Table 1.

Clinical and Biologic Rationales for Maintenance Chemotherapy

Rationale	Explanation
Increase exposure to effective therapies	At time of disease progression, only 20%–80% of patients with advanced NSCLC receive potentially effective second-line therapies. With a switch maintenance (ie, sequential or early second-line) strategy, > 90% of eligible patients receive the intended therapy.16,17
Decrease chemotherapy resistance	Because resistance depends on spontaneous mutations and therefore increases with time (Goldie and Coldman hypothesis), early use of non–cross-resistant therapies may increase the likelihood of killing more cancer cells before resistance develops.18
Maximize antitumor efficacy of therapy	Solid tumors are composed of faster growing cells, which are sensitive to therapy, and slower growing, more resistant cells (Norton-Simon hypothesis). Maximum antitumor effect is therefore achieved with sequential, non–cross-resistant regimens.19,20
Antiangiogenic effects	Metronomic (ie, low-dose, continuous) chemotherapy reduces tumor blood vessel formation via direct cytotoxic effects on endothelial cells; altering the balance of angiogenic growth factors and inhibitors; and effects on recruitment of bone marrow–derived endothelial progenitor cells. Cytotoxic agents with antiangiogenic effects in preclinical models include cyclophosphamide, doxorubicin, taxanes, and vinca alkaloids, among others.21–24
Alter antitumor immunity	Metronomic (ie, low-dose, continuous) chemotherapy decreases CD4+CD25+ regulatory T cells, in turn augmenting antitumor immune responses. Immunomodulatory effects have been seen with prolonged, low-dose administration of alkylating agents such as cyclophosphamide and temozolomide.25,26

Abbreviation: NSCLC, non–small-cell lung cancer.