Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Combined modality treatment with chemotherapy and thoracic radiation therapy (TRT) is the standard treatment for patients with limited-stage disease (LD) small cell lung cancer (SCLC). Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1-4][Level of evidence: 1iiA] The combination of platinum and etoposide with TRT is the most widely used treatment regimen.

Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3-7][Level of evidence: 1iiA] As noted above, no consistent survival benefit has resulted from increased dose intensity or dose density, administration of additional drugs, altered modes of administration of various chemotherapeutic agents, or maintenance chemotherapy.[8-15][Level of evidence: 1iiA] The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.

The optimal dose and timing of TRT remain controversial, and multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3-6,8-10,16-19][Level of evidence: 1iiA] The amount of time from start to completion of TRT in LD SCLC may also impact on overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk = 0.62; 95% CI, 0.49–0.80; P = .0003).[19][Level of evidence: 1iiA]

Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years, P = .04).[16][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[20][Level of evidence: 3iiiA] The current standard treatment of patients with LD SCLC should be a combination containing etoposide and cisplatin with chest radiation.

The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[21] Elderly patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and prophylactic cranial irradiation (PCI). Elderly patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in elderly patients with LD SCLC has been reported; however, three secondary analyses of cooperative group trials have been published evaluating outcomes in patients 70 years or older.[22-24] The survival outcomes for the elderly patients were identical to their younger counterparts in both trials. The elderly patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the INT-0096 trial comparing etoposide and cisplatin with either once-daily or twice-daily radiation (1% for patients <70 years vs. 10% for patients ≥70 years; P = .01).[23] Because the elderly patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of elderly patients.

Patients presenting with superior vena cava syndrome are treated with combination chemotherapy with (for patients with LD SCLC) or without radiation therapy.[25,26] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

A small minority of LD patients with adequate pulmonary function and with tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes may possibly benefit from surgical resection with or without adjuvant chemotherapy.[27-31][Level of evidence: 3iiiDii] However, patients who have undergone surgery generally have had very limited disease; no randomized trials have been conducted evaluating the addition of surgery to chemoradiation therapy.

The only randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[32][Level of evidence: 1iiA]

Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[31,33,34] The majority of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% by the administration of PCI.[33] A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[33][Level of evidence: 1iiA]

Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[31,34-37] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[37] In addition, the majority of patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[37] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[35-37] Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Standard treatment options:

1. Combination chemotherapy and chest radiation (with or without PCI given to patients with complete responses).
2. Combination chemotherapy (with or without PCI in patients with complete responses) for patients with impaired pulmonary function or poor performance status.
3. Surgical resection followed by chemotherapy or chemotherapy plus chest radiation therapy (with PCI in patients with complete responses) for patients with stage I disease.[30]

Treatment options under clinical evaluation:

Areas of active clinical evaluation for patients with LD SCLC include new drug regimens, variation of drug doses in current regimens, surgical resection of the primary tumor, new radiation therapy schedules and techniques (e.g., three-dimensional treatment planning), and timing of thoracic radiation.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with limited stage small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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