Review Article
Neoadjuvant Therapy: An Emerging Concept in Oncology
Abstract
Neoadjuvant therapy, an adjunctive therapy given before the main therapy, has become an integral part of modern multidisciplinary cancer management. Organized by the primary organ involved by cancer, this review summarizes the outcomes of neoadjuvant therapy for common malignant solid tumors, based on large, randomized, controlled trials. In locally advanced rectal, laryngeal, and breast cancer, neoadjuvant therapy enables organ preservation; however, it does not improve overall survival when compared with definitive treatment followed by adjuvant therapy. In locally advanced bladder and cervical cancer, patients who undergo neoadjuvant therapy before radical surgery appear to have better survival than those receiving definitive therapy alone; however, it is unclear if the neoadjuvant approach will be superior to definitive therapy followed by adjuvant therapy. To date, the survival benefits of neoadjuvant therapy for resectable non-small cell lung, esophageal, gastric, and prostate cancer remains under investigation.
Key Points
* In locally advanced resectable rectal, laryngeal, and breast cancer, neoadjuvant therapy enables organ preservation, but it does not improve overall survival.
* In locally advanced bladder and cervical cancer, patients who undergo neoadjuvant therapy before radical surgery appear to have better survival than those receiving definitive therapy alone.
* The survival benefits of neoadjuvant therapy for resectable non-small cell lung, esophageal, gastric, and prostate cancer remains under investigation.
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References
1. Hyams DM, Mamounas EP, Petrelli N, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 1997;40:131–139.
2. Miranda CR, de Resende CN, Melo CF, et al. Depression before and after uterine cervix and breast cancer neoadjuvant chemotherapy. Int J Gynecol Cancer 2002;12:773–776.
3. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–715.
4. Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between pre-operative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90–01 randomized trial. J Clin Oncol 1999;17:2396–2402.
5. Improved survival with preoperative radiotherapy in respectable rectal cancer: Swedish Rectal Cancer Trial. N Engl J Med 1997;336:980–987.
6. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638–646.
7. Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA. 2000;284:1008–1015.
8. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med1991;324:1685–1690.
9. Lefebvre JL, Chavalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. J Natl Cancer Inst 1996;88:890–899.
10. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med2001;7:345:1890–1900.
11. Jaulerry C, Rodriguez J, Brunin F, et al. Induction chemotherapy in advanced head and neck tumors: results of two randomized trials. Int J Radiat Oncol Biol Phys 1992;23:483–489.
12. Depondt J, Gehanno P, Martin M, et al. Neoadjuvant chemotherapy with carboplatin/5-fluorouracil in head and neck cancer. Oncology 1993;50(Suppl 2):23–27.
13. Paccagnella A, Orlando A, Marchiori C, et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265–272.
14. Richard JM, Kramar A, Molinari R, et al. Randomized EORTC head and neck cooperative group trial of preoperative intra-arterial chemotherapy in oral cavity and oropharynx carcinoma. Eur J Cancer1991;27:821–827.
15. Domenge C, Hill C, Lefebvre JL, et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. Br J Cancer 2000;83:1594–1598.
16. Mohr C, Bohndorf W, Carstens J, et al. Preoperative radiochemotherapy and radical surgery in comparison with radical surgery alone: a prospective, multicentric, randomized DOSAK study of advanced squamous cell carcinoma of the oral cavity and the oropharynx (a 3-year follow-up). Int J Oral Maxillofac Surg 1994;23:140–148.
17. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456–1461.
18. Powles TJ, Hickish TF, Makris A, et al. Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer. J Clin Oncol 1995;13:547–552.
19. Makris A, Powles TJ, Ashley SE, et al. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol1998;9:1179–1184.
20. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483–2493.
21. Dixon JM, Renshaw L, Bellamy C, et al. The effect of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study.Clin Cancer Res 2000;6:2229–2235.
22. Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001;12:1527–1532.
23. Smith IC, Heys SD, Hutcheon AW, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 2002;20:1456–1466.
24. Buzdar AU, Singletary SE, Theriault RL, et al. Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 1999;17:3412–3417.
25. Von Minckwitz G, Costa SD, Raab G, et al. Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study. J Clin Oncol2001;19:3506–3515.
26. Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al. Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol 2003;21:843–850.
27. Mauriac L, MacGrogan G, Avril A, et al. Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicenter randomized trial with a 124-month median follow up. Ann Oncol1999;10:47–52.
28. Skinner DG, Lieskovsky G. Contemporary cystectomy with pelvic node dissection compared to preoperative radiation therapy plus cystectomy in management of invasive bladder cancer. J Urol1984;131:1069–1072.
29. Millikan R, Dinney C, Swanson D, et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol 2001;19:4005–4013.
30. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–866.
31. Kaufman DS, Shipley WU, Griffin PP, et al. Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med 1993;329:1377–1382.
32. Wallace DM, Raghavan D, Kelly KA, et al. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 1991;67:608–615.
33. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy. J Clin Oncol 1998;16:3576–3583.
34. Sengelov L, von der Maase H, Lundbeck F, et al. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol 2002;41:447–456.
35. Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med1990;323:940–945.
36. Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung Cancer 1994;10(Suppl 1):S239–S244.
37. Cullen MH, Billingham LJ, Woodroffe CM, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999;17:3188–3194.
38. Sause W, Kolesar P, Taylor S IV, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000;117:358–364.
39. Mattson K, Holsti LR, Holsti P, et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988;24:477–482.
40. Morton RF, Jett JR, McGinnis WL, et al. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. Ann Intern Med 1991;115:681–686.
41. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692–2699.
42. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 2001;121:472–483.
43. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med1994;330:153–158.
44. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in respectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst1994;86:673–680.
45. Pass HI, Pogrebniak HW, Steinberg SM, et al. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992;53:992–998.
46. Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in respectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002;20:247–253.
47. Mattson KV, Abratt RP, Ten Velde G, Krofta K. Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomized phase III study. Ann Oncol2003;14:116–122.
48. Albain KS, Scott CB, Rusch VR, et al. Phase III comparison of concurrent chemotherapy plus radiotherapy (CT/RT) and CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): initial results from intergroup trial 0139 (RTOG 93–09) (abstr 2497). Proc Am Soc Clin Oncol 2003;22:621.
49. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351–360.
50. Benedetti-Panici P, Greggi S, Colombo A, et al. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 2002;20:179–188.
51. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med1999;340:1154–1161.
52. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462–467.
53. Bosset JF, Gignoux M, Triboulet, at al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161–167.
54. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305–313.
55. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. Arch Surg 1992;127:1446–1450.
56. Law S, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg1997;114:210–217.
57. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long-term survival of patients with respectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001;91:2165–2174.
58. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in esophageal cancer: a randomized controlled trial. Lancet 2002;359:1727–1733.
59. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979–1984.
60. Urschel JD, Vasan H, Blewett CJ. A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg2002;183:274–279.
61. Songan I, Keizer HJ, Hermans J, et al. Chemotherapy for operable gastric cancer: results of the Dutch randomized FAMTX trial: the Dutch Gastric Cancer Group (DGCG). Eur J Cancer 1999;35:558–562.
62. Wang XL, Wu GX, Zhang MD, et al. A favorable impact of preoperative FPLC chemotherapy on patients with gastric cardia cancer. Oncol Rep 2000;7:241–244.
63. Yonemura Y, Sawa T, Kinoshita K, et al. Neoadjuvant chemotherapy for high-grade advanced gastric cancer. World J Surg 1993;17:256–261.
64. Zhang ZX, Gu XZ, Yin WB, et al. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)-report on 370 patients. Int J Radiat Oncol Biol Phys 1998;44:929–934.
65. MacDonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med2001;345:725–730.
66. Labrie F, Dupont A, Cusan L, et al. Downstaging of localized prostate cancer by neoadjuvant therapy with flutamide and lupron: the first controlled randomized trial. Clin Invest Med 1993;16:499–509.
67. Soloway MS, Sharifi R, Wajsman Z, et al. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. J Urol 1995;154:424–428.
68. Goldenberg SL, Klotz LH, Srigley J, et al. Randomized, prospective, controlled study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer: Canadian Urologic Oncology Group. J Urol 1996;156:873–877.
69. Dalkin BL, Ahmann FR, Nagle R, Johnson CS. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer.J Urol 1996;155:1357–1360.
70. Van Poppel H, De Ridder D, Elgamal AA, et al. Neoadjuvant hormonal therapy before radical prostatectomy decreases the number of positive surgical margins in stage T2 prostate cancer: interim results of a prospective randomized trial. J Urol 1995;154:429–434.
71. Fair WR, Cookson MS, Stroumbakis N, et al. The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostate cancer: Memorial Sloan-Kettering Cancer Center results. Urology 1997;49(3A Suppl):46–55.
72. Gleave ME, Goldenberg SL, Chin JL, et al. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol2001;166:500–506.
73. Laverdiere J, Gomez JL, Cusan L, et al. Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys. 1997;37:247–252.
74. Shipley WU, Lu JD, Pilepich MV, et al. Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: a secondary analysis of the randomized protocol RTOG 86–10. Int J Radiat Oncol Biol Phys. 2002;54:1302–1310.
