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  • Review Article
  • Published:

Drug rechallenge and treatment beyond progression—implications for drug resistance

Key Points

  • Reuse of the same anticancer therapy following disease progression is often considered to be futile owing to drug resistance; however, many cancers show sensitivity to therapy reintroduction after disease progression

  • Spontaneous, reversible and epigenetic resistance mechanisms might explain the retreatment phenomenon; alternatively, cancer cells might proliferate independently of drug resistance

  • Selection of drug-resistant clones is not necessarily a major contributor to response to therapy in many patients

  • Drug resistance definitions need to be re-evaluated; for example, disease progression based on RECIST criteria might be a poor indicator of drug resistance and when to change a course of treatment

  • Applying transient drug-resistance mechanisms to clinical practice could offer advantages over traditional therapy regimens, including increased therapeutic options, reduced costs, and improvements in quality of life, without compromising efficacy

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.

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Figure 1: Conventional and nonconventional (drug rechallenge and treatment beyond progression) therapy regimens in medical oncology.
Figure 2: Efficacy of drug rechallenge following disease progression on or off therapy.
Figure 3: Efficacy of treatment beyond progression in four randomized phase II or III clinical trials.
Figure 4: Mechanisms of drug resistance during drug rechallenge (panels a–d) and treatment beyond progression regimens (panels e–f).

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Acknowledgements

Grant and funding support for this Review came from the Canadian Liver Foundation (E. A. Kuczynski), the Canadian Institutes of Health Research, the Canadian Breast Cancer Foundation, the National Institutes of Health, USA (R. S. Kerbel); Mayo Clinic Cancer Center National Cancer Institute grant (D. J. Sargent, A. Grothey).

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E. A. Kuczynski and R. S. Kerbel researched data for the article. E. A. Kuczynski, D. J. Sargent and R. S. Kerbel wrote the article. All authors made a substantial contribution to discussion of the content, and reviewed and edited the manuscript prior to submission.

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Correspondence to Robert S. Kerbel.

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Competing interests

D. J. Sargent received consulting fees from Genentech, and has associations and received consulting feeds from Abbott, Bayer, Medivation and Novartis. A. Grothey receives research support for clinical trials from the following companies: Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Genentech, ImClone Systems/ Eli Lilly, Morphotek and Sanofi. R. S. Kerbel declares association with the following companies: Taiho Pharmaceuticals, Cerulean Pharma, MolMed sPA, Pfizer, Angiocrine Biosciences, and YM Biosciences. He has received honoraria from Roche/Genentech, Pfizer, Regeneron/Sanofi. E. A. Kuczynski declares no competing interests.

Supplementary information

Supplementary Table 1

Drug rechallenge following progression off therapy (DOC 36 kb)

Supplementary Table 2

Drug rechallenge following progression on therapy (DOCX 27 kb)

Supplementary Table 3

Continuation of treatment beyond progression, phase II and III randomized clinical trials (DOCX 27 kb)

Supplementary Text

Additional rechallenge agents (DOCX 40 kb)

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Kuczynski, E., Sargent, D., Grothey, A. et al. Drug rechallenge and treatment beyond progression—implications for drug resistance. Nat Rev Clin Oncol 10, 571–587 (2013). https://doi.org/10.1038/nrclinonc.2013.158

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