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Breaking the Cure Barrier 25 Years Later

Mount Sinai School of Medicine, New York, NY

While cancer cure is still a vast and intriguing biologic conundrum, the conceptual barrier has been cracked. Chemotherapy alone as a cure has been focused on the qualitative difference in the unique gene recombination of chronic myelocytic leukemia. Although still early to claim cure, 89% of patients survive at 5 years,¹ without evident residual disease by the most sensitive methodology in a substantial fraction, which augurs well for a major cure rate. More tumors have joined the category of sub-curable, where chemotherapy together with surgery and/or radiation, and sometimes passive immunotherapy, has substantially increased cure rates for breast cancer and lymphomas. Palpable gains have been recognized for colon, lung, ovary, and squamous cell head and neck cancers.

The existence of tumor stem cells has been invoked to account for chemotherapeutic failures. The chemotherapeutically curable tumors, choriocarcinoma, testis cancer, large cell lymphomas, Hodgkin's disease, and acute lymphocytic leukemia of children cast doubt on this invocation. The increased percentage of cures of acute myelocytic leukemia, acute lymphocytic leukemia in adults, chronic myelocytic leukemia, adjuvantly treated osteosarcoma and breast cancers, and several pediatric solid tumors, recognized by breaks in the survival curves, suggest that appropriate treatments can achieve tumor eradication. In the adjuvant treatment of breast cancer, which really is the treatment of a variable proportion of patients with micrometastatic disease, two active regimens in succession have been shown to be more effective than a single regimen of chemotherapy, or a rotation of the two treatments every other cycle. Furthermore, giving drugs after surgery in intensified regimens every 2 rather than every 3 weeks, using filgrastim to accelerate granulocyte recovery, has significantly improved disease-free and overall survival. All the curative regimens contain at least one alkylating agent, a DNA complexing agent, or multiple repetitive cycles of drugs that depend on activity during the metabolic reactions of the cell cycle.

There is new basis for optimism. An increased understanding of some molecular biologic characteristics of neoplastic growth has identified new targets. Qualitative differences between tumors and most normal tissues, such as telomerase, offer opportunity for targeted exploitation. The concept of specific targeting is not new: methotrexate and fluorouracil both target specific enzymes, but their targets are quantitatively different, and are not unique to cancer tissues. Receptor tyrosine kinases (other than the unique one of chronic myelocytic leukemia) that are critical to cell survival have been imputed or identified. Two types of inhibitors have been produced: small synthetic molecules and specific antibodies. Imatinib, sunitinib, and sorafenib have elicited responses in GI stromal tumors, renal cancer, and hepatocellular carcinoma; cancers hitherto totally refractory. Cetuximab, trastuzumab, and panitumumab achieve similar downregulation of receptor tyrosine kinases by immunologic impact on growth factor receptors upstream.

Immunotherapy has thus reached acceptance as a critical component of treatment. In addition to the antibodies aforementioned, rituximab has importantly improved therapy of many lymphomas. Bevacizumab, an immunotherapeutic approach to impairing the effects of vascular endothelial growth factor on tumor neovasculature (and more) exemplifies therapeutic efforts aimed at the host's relationship to, and nurture of, the neoplasm. Components of the host's own immunologic system may yet be upregulated or downregulated to enhance an effective immunologic defense. Cancer vaccines, of great heuristic promise, are still just over the horizon, except for already-developed viral vaccines of human papilloma virus.

Epigenetic changes have been indicted as part of cancer pathogenesis. Genes silenced by methylation have been successfully modulated by azacitidine, leading to increased survival in myelodysplasia. Blocking histone deacetylation by vorinostat has led to regression of cutaneous T-cell lymphomas. These promising developments suggest that combinations, or other methods of returning cellular metabolomics toward normal, could have profound effects on curability of a wide spectrum of cancers.

In summary, a few more cancers are curable. Many more of the sub-curable cancers are treated successfully with combined-modality therapy, and several of the precurable cancers have revealed glimmers of vulnerability to chemotherapy and/or immunotherapy. The accomplishments of the last 25 years represent progress, slow but sure, and reinforce the concept that there are no incurable cancers: just scientists and physicians, still fenced in by ignorance, inching forward, happily at an increasing pace.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCE

1. Druker BJ, Guilhot F, O’Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. New Engl J Med 355:2408-2417, 2006[Abstract/Free Full Text]

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This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Holland, J. F. Search for Related Content PubMed PubMed Citation Articles by Holland, J. F. Related Articles Related Article