Chemotherapy uses drugs to destroy cancer cells, stop their growth, or ameliorate symptoms. In neoadjuvant (also called preoperative or primary) chemotherapy, treatment is performed before surgical extraction of a tumor with the objective of reducing its size. Reduction of tumor mass decreases the extent and invasiveness of a surgery and leads to an improvement in the ability to discern between normal and cancerous tissue[IM1] . In tumors initially diagnosed as non-operable or of borderline respectability, shrinking of the cancerous lesion can enable surgery and allow for adequate clean margins[IM2] . Altogether, these factors not only facilitate the procedure but can also improve postoperative recovery and the long-term outcome for the patient.
The choice of a systemic treatment, such as chemotherapy, also depends on the perceived risk of distant metastasis. Particularly in locally advanced tumors with high metastatic potential, neoadjuvant chemotherapy offers the possibility to treat both primary lesions and micrometastases at distant sites[IM3] . Unfortunately, chemotherapy is associated with serious side effects which can aggravate the overall health status of patients. Increase in co-morbidities may prevent patients from being fit for surgery or increase the risk of postoperative complications.
Treatment in the neoadjuvant setting is typically indicated for inoperable breast, colorectal and lung cancers[IM4] 1-4 and is emerging as a treatment option in many other tumors. Preoperative treatment is also employed in breast-conserving surgery 1, tumors with borderline resectability[IM5] 2,5 and locally advanced cancers6. Recent review articles published in the Journal of Surgical Oncology and related clinical journals show that neoadjuvant chemotherapy is being evaluated in different settings of esophageal, gastric, pancreatic, prostate, soft-tissue sarcoma, ovarian[IM6] and cervical cancers7-13. In some disease settings, the primary neoadjuvant treatment is radiotherapy and chemotherapy can be administered concurrently or in sequence with radiation, in chemoradiation regimen[IM7] s.
The administration of neoadjuvant chemotherapy is performed in cycles, with each cycle consisting of a treatment period followed by a resting phase. Chemotherapy agent(s) can be given orally or intravenously during a variable number of cycles spanning a total treatment time between three to six months14-16. Response to chemotherapy and patient fitness are important criteria in determining patient eligibility for surgery17. In selected patients, surgery can be performed weeks to months after [IM8] the last cycle of preoperative chemotherapy[IM9] .
The long term benefits of neoadjuvant therapy when compared with surgery alone are source of debate in many cancer areas. In gastric, esophageal and cervical cancers only modest survival improvements have been observed with unclear risk-benefit ratios18-20. Significant survival benefits have been established in breast21 and lung22,23 cancers. Translation of clinical trial results to medical practice can be complex and is dependent on many factors. For example, in breast cancer, preoperative chemotherapy is currently recommended in locally advanced tumors21,24, however, the standard course of treatment for early stages of the disease is unclear25.
Chemotherapy: Before or after surgery?
The scheduling of chemotherapy relative to the surgical intervention is an area of active investigation in many cancers. Despite potential benefits, neoadjuvant chemotherapy also has some risks when compared to treatment in the postoperative setting. Delaying surgery and allowing metastatic development in non-responsive tumors are potential shortcomings26. In breast cancer, a combined analysis of several clinical trials has not found significant differences between the efficacy of chemotherapy given before or after surgery27. Recent results from large clinical trials support this idea while showing that, despite similar survival outcomes, breast-conservation rates are improved with neoadjuvant chemotherapy28.
In lung cancer, the scheduling of chemotherapy is surrounded with uncertainty and debate29. There is lack of conclusive evidence supporting either approach and has been argued that a general solution to the question might not be found30. As in other cancers (including breast and colorectal), the research is focusing on the development of personalized strategies that take into account many prognostic factors31. Deciding on the type and schedule of therapy will become increasingly more complex but also more individualized.
Michael C Perry, The Chemotherapy Source Book, Lippincott Williams & Wilkins; Fourth Edition edition (October 1, 2007).
B. Sevin, P. Knapstein, O. Kochli, R. Angioli, Multimodality Therapy in Gynecologic Oncology, Thieme Medical Publishers; 1st edition (January 15, 1996).
MD Anderson Cancer Center
University of Florida IFAS Extension
1. Liu SV, Melstrom L, Yao K, et al: Neoadjuvant therapy for breast cancer. J Surg Oncol 101:283-91, 2010
2. Julien LA, Thorson AG: Current neoadjuvant strategies in rectal cancer. J Surg Oncol 101:321-6, 2010
3. Fathi AT, Brahmer JR: Chemotherapy for advanced stage non-small cell lung cancer. Semin Thorac Cardiovasc Surg 20:210-6, 2008
4. Balmanoukian A, Ettinger DS: Managing the patient with borderline resectable lung cancer. Oncology (Williston Park) 24:234-41, 2010
5. Browner I, Purtell M: Chemotherapy in the older patient with operable non-small cell lung cancer: neoadjuvant and adjuvant regimens. Thorac Surg Clin 19:377-89, 2009
6. Socinski MA, Veeramachaneni NK, Haithcock BE: The many controversies of stage IIIA/IIIB lung cancer. Oncology (Williston Park) 24:256, 259, 2010
7. Hyngstrom JR, Posner MC: Neoadjuvant strategies for the treatment of locally advanced esophageal cancer. J Surg Oncol 101:299-304, 2010
8. Mezhir JJ, Tang LH, Coit DG: Neoadjuvant therapy of locally advanced gastric cancer. J Surg Oncol 101:305-14, 2010
9. Morganti AG, Massaccesi M, La Torre G, et al: A systematic review of resectability and survival after concurrent chemoradiation in primarily unresectable pancreatic cancer. Ann Surg Oncol 17:194-205, 2010
10. Schutz FA, Oh WK: Neoadjuvant and adjuvant therapies in prostate cancer. Urol Clin North Am 37:97-104, Table of Contents, 2010
11. Weinberg LE, Rodriguez G, Hurteau JA: The role of neoadjuvant chemotherapy in treating advanced epithelial ovarian cancer. J Surg Oncol 101:334-43, 2010
12. Reynoso D, Subbiah V, Trent JC, et al: Neoadjuvant treatment of soft-tissue sarcoma: a multimodality approach. J Surg Oncol 101:327-33, 2010
13. Mori T, Hosokawa K, Kinoshita Y, et al: Neoadjuvant chemotherapy with weekly carboplatin and paclitaxel for locally advanced cervical carcinoma. Int J Gynecol Cancer 18:85-9, 2008
14. National Cancer Institute: Adjuvant and Neoadjuvant Therapy for Breast Cancer, 2010
15. American Cancer Society: Chemotherapy, Detailed Guide: Breast Cancer, 2010
16. Cancer Research UK: Why plan chemotherapy, 2010
17. Buchholz TA, Hunt KK, Whitman GJ, et al: Neoadjuvant chemotherapy for breast carcinoma: multidisciplinary considerations of benefits and risks. Cancer 98:1150-60, 2003
18. Morabito A, Carillio G, Longo R: Systemic treatment of gastric cancer. Crit Rev Oncol Hematol 70:216-34, 2009
19. Raja SG, Salhiyyah K, Nagarajan K: Does neoadjuvant chemotherapy improve survival in patients with resectable thoracic oesophageal cancer? Interact Cardiovasc Thorac Surg 6:661-4, 2007
20. Rydzewska L, Tierney J, Vale CL, et al: Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev:CD007406, 2010
21. Minckwitz Gv: Principles of preoperative chemotherapy. Breast Cancer Online 7, 2004
22. Song WA, Zhou NK, Wang W, et al: Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 5:510-6, 2010
23. Burdett S, Stewart LA, Rydzewska L: A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 1:611-21, 2006
24. Kaufmann M, von Minckwitz G, Rody A: Preoperative (neoadjuvant) systemic treatment of breast cancer. Breast 14:576-81, 2005
25. Cuppone F, Bria E, Carlini P, et al: Taxanes as primary chemotherapy for early breast cancer: meta-analysis of randomized trials. Cancer 113:238-46, 2008
26. Sevin BU: Multimodality Therapy in Gynecologic Oncology (ed Rev edition), Thieme Medical Pub, 1996
27. Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97:188-94, 2005
28. 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 26:778-85, 2008
29. Strauss GM: Adjuvant vs Neoadjuvant Chemotherapy in Resectable NSCLC: Is That the Real Question? Oncology (Williston Park) 23, 2010
30. Besse B, Le Chevalier T: Adjuvant or induction cisplatin-based chemotherapy for operable lung cancer. Oncology (Williston Park) 23:520-7, 2009
31. Overdevest JB, Theodorescu D, Lee JK: Utilizing the molecular gateway: the path to personalized cancer management. Clin Chem 55:684-97, 2009
[IM1]This is because the inflammation that is associated with tumor growth is alleviated.
[IM2]Healthy tissue surrounding tumor. Failure to use adequate clean margins has been associated with recurrence.
[IM3]Specifically, the theoretical advantages of neoadjuvant chemotherapy are related to the potential establishment of metastatic sites at microscopic level (micro metastases).
Micro-metastases cannot be detected by current diagnostic tools. In general metasases cannot be treated surgically. Therefore they can only be treated by systemic therapies.
Since micro-metastases cannot be detected, this specific argument is based on a prophylactic concept. Some question the value of considering a prophylactic measure in the evaluation of the use of toxic therapies.
[IM4]Non-small cell lung cancer
[IM5]eg, curative surgery
[IM8]normally a month for breast cancer if blood analyses show regular results after chemotherapy
[IM9]in come cases chemotherapy can be given before and after surgery.