes toward therapy need to be ascertained to determine the best course of treatment, with the risks and benefits openly discussed.

At least two studies have shown that a patient's prediagnosis quality of life is an important prognostic factor for overall survival.[8,9] Along with performance status and weight loss, prediagnosis quality of life is an indicator and perhaps a predictor of how patients would tolerate or respond to chemotherapy. Among patients who have progressed while on first-line chemotherapy or who have had a short (< 3-month) interval before relapse, additional chemotherapy may be detrimental, especially if they have experienced significant toxicities or a decline in ECOG performance status during initial therapy.

Therapy for Recurrent or Refractory SCLC

Given the results of these quality-of- life studies, the choice of chemotherapy for patients with refractory disease greatly depends on the patient's overall condition. Single-agent therapies such as topotecan, gemcitabine (Gemzar), vinorelbine (Navelbine), taxanes, and recently, irinotecan (Camptosar) have all produced significant response rates in various studies. However, none of these drugs other than topotecan has been tested in prospective randomized studies,[ 10] and the response rates are in the 2% to 7% range for refractory disease and in the 16% to 25% range for recurrent disease, when the progression- free interval has exceeded at least 3 months.

Moreover, each of these drugs has known side effects and should be given with caution in patients who may already be experiencing complications of prior platinum therapy. Selection of an agent should be based, in part, on potential toxicities and compromised organ systems in a given patient.

Like oral topotecan, oral etoposide has been used in selected patients with extensive SCLC. However, benefit from oral etoposide appears to be isolated to patients who have demonstrated a response to first-line therapy, with several studies showing no response in those who have failed initial therapy.[11,12] Furthermore, in Cancer and Leukemia Group B (CALGB) protocol 9033, quality-oflife measurements were similar for oral and IV etoposide, with overall responses proving inferior for oral etoposide in one randomized study.

Dearth of Clinical Trials

The current treatment of SCLC was largely established by the late 1980s through studies of patients with extensive disease, with the exception of recent findings indicating that combinations of platinums and topoisomerase I inhibitors are superior to topoisomerase II inhibitors. Most community oncologists feel comfortable treating this disease.

Consequently, despite the fact that in 2002 SCLC accounted for 18% of all newly diagnosed cancers in the United States (approximately 32,000 to 35,000 cases per year), few recent randomized trials of the disease have had any significant impact on the field. Even fewer agents have been tested in the second-line setting, although selected trials of novel agents are testing biologically plausible interventions that began to accumulate in the late 1990s.

Future Directions

Nevertheless, newer treatment options are still under investigation for SCLC. For example, oral matrix metalloprotease inhibitors (MMPIs), oral epidermal growth factor-receptor (EGFR) or ERB1-receptor inhibitors, and hematopoetic stem cell transplants have all been explored with mixed results.

The results of preliminary studies with MMPIs by British Biotech (Marimastat), Novartis (MM1 270), and Bayer (Tanomastat) have all been disappointing. Worldwide SCLC studies of Tanomastat were stopped when preliminary results from a randomized clinical trial demonstrated that the MMPI was performing worse than placebo.[13] While EGFR research has shown that expression of the EGFR receptor in SCLC cell lines can be inhibited by various agents,[14-16] including imatinib mesylate (STI-571, Gleevec),[17] no clinical trials have yet demonstrated treatment efficacy or significant response in SCLC patients.

High-dose chemotherapy with autologous bone marrow transplant has been studied as a treatment modality for SCLC, but in the one reported trial of 45 patients who were randomized to additional therapy or bone marrow transplant after initial therapy, investigators noted only a trend showing improved relapse-free survival, but not overall survival, in the transplanted patients.[18] The sample size was considered too small to draw other conclusions. Few definitive studies have evaluated the efficacy of high-dose therapy in the second-line setting. Perhaps newer therapies with peripheral stem cell transplant may emerge as less toxic and more beneficial alternatives.

As Dr. Eckardt aptly suggests, more research is needed to find novel therapies for refractory SCLC. With new ways of measuring quality of life, better symptom control, and an emphasis on providing comfort for patients with end-stage disease, every clinician can help improve patient outcomes.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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