Drug rechallenge and treatment beyond progression--implications for drug resistance

Abstract

The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care.

Figure 1

Conventional and nonconventional (drug rechallenge and treatment beyond progression) therapy regimens in medical oncology. a | Typical sequences of therapy in relation to disease progression. b | Two major types of drug rechallenge. In drug rechallenge, treatment with a previously used agent(s) is repeated despite prior failure of the treatment, consisting of disease progression on therapy or after discontinuation of the therapy. c | In treatment beyond progression a therapy is continued with no break or a minimal break at disease progression. Arrowheads: progressive disease. Black lines: drug-free interval.

Figure 2

Efficacy of drug rechallenge following disease progression on or off therapy. a | Examples of response rates at initial treatment and rechallenge. Tumour control rates are good, although generally weaker at rechallenge, and fewer objective responses are achieved. b | PFS or TTP at initial therapy and at rechallenge in relation to the length of treatment-free interval. The rate of disease progression at rechallenge is favourable, although shorter at rechallenge. A longer treatment-free interval is often related to the rechallenge PFS or TTP. Treatment-free interval consists of an intervening treatment if rechallenge is post-progression on therapy. In the study by Mahon 2010, rechallenge ORR includes 62% of patients with complete molecular response and 38% of patients with declining BCR–ABL transcripts. In the study by Loriot 2012, ORR is defined as PSA decline ≥ 50%, at rechallenge SD is defined as PS decline between 30–50%. Abbreviations: B-CLL, B-cell chronic lymphocytic leukaemia; CRC, colorectal cancer; CRPC, castration-resistant prostate cancer; GIST, gastrointestinal stromal tumour; MM, multiple myeloma; NSCLC, non-small-cell lung cancer; ORR, overall response rate; Pro, prospective study; PFS, progression-free survival; RCC, renal cell carcinoma; Retro, retrospective study; SD, stable disease; TTP, time to progression.^,,,,,,,,,,

Figure 3

Figure 4

Mechanisms of drug resistance during drug rechallenge (panels a–d) and treatment beyond progression regimens (panels e–f). a | Resistance caused by non-heritable cellular adaptation might be reversed by a drug holiday. b | Cells spontaneously cycle between drug-resistant and drug-sensitive states enabling cell survival at initial treatment and resensitization after therapy rechallenge. c | Altered proportions of fast-growing/sensitive and slow-growing/resistant cells results in tumour regrowth during a drug holiday or intervening therapy, but drug sensitivity at retreatment. d | A slow-growing tumour, that had not yet acquired resistance, might be mistakenly classified as progressive disease based on RECIST; therefore, it is sensitive to rechallenge therapy. e | At first progression the tumour had not yet acquired resistance to the agent used for treatment beyond progression; therefore, switching the chemotherapy backbone, but continuing the other agent or rechallenging with an old agent could be beneficial. f | The tumour becomes resistant to both agents at disease progression. The agent continued beyond progression combines synergistically with a newly introduced agent, thus bypassing previous resistance mechanisms.