Rechallenge of drugs in the era of targeted therapy

摘要

Switching of treatment after disease progression is a basic principle for cancer chemotherapy, because tumours progressing on therapy are thought to change permanently and become refractory to the treatment with associated resistance mutations either by selection pressure of previous therapy or by spontaneous acquisition of resistance. Progressive disease is used as a synonym of drug resistance and non-cross resistant drugs are required for subsequent therapy. After completion of standard treatment, patients are encouraged to enrol in clinical trials if available or to receive best supportive care without any therapeutic agents. Drug rechallenge and treatment continuation beyond progression, however, have emerged as potential strategies in the past decade, especially for molecularly targeted agents. Theories about rechallenge and continuation of therapy after previous progression are based on the facts that a significant subset of cancer cells remains sensitive to targeted agents after progression because of tumour heterogeneity and that radiographic disease progression (as assessed by RECIST criteria) does not always reflect clinically significant progression and drug resistance in the targeted era. Another reason for rechallenge or continuation might include the concern of so-called rebound progression or disease flare on withdrawal of tyrosine-kinase inhibitors (TKIs). Whether patients with EGFR-mutated or ALK-rearranged lung cancer after TKI treatment should rernain on therapy until multisite progression or clinical disease progression (with solitary or limited progressing sites be treated by local therapy) is contentious.