Chest
Small Cell Lung Cancer: State-of-the-Art Therapy in 1996
Section snippets
Pathobiology of SCLC
SCLC is characterized by small “blue” malignant cells about twice the size of lymphocytes, with sparse cytoplasmic and nuclear features having finely dispersed chromatin without distinct nucleoli. Nuclear molding is considered characteristic in well-preserved specimens, although a nondiagnostic “crush” artifact is more frequently observed. The histologic subtypes recognized in the pathology literature, classic oat cell and intermediate cell types, do not appear to behave differently
Clinical Presentation, Staging, and Prognostic Factors
SCLC usually presents as a large hilar mass with bulky mediastinal adenopathy causing cough, dyspnea, weight loss, and debility with or without postobstructive pneumonia.
SCLC can occasionally present with peripheral nodules. However, a solitary peripheral nodule without central adenopathy is sufficiently uncommon that cytologic diagnosis from a fine-needle aspirate might not adequately differentiate SCLC from typical or atypical carcinoid or well-differentiated neuroendocrine tumor. In this
Chemotherapy for SCLC
In the 1970s, SCLC was a candidate to be the first “curable” solid malignancy because of its apparent marked sensitivity to chemotherapy.5 Twenty years and numerous clinical trials later, physicians have become far more circumspect in their optimism. Since patients with SCLC usually present with disseminated disease, treatment strategies have focused on systemic therapy. Both single-agent and combination chemotherapy have produced a high degree of responsiveness. With aggressive
High-Dose Intensive Treatment of SCLC
Using hematopoietic cytokines with stem cell support (marrow or peripheral blood mononuclear cells) to protect patients from uncontrolled myelosuppression facilitates evaluation of dose response to the limits of organ tolerance. A number of small trials evaluating dose intensification with marrow support in SCLC have shown improved CR rates but have had no impact on overall survival.32 By comparison with today’s standards, however, these trials are compromised by their small size, high
Salvage Therapy
Salvage therapy produces a median survival of 4 to 5 months in relapsed patients. Second-line chemotherapy provides significant palliation in many patients, although the likelihood of response depends highly on the time from last therapy to relapse. If less than 2 or 3 months has elapsed, response to most agents or regimens is poor (refractory SCLC). If more time has elapsed, response rates of 20 to 50% can be expected. In patients receiving first-line CAV chemotherapy, etoposide/cisplatin can
New Agents
There are new agents that have significant single-agent activity against SCLC, including paclitaxel, docetaxel, vinorelbine, gemcitabine, and the topoisomerase I inhibitors, topotecan and irinotecan. Many ongoing phase I/II trials are adding these drugs to currently used first-line and salvage regimens to evaluate their place in the treatment of SCLC. One appropriate surrogate end point for known active agents or combinations, for example, would be to increase the CR rate (eg, from 15 to 30% in
Role of Thoracic Radiotherapy
The addition of radiotherapy to the thorax has improved median survival to between 14 and 18 months in patients with disease confined to the chest (LD).1, 39 Meta-analyses of over 2,000 patients suggest that thoracic irradiation for LD results in a reduction in local failure of 25 to 30% and a corresponding 5 to 7% improvement in long-term (2-year) survival.7, 8 The achievement of local control with conventional chemoradiotherapy remains a challenge.40 In a three-arm randomized study by Perry
Prophylactic Cranial Radiotherapy
Intracranial metastases occur clinically in up to 39% of patients with SCLC and are identified in about 40 to 50% at autopsy. Both randomized and nonrandomized studies demonstrate that prophylactic cranial irradiation (PCI) is effective in preventing cerebral metastases (6 vs 20% incidence in PCI-treated vs untreated patients, respectively) but does not improve survival.46, 47 Moreover, late neurologic sequelae have been ascribed to radiotherapy, particularly in series using fractions of >300
Surgical Resection of Early Stage SCLC
Early stage SCLC is detected in <10% of patients. Surgery alone is generally not recommended in this setting. Postoperative adjuvant therapy produces overall 5-year survivals of about 35 to 40%. Patients with node-negative findings fare better than those with positive nodes. Generally, mediastinal involvement is associated with poor outcomes, even in patients undergoing surgical resection. Preoperative chemotherapy followed by surgery yields 5-year survivals of 35 to 65%. Whether preoperative
Consolidation of Response with Biologicals
Many trials have attempted to evaluate immunologic approaches in patients with SCLC with minimal tumor burden (ie, in first CR or partial response after chemotherapy). Conflicting results are occasionally reported, but in general, bacille Calmette-Guérin, methanol-extruded residue, thymosin, and interferon have had no significant biologic effect.49 Interleukin-2 has produced some minor responses in patients with bulky SCLC but has not been evaluated in a phase III setting.50 Given their low
Current Management of SCLC
For LD SCLC, concurrent chemoradiotherapy using a platinum/etoposide-based regimen for four to six cycles is recommended. Chest radiotherapy should begin by cycle 4 (if not earlier) and should provide a biologically equivalent dose of ≥5,000 cGy in daily fractions of 180 cGy. I personally recommend PCI for patients in CR. For younger patients with no major comorbid disease, high-dose consolidation therapy might be considered.
For ED SCLC, until new effective approaches are developed, aggressive
Future Directions
The many biologic facets of SCLC may present opportunities for new therapeutic approaches. Replacement of retinoblastoma or p53 gene function or the as-yet-unknown 3p tumor suppressor genes, targeting of the numerous tumor-associated antigen clusters, and vaccine development all represent exciting new avenues for therapy. Additionally, evaluation of new chemotherapy agents is advocated in patients with refractory as well as residual disease (ie, disease that cannot be eradicated with current
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Reprint requests: Anthony D. Elias, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115