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  • Perspective
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Conventional chemotherapy: millions of cures, unresolved therapeutic index

Nature Reviews Cancer volume 25, pages 209–218 (2025)Cite this article

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Abstract

In recent decades, millions of patients with cancer have been cured by chemotherapy alone. By ‘cure’, we mean that patients with cancers that would be fatal if left untreated receive a time-limited course of chemotherapy and their cancer disappears, never to return. In an era when hundreds of thousands of cancer genomes have been sequenced, a remarkable fact persists: in most patients who have been cured, we still do not fully understand the mechanisms underlying the therapeutic index by which the tumour cells are killed, but normal cells are somehow spared. In contrast, in more recent years, patients with cancer have benefited from targeted therapies that usually do not cure but whose mechanisms of therapeutic index are, at least superficially, understood. In this Perspective, we will explore the various and sometimes contradictory models that have attempted to explain why chemotherapy can cure some patients with cancer, and what gaps in our understanding of the therapeutic index of chemotherapy remain to be filled. We will summarize principles which have benefited curative conventional chemotherapy regimens in the past, principles which might be deployed in constructing combinations that include modern targeted therapies.

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Fig. 1: Apoptotic priming determines whether conventional chemotherapy induces cell death.
Fig. 2: Therapeutic index in tumours is dictated by replication stress, oxidative stress, p53 or DNA repair statuses.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Anthony Letai

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Anthony Letai

  3. College de France, CIRB, INSERM, CNRS, Université PSL Paris, Paris, France

    Hugues de The

  4. Hematology Laboratory, St Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

    Hugues de The

  5. IRSL, INSERM, CNRS, Université Paris-Cité, Paris, France

    Hugues de The

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  1. Anthony Letai
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  2. Hugues de The
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Correspondence to Anthony Letai or Hugues de The.

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A.L. is on the scientific advisory board of Zentalis Pharmaceuticals and Flash Therapeutics.

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Nature Reviews Cancer thanks Adam Palmer who co-reviewed with Robert Allen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

SEER 12 database: https://seer.cancer.gov/statfacts/html/dlbcl.html

Glossary

Conventional chemotherapy

Cytotoxic cancer drugs generally targeting DNA or microtubules, whose use originated in the twentieth century.

Cyclophosphamide

A type of conventional chemotherapy classified as an alkylating agent, derived from the original nitrogen mustard drugs, whose mode of action is most commonly considered to be direct DNA alkylation.

Doxorubicin

A type of conventional chemotherapy classified as an anthracycline, derived from bacteria, whose mode of action is most commonly considered to be indirect inhibition of topoisomerase II following intercalation of DNA.

Etoposide

A type of conventional chemotherapy whose mode of action is most commonly considered to be inhibition of topisomerase II.

Platinum-based chemotherapies

A family of conventional chemotherapeutic drugs including cisplatin, carboplatin and oxaliplatin, whose mode of action is most commonly considered to be cross-linking of DNA strands.

Prednisone

A high-potency corticosteroid given orally to kill malignant lymphocytes.

Rituximab

A monoclonal antibody drug recognizing CD20 used in the treatment of B cell lymphomas.

Taxanes

A family of conventional chemotherapeutic drugs including paclitaxel, docetaxel and carbazitaxel, initially derived from the western yew tree, whose mode of action is most commonly considered to be inhibition of microtubule depolymerization.

Vincristine

A type of conventional chemotherapy classified as a vinca alkaloid, derived from the periwinkle plant family, whose mode of action is most commonly considered to be disruption of microtubules.

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Letai, A., de The, H. Conventional chemotherapy: millions of cures, unresolved therapeutic index. Nat Rev Cancer 25, 209–218 (2025). https://doi.org/10.1038/s41568-024-00778-4

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