Combination chemotherapy for relapsed small-cell lung cancer—perspective on mechanisms of chemoresistance

Small cell lung cancer (SCLC) has a dismal prognosis due to early dissemination and aggressive growth. Despite high response rates to initial chemotherapy, SCLC relapses fast and exhibits broad chemoresistance. The JCOG0605 Japanese trial reported increased survival for a regimen combining cisplatin with etoposide and irinotecan compared to topotecan in chemosensitive patients and proposed this treatment as standard chemotherapy. Analysis of the trial data indicates an enrichment of patients with favorable prognosis in the combination chemotherapy arm, questioning the feasibility of this highly aggressive regimen in typical SCLC patients of higher age and afflicted by comorbidities. Considering the modest prolongation of life with current therapies, quality of live should be traded against extension of survival rated in months. Circulating tumor cell (CTC) lines established from relapsed SCLC patients suggest chemoresistance due to formation of large spheroidal multicellular aggregates, termed tumorospheres, which restrict drug access and contain quiescent and hypoxic cells. With the possible exception of metformin, clinical means to eliminate such tumor spheroids are confined to experimental research with cell lines and xenografts, but this new insight into chemoresistance of SCLC discloses entirely new modes of efficient treatment of SCLC.