SCLC extensive disease – treatment guidance by extent or/and biology of response?

For the first time an improved survival was shown for PCI by the mentioned EORTC-study in this favorable subgroup (at least partial response to chemotherapy). The bottom line was an increase of overall survival (27 vs. 13% one-year survival) based on improved local control with a highly significant reduction of symptomatic cerebral metastasis for patients treated with PCI (41 vs. 17%). With the shortest of the applied radiation regimens this meant a gain in overall-survival of six weeks (5.4 vs. 6.7 months median survival) with a therapy of one week. The assessed quality of life was significantly better in the radiation group due to acceptable toxicities and reduced morbidity caused by cerebral metastasis. An additional advantage of PCI and related lower morbidity was the increased applicability of second-line chemotherapy. The study was designed with focus on easy feasibility and cost-effectiveness. So, patients with symptomatic brain metastases were excluded and cross sectional imaging was not routinely demanded but performed in case of defined key symptoms. However, treatment of occult brain metastasis by PCI cannot be finally ruled out. Despite of this potential limitation, an older meta-analysis evaluating complete responders of SCLC illustrates the main principle that PCI improves survival (benefit of 5.4% at 3 years) [3]. Approximately 20% of complete responders included in this meta-analysis were staged as extensive disease. The subgroup-analysis revealed no significant difference between limited and extensive disease (relative risk of death for limited/extensive SCLC: 0.85 vs. 0.77 p= 0.88).

Local recurrence plays an increasing role in ED-SCLC. After thoracic radiation treatment, in-field relapse occurred in 24% of the cases as the first site of relapse [4]. Without local treatment 89–93% patients suffered from local progress in the first year after primary therapy [2].

Already in 1999 a study performed by a Serbian group [5] evaluated different local treatment approaches depending on response to initial chemotherapy. Those who had complete response at least at distant levels were randomized to receive either two courses of cisplatin/etoposide (each 80 mg/m²) or TRT with daily carboplatin/etoposide (each 50 mg/m²). Subsequently, PCI and two more courses chemotherapy were performed. Interestingly thoracic radiochemotherapy improved 5-year overall-survival compared to chemotherapy (9.1% vs. 3.7%).

Four older studies [6‐9] investigating the value of TRT without standard PCI for extensive disease were unable to detect any benefit from treatment. However, besides absence of PCI, chemotherapy was applied sequentially and not concurrent with TRT. Furthermore, the limited case number of all four trials together (129 vs. 109 in the study of Jeremic et al.) suggests a lower statistical power of the negative studies. Staging deficits of the earlier investigations in the late eighties might also be assumed. A possible interpretation of these data on TRT could be a survival benefit of local control by simultaneous radiochemotherapy in the case of improved distant control due to chemotherapy and PCI. TRT has never been implemented into clinical treatment concepts for ED-SCLC. However, these findings are noteworthy on all accounts potentially improving the outcome of good responders with extensive disease.