Interaction of Chemotherapy, Radiotherapy, and Timing



New methods that have been developed to regulate and modify the biological response of tumors and of normal tissues to radiation to achieve maximum benefit with minimum harm to the adjacent normal tissues should be considered be among the most significant developments in radiotherapy (RT) in recent years. These methods include different fractionation schemes, the application of chemical and biological agents, and effective therapies targeted toward molecular pathway-signal transduction mechanisms. Among these treatment strategies, the most widely used method in clinical practice is the combination of chemotherapy (CT) with RT. Since the development of CT and RT, many studies have been published regarding adjuvant treatment of breast cancer, which remains a controversial issue. However, despite advances and innovations in breast cancer treatment, there is still no consensus on the optimal treatment approach, mainly because breast cancer is a heterogeneous group of diseases with a wide spectrum of biological behaviors. In this section, the molecular biological mechanisms of the interaction between RT and CT in breast cancer, as well as the optimal timing of RT and CT, will be discussed in light of relevant randomized trials.


Breast Cancer Accelerate Partial Breast Irradiation Local Advanced Breast Cancer Partial Breast Irradiation Optimal Treatment Approach 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Steel GG, Peckham MJ. Exploitable mechanisms in combined radiotherapy chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys. 1979;5:85–91.PubMedCrossRefGoogle Scholar
  2. 2.
    Choy H, MacRae R, Story M. Basic concepts of chemotherapy and irradiation interaction. In: Halperin EC, Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 5th ed. Philadelphia, USA: Lippincott Williams & Wilkins; 2008. p. 669–88.Google Scholar
  3. 3.
    Gregoire V, Baumann M. Combined radiotehapy and chemotherapy. In: Joiner M, van der Kogel A, editors. Basic clinical radiobiology. 4th ed. London: Edward Arnold; 2009. p. 246–58.Google Scholar
  4. 4.
    MacRae RM, Choy H. Taxanes in combined modality therapy. In: Choy H, editor. Chemoradiation in cancer therapy. 1st ed. New Jersey: Humana Press Totowa; 2003. p. 65–92.Google Scholar
  5. 5.
    Milas L, Fujii T, Hunter N, et al. Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Res. 1999;59:107–14.PubMedGoogle Scholar
  6. 6.
    Kumar P. Tumor hypoxia and anemia: impact on the efficacy of radiation therapy. Semin Hematol. 2000;37:4–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Milas L, Hunter N, Mason KA, Milross C, Peters LJ. Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse. Acta Oncol. 1995;34:409–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Bellon JR. A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma. Cancer. 2004;7:1358–64.CrossRefGoogle Scholar
  9. 9.
    Arcangeli G, Pinnaro P, Rambone R, et al. A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer. Int J Radiat Oncol Biol Phys. 2006;64:161–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Toledano A, Azria D, Garaud P, et al. Phase III Trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for Early Stage Breast Cancer: final results of the ARCOSEIN Trial. J Clin Oncol. 2007;25:405–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Toledano A, Garaud P, Serin D, et al. Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conservative surgery enhances late toxicities. Cancer Radiother. 2006;10:158–67.PubMedCrossRefGoogle Scholar
  12. 12.
    Wallgren A, Bernier J, Gelber RD, et al. Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys. 1996;35:649–59.PubMedCrossRefGoogle Scholar
  13. 13.
    Bull JM, Torney DC, Li SH, et al. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978;41:1649–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Clark RM, Wilkinson RH, Miceli PN, MacDonald WD. Breast cancer: experiences with conservation therapy. Am J Clin Oncol. 1987;10:461–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials. N Engl J Med. 1995;333:1444–55.CrossRefGoogle Scholar
  16. 16.
    Shapiro CL, Hardenbergh PH, Gelma R, et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol. 1998;16:3493–501.PubMedGoogle Scholar
  17. 17.
    Fiets WE, van Helvoirt RP, Nortier JW, et al. Acute toxicity of concurrent adjuvant radiotherapy and chemotherapy (CMF or AC) in breast cancer patients. A prospective, comparative, non-randomised study. Eur J Cancer. 2003;39:1081–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med. 1996;33:1356–61.CrossRefGoogle Scholar
  19. 19.
    Bellon JR, Come SE, Gelman RS, et al. Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol. 2005;23:1934–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Cakır S, Gursel B, Meydan D, Yıldız L. The sequencing of radiation therapy and chemotherapy after mastectomy in premenopausal women with breast cancer. Jpn J Clin Oncol. 2003;33:563–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tummors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990;8:1483–96.PubMedGoogle Scholar
  22. 22.
    Hickey BE, Francis D, Lehman MH. Sequencing of chemotherapy and radiation therapy for early breast cancer. Cochrane Database Syst Rev. 2006;4:CD005212.Google Scholar
  23. 23.
    Wahl AF, Donaldson KL, Fairchild C, et al. Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nat Med. 1996;2:72–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Vikhanskaya F, Vignati S, Beccaglia P, et al. Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclitaxel by inducing G2/M arrest and apoptosis. Exp Cell Res. 1998;241:96–101.PubMedCrossRefGoogle Scholar
  25. 25.
    Zaffaroni N, Silvestrini R, Orlandi L, et al. Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and -resistant human ovarian cells. Br J Cancer. 1998;77:1378–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21:976–83.PubMedCrossRefGoogle Scholar
  27. 27.
    De Laurentiis M, Cancello G, D’Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol. 2008;26:44–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Skinner KA, Silberman H, Florentine B, et al. Preoperative paclitaxel and radiotherapy for locally advanced breast cancer: surgical aspects. Ann Surg Oncol. 2000;7:145–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Bellon JR, Lindsley KL, Ellis GK, et al. Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer. Int J Radiat Oncol Biol Phys. 2000;48:393–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Ellerbroek N, Martino S, Mautner B, et al. Breast-conserving therapy with adjuvant paclitaxel and radiation therapy: feasibility of concurrent treatment. Breast J. 2003;9:74–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Hanna YM, Baglan KL, Stromberg JS, et al. Acute and subacute toxicity associated with concurrent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy. Breast J. 2002;8:149–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Formenti SC, Volm M, Skinner KA, et al. Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and post-operative doxorubicin based chemotherapy in locally advanced breast cancer: a phase I/II tiral. J Clin Oncol. 2003;21:864–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Taghian AG, Assaad S, Niemierko A, et al. Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel. J Natl Cancer Inst. 2001;93:1806–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005;23:3686–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Francis P, Crown J, Di Leo A, et al. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02–98 randomized trial. J Natl Cancer Inst. 2008;100:121–33.PubMedCrossRefGoogle Scholar
  36. 36.
    Bellon JR, Harris JR. Chemotherapy and radiation therapy for breast cancer: what is the optimal sequence? J Clin Oncol. 2005;23:5–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Sartor CI, Peterson BL, Woolf S, et al. Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node positive breast cancer: Cancer and Leukemia Group B 9344. J Clin Oncol. 2005;23:30–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer. Ann Oncol. 2005;16:1569–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22:1736–47.PubMedCrossRefGoogle Scholar
  40. 40.
    National Comprehensive Cancer Network (NCCN) Guidelines Version 3.2012. Breast Cancer.
  41. 41.
    Fisher ER, Wang J, Bryant J, et al. Pathobiology of preoperative chemotherapy: findings from National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer. 2002;95:681–95.PubMedCrossRefGoogle Scholar
  42. 42.
    van der Hage JA, Cornelis JH, van de Velde CJ, et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001;19:4224–37.PubMedGoogle Scholar
  43. 43.
    Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778–85.PubMedCrossRefGoogle Scholar
  44. 44.
    Huang EH, Tucker SL, Strom EA, et al. Radiation treatment improves local-regional control and cause-specific survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol. 2004;22:4691–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14:2738–46.PubMedGoogle Scholar
  46. 46.
    Recht A. Breast cancer. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. 2nd ed. New York: Elsevier Churchill Livingstone; 2007. p. 1475–502.Google Scholar
  47. 47.
    Morrow M. Breast conservation and negative margins: how much is enough? Breast. 2009;18:S84–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Recht A, Come SE, Gelman RS, et al. Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage node positive breast cancer: sequencing, timing, and outcome. J Clin Oncol. 1991;9:1662–7.PubMedGoogle Scholar
  49. 49.
    Haffty MD, Vicini FA, Beitsch P, et al. Timing of chemotherapy after mammosite radiation therapy system breast brachytherapy: analysis of the American Society of breast surgeons mammosite breast brachytherapy registry trial. Int J Radiat Oncol Biol Phys. 2008;72:1441–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Vaidya JS, Baum M, Tobias JS, et al. Long-term results of targeted introoperative radiotherapy (TARGIT) boost during breast-conserving surgery. Int J Radiat Oncol Biol Phys. 2011;81:1091–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Ann Surg. 1894;20:497–555.PubMedCrossRefGoogle Scholar
  52. 52.
    Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis. JAMA. 2011;305:569–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Radiation Oncology DepartmentOndokuz Mayis University, School of MedicineSamsunTurkey
  2. 2.Radiation Oncology DepartmentEge University, School of MedicineBornovaTurkey

Personalised recommendations