Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspectives
  • Published:

Reducing the toxicity of cancer therapy: recognizing needs, taking action

Abstract

Our understanding of the biology of cancer and the application of this knowledge to cancer treatment has greatly outpaced what we know of the biology underlying the symptoms and toxic effects that therapies produce. These adverse effects of therapy cause substantial discomfort and distress to patients and their families, limit treatment tolerability and can persist indefinitely in post-treatment survivorship. Despite these concerns, little research effort is targeted at documenting the nature of these effects. Similarly, limited efforts are being made in the drug-development arena to identify or develop treatments that might prevent or reduce toxicities. A panel of clinicians and researchers as well as representatives from advocacy groups, federal agencies and the pharmaceutical industry was convened to identify gaps in cancer treatment toxicity research and to provide direction for future action. With an emphasis on coordinating multidisciplinary efforts, this panel has presented a strategy to increase funding for the field and develop a coherent research agenda.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Centers for Disease Control and Prevention (CDC). Cancer survivors—United States, 2007. MMWR Morb. Mortal. Wkly Rep. 60, 269–272 (2011).

  2. Dantzer, R., Meagher, M. W. & Cleeland, C. S. Translational approaches to treatment-induced symptoms in cancer patients. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2012.88

  3. Segota, E. & Bukowski, R. M. The promise of targeted therapy: cancer drugs become more specific. Cleve. Clin. J. Med. 71, 551–560 (2004).

    Article  PubMed  Google Scholar 

  4. Fakih, M. & Vincent, M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr. Oncol. 17 (Suppl. 1), S18–S30 (2010).

    PubMed  PubMed Central  Google Scholar 

  5. Sankhala, K. et al. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target. Oncol. 4, 135–142 (2009).

    Article  PubMed  Google Scholar 

  6. Shepard, D. R. & Garcia, J. A. Toxicity associated with the long-term use of targeted therapies in patients with advanced renal cell carcinoma. Expert Rev. Anticancer Ther. 9, 795–805 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Subbiah, I. M., Lenihan, D. J. & Tsimberidou, A. M. Cardiovascular toxicity profiles of vascular-disrupting agents. Oncologist 16, 1120–1130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yang, X. et al. Kinase inhibition-related adverse events predicted from in vitro kinome and clinical trial data. J. Biomed. Inform. 43, 376–384 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bostrom, P. J. & Soloway, M. S. Secondary cancer after radiotherapy for prostate cancer: should we be more aware of the risk? Eur. Urol. 52, 973–982 (2007).

    Article  PubMed  Google Scholar 

  10. Chaturvedi, A. K. et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J. Natl Cancer Inst. 99, 1634–1643 (2007).

    Article  PubMed  Google Scholar 

  11. Kry, S. F. et al. The calculated risk of fatal secondary malignancies from intensity-modulated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 62, 1195–1203 (2005).

    Article  PubMed  Google Scholar 

  12. Nieder, A. M., Porter, M. P. & Soloway, M. S. Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J. Urol. 180, 2005–2009 (2008).

    Article  PubMed  Google Scholar 

  13. Smith, R. E., Bryant, J., DeCillis, A. & Anderson, S. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J. Clin. Oncol. 21, 1195–1204 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Basch, E. et al. Symptom measurement in clinical trials. Conference on Clinical Cancer Research, November 2011 [online], (2011).

    Google Scholar 

  15. Movsas, B. et al. Decreasing the adverse effects of cancer therapy: National Cancer Institute guidance for the clinical development of radiation injury mitigators. Clin. Cancer Res. 17, 222–228 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Smith, T. J. et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J. Clin. Oncol. 30, 880–887 (2012).

    Article  PubMed  Google Scholar 

  17. Rose, D. E. et al. Prevalence, predictors, and patient outcomes associated with physician co-management: findings from the Los Angeles Women's Health Study. Health Serv. Res. 47, 1091–1116 (2012).

    Article  PubMed  Google Scholar 

  18. FDA. Drugs: Adverse Event Reporting System (AERS) [online], (2012).

  19. Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Emerging safety science: workshop summary [online], (2008).

  20. FDA. Safety: FDA's Sentinel Initiative [online], (2012).

  21. American College of Surgeons. Cancer programs: national cancer data base [online], (2011).

  22. National Cancer Institute. Surveillance Epidemiology and End Results [online].

  23. Centers for Disease Control and Prevention. National Program of Cancer Registries (NPCR) [online], (2012).

  24. Abernethy, A. P. et al. Rapid-learning system for cancer care. J. Clin. Oncol. 28, 4268–4274 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  25. National Cancer Institute. Factsheet: NCI's clinical trials cooperative group program [online], (2012).

  26. PatientsLikeMe® [online], (2012).

  27. Wicks, P., Vaughan, T. E., Massagli, M. P. & Heywood, J. Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm. Nat. Biotechnol. 29, 411–414 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Oeffinger, K. C. et al. Chronic health conditions in adult survivors of childhood cancer. N. Engl. J. Med. 355, 1572–1582 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. ADNI Alzheimer's Disease Neuroimaging Initiative [online], (2012).

  30. Lacouture, M. E. et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support. Care Cancer 19, 1079–1095 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Busaidy, N. L. et al. Management of metabolic effects (hyperlipidemia and hyperglycemia) associated with anticancer agents targeting the pi3k-Akt-mTOR (PAM) pathway. J. Clin. Oncol. (in press).

  32. National Comprehensive Cancer Institute. NCCN Guidelines & Clinical Resources: NCCN guidelines for supportive care [online].

  33. Ettinger, D. S. et al. Antiemesis clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 7, 572–595 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Rodgers, G. M. III. et al. Cancer- and chemotherapy-induced anemia. J. Natl Compr. Canc. Netw. 10, 628–653 (2012).

    Article  PubMed  Google Scholar 

  35. Basch, E. et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 29, 4189–4198 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hensley, M. L. et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J. Clin. Oncol. 27, 127–145 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Lyman, G. H. et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J. Clin. Oncol. 25, 5490–5505 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Eagle, D. & Sprandio, J. A care model for the future: the oncology medical home. Oncology (Williston Park) 25, 571–576 (2011).

    Google Scholar 

  39. National Cancer Research Institute. Rapid review of research in survivorship after cancer and end of life care [online] (2010).

  40. National Cancer Institute. Division of Cancer Prevention programs & resources: Community Clinical Oncology Program (CCOP) [online].

  41. National Cancer Institute. Cancer survivorship research: cancer control and population sciences [online], (2012).

  42. Hoofnagle, J. H. Drug-induced liver injury network (DILIN). Hepatology 40, 773 (2004).

    Article  PubMed  Google Scholar 

  43. Stang, P. E. et al. Advancing the science for active surveillance: rationale and design for the Observational Medical Outcomes Partnership. Ann. Intern. Med. 153, 600–606 (2010).

    Article  PubMed  Google Scholar 

  44. International Conference on Harmonisation (ICH). Safety guidelines [online], (2012).

  45. Olson, H. et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Seigers, R. & Fardell, J. E. Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci. Biobehav. Rev. 35, 729–741 (2011).

    Article  PubMed  Google Scholar 

  47. Bowen, J. M., Gibson, R. J. & Keefe, D. M. Animal models of mucositis: implications for therapy. J. Support. Oncol. 9, 161–168 (2011).

    Article  PubMed  Google Scholar 

  48. Walker, E. A. Animal models. Adv. Exp. Med. Biol. 678, 138–146 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Meagher, M. W. in Cancer Symptom Science: Measurement, Mechanisms, and Management (eds Cleeland, C. S., Fisch, M. J. & Dunn, A. J.) 124–141 (Cambridge University Press, Cambridge UK, 2011).

    Google Scholar 

  50. Clement, C. G. et al. Stimulation of lung innate immunity protects against lethal pneumococcal pneumonia in mice. Am. J. Respir. Crit. Care Med. 177, 1322–1330 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Force, T. & Kolaja, K. L. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat. Rev. Drug Discov. 10, 111–126 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, H., Yoon, S. Y., Zhang, H. & Dougherty, P. M. Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy. J. Pain 13, 293–303 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mandenius, C. F. et al. Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review. J. Appl. Toxicol. 31, 191–205 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Turteltaub, K. W. et al. Identification and elucidation of the biology of adverse events: the challenges of safety assessment and translational medicine. Clin. Cancer Res. 17, 6641–6645 (2011).

    Article  PubMed  Google Scholar 

  55. Abernethy, D. R., Woodcock, J. & Lesko, L. J. Pharmacological mechanism-based drug safety assessment and prediction. Clin. Pharmacol. Ther. 89, 793–797 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Reagan–Udall Foundation for the FDA. Projects [online], (2012).

  57. Basch, E. et al. Adverse symptom event reporting by patients vs clinicians: relationships with clinical outcomes. J. Natl. Cancer Inst. 101, 1624–1632 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Basch, E. M. et al. Electronic toxicity monitoring and patient-reported outcomes. Cancer J. 17, 231–234 (2011).

    Article  PubMed  Google Scholar 

  59. US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research & Center for Devices and Radiological Health. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims [online], (2009).

  60. Dempke, W. C., Suto, T. & Reck, M. Targeted therapies for non-small cell lung cancer. Lung Cancer 67, 257–274 (2010).

    Article  PubMed  Google Scholar 

  61. Yap, T. A. & Workman, P. Exploiting the cancer genome: strategies for the discovery and clinical development of targeted molecular therapeutics. Annu. Rev. Pharmacol. Toxicol. 52, 549–573 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Yeung, D. T. & Hughes, T. P. Therapeutic targeting of BCR-ABL: prognostic markers of response and resistance mechanism in chronic myeloid leukaemia. Crit. Rev. Oncog. 17, 17–30 (2012).

    Article  PubMed  Google Scholar 

  63. Brooks, P. et al. OMERACT 10—International consensus conference on outcome measures in rheumatology clinical trials. J. Rheumatol. 38, 1450–1451 (2011).

    Article  PubMed  Google Scholar 

  64. Wortel, C. H. et al. Interleukin-6 mediates host defense responses induced by abdominal surgery. Surgery 114, 564–570 (1993).

    CAS  PubMed  Google Scholar 

  65. Kerawala, C. J. Complications of head and neck cancer surgery - prevention and management. Oral Oncol. 46, 433–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Williams, J. P., Johnston, C. J. & Finkelstein, J. N. Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr. Drug Targets 11, 1386–1394 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Abratt, R. P. & Morgan, G. W. Lung toxicity following chest irradiation in patients with lung cancer. Lung Cancer 35, 103–109 (2002).

    Article  PubMed  Google Scholar 

  68. Armstrong, T. & Gilbert, M. R. Central nervous system toxicity from cancer treatment. Curr. Oncol. Rep. 6, 11–19 (2004).

    Article  PubMed  Google Scholar 

  69. Kim, J. H., Brown, S. L., Jenrow, K. A. & Ryu, S. Mechanisms of radiation-induced brain toxicity and implications for future clinical trials. J. Neurooncol. 87, 279–286 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Perry, A. & Schmidt, R. E. Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol. 111, 197–212 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Sonis, S. T. Regimen-related gastrointestinal toxicities in cancer patients. Curr. Opin. Support. Palliat. Care 4, 26–30 (2010).

    Article  PubMed  Google Scholar 

  72. Sul, J. K. & DeAngelis, L. M. Neurologic complications of cancer chemotherapy. Semin. Oncol. 33, 324–332 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Cleeland, C. S., Farrar, J. T. & Hausheer, F. H. Assessment of cancer-related neuropathy and neuropathic pain. Oncologist. 15 (Suppl. 2), 13–18 (2010).

    Article  PubMed  Google Scholar 

  74. Hagiwara, H. & Sunada, Y. Mechanism of taxane neurotoxicity. Breast Cancer 11, 82–85 (2004).

    Article  PubMed  Google Scholar 

  75. Mohty, B. et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica 95, 311–319 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Albini, A. et al. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J. Natl Cancer Inst. 102, 14–25 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Curigliano, G., Mayer, E. L., Burstein, H. J., Winer, E. P. & Goldhirsch, A. Cardiac toxicity from systemic cancer therapy: a comprehensive review. Prog. Cardiovasc. Dis. 53, 94–104 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Daher, I. N. & Yeh, E. T. Vascular complications of selected cancer therapies. Nat. Clin. Pract. Cardiovasc. Med. 5, 797–805 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Ahn, S. & Lee, Y. S. Predictive factors for poor prognosis febrile neutropenia. Curr. Opin. Oncol. http://dx.doi./org/10.1097/CCO.0b013e328352ead2 (2012).

  80. Greenspan, S. L. et al. Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J. Clin. Endocrinol. Metab. 90, 6410–6417 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Krychman, M. L. & Katz, A. Breast cancer and sexuality: multi-modal treatment options. J. Sex. Med. 9, 5–25 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Di Lorenzo, G. et al. Toxicities of targeted therapy and their management in kidney cancer. Eur. Urol. 59, 526–540 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Force, T. & Kerkelä, R. Cardiotoxicity of the new cancer therapeutics—mechanisms of, and approaches to, the problem. Drug Discov. Today 13, 778–784 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tesfa, D. & Palmblad, J. Late-onset neutropenia following rituximab therapy: incidence, clinical features and possible mechanisms. Expert Rev. Hematol. 4, 619–625 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Tim Ahles (American Association for Cancer Research Survivorship Task Force, New York, NY, USA), Ann O'Mara (National Cancer Institute [NCI], Bethesda, MD, USA), Jamie H. Von Roenn (ASCO, Chicago, IL, USA), Elaine B. Yu (Genentech, San Francisco, CA, USA) and Nora Janjan (National Center for Policy Analysis, Dallas, TX, USA) for their insightful comments during the drafting of this article. We also acknowledge Jeanie F. Woodruff for editorial assistance, and M. Catherine Rodgers for administrative assistance (both at The University of Texas MD Anderson Cancer Center, Houston, TX, USA). The authors wish to acknowledge the overall contribution of those who participated in and contributed to the March 2011 colloquium entitled Developing Strategies for Reducing Cancer Treatment-Related Toxicities and Symptoms in Houston, TX, USA: Lyndah K. Dreiling (Amgen, Thousand Oaks, CA, USA), Marilee Duffield (Alere Health, Marietta, GA, USA), Robert F. Gagel (The University of Texas MD Anderson Cancer Center, Houston, TX, USA), Mark Gorman (National Coalition for Cancer Survivorship, Silver Spring, MD, USA), Amy Guo (Novartis, East Hanover, NJ, USA), Carol A. Hahn (American Society for Therapeutic Radiation Oncology, Durham, NC, USA), Joan S. McClure (National Comprehensive Cancer Network, Fort Washington, PA, USA), Andrew Miller (Lance Armstrong Foundation, Austin, TX, USA), Scarlott K. Mueller (Oncology Nursing Society Foundation, Pittsburgh, PA, USA), Robert Z. Orlowski (The University of Texas MD Anderson Cancer Center, Houston, TX, USA), Lorna Patrick (NCI, Rockville, MD, USA), Ellen B. Smith (Texas Oncology, Austin, TX, USA), Mark Stephens (National Patient Advocate Foundation, Washington, DC, USA), Steve G. Waguespack (The University of Texas MD Anderson Cancer Center, Houston, TX, USA), Robert A. Warriner III (patient advocate and Diversified Clinical Services, Spring, TX, USA) and Armin D. Weinberg (Baylor College of Medicine, Houston, TX, USA). Funding support for the meeting was provided by the C. Stratton Hill Colloquium on Pain and Its Relief. The opinions expressed in this article are those of the panellists and do not constitute a policy position of the NIH, National Cancer Institute, US Department of Health and Human Services or the US government.

Author information

Authors and Affiliations

Authors

Contributions

All authors participated in the colloquium, contributed to the discussion of the article content and took part in the initial drafting of the article, after which C. S. Cleeland and S. A. Roberts wrote the full manuscript. All authors edited the manuscript before submission.

Corresponding author

Correspondence to Charles S. Cleeland.

Ethics declarations

Competing interests

C. S. Cleeland has acted as a consultant or advisor for Abbott, Amgen, Bristol–Myers Squibb, Exelixis, Genentech and Pfizer and has received research funding from AstraZeneca. S. A. Giralt has acted as a consultant or advisor for Celgene, Novartis and Millennium and has received funding from Celgene. A. Y. Khakoo is employed by and owns stock in Amgen. J. Skillings is employed by Pfizer. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cleeland, C., Allen, J., Roberts, S. et al. Reducing the toxicity of cancer therapy: recognizing needs, taking action. Nat Rev Clin Oncol 9, 471–478 (2012). https://doi.org/10.1038/nrclinonc.2012.99

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2012.99

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer