Neoadjuvant cancer therapy: Benefitting patients and improving cancer care

As cancer therapy has evolved, the oncology community has gained new insights into the characteristics of different cancers, developed more targeted cancer therapies, and is often able to diagnose cancers at earlier stages than in the past.

Surgery has been the first line of treatment for solid cancers for most patients for many years. Increasingly, however, systemic therapy is given before definitive surgical resection. Some tumors, unfortunately, are diagnosed at a more advanced stage. They may be operable but would require resecting a large amount of tissue and potentially adjacent structures. Others are inoperable because of involvement of adjacent anatomic structures.

Benefits of neoadjuvant therapy

The rationale for neoadjuvant therapy is to reduce the size or extent of the cancer before operating, making surgical procedures easier, reducing the amount of tissue that needs to be removed, and, therefore, reducing the morbidity associated with radical surgical resections. In addition to local effects, neoadjuvant therapy treats regional lymph nodes, converting positive nodes to negative nodes in a proportion of cases. The National Cancer Institute defines neoadjuvant therapy as “Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and endocrine therapy. It is a type of induction therapy.”1

Neoadjuvant therapy has successfully reduced the size and extent of many cancers, benefitting our patients and allowing surgeons to perform better and safer operations. Neoadjuvant therapy can turn a tumor from unresectable to resectable by shrinking the volume of the tumor. Often it can be unclear which surrounding structures are directly involved in the disease, and there may be difficulty in differentiating those anatomic structures from inflammation on imaging. After administering neoadjuvant therapy, this differentiation often can be more easily achieved. Neoadjuvant therapy is sometimes given in anticipation that a response will be seen so that a decision can be made with regard to the next course of action. In addition, neoadjuvant therapy acts on micrometastatic disease and can therefore down-stage tumors. Neoadjuvant therapy can lead to improved long-term survival for patients.2-5

The use of neoadjuvant therapy has gained wide acceptance over the last decade, but it is not a new idea. Several milestones in the use of neoadjuvant therapy have occurred. In 1956, neoadjuvant therapy was used to treat choriocarcinoma.6,7 In 1968, the concept of perioperative chemotherapy for breast cancer was introduced.8 Neoadjuvant therapy for rectal cancer was presented in 1986 and for pancreatic cancer in 1990.9,10

Tumor reduction with neoadjuvant systemic therapy can result in three patterns of response: concentric shrinkage of the tumor, concentric shrinkage of the tumor with surrounding small satellite lesions, or shrinkage of the tumor volume with residual multiple small satellite lesions.11

Current trials

Clinical trials of drugs in the neoadjuvant setting allow assessment of new agents and novel therapeutic strategies. Studies in the neoadjuvant setting use pathologic complete response (pCR), a surrogate marker for survival, as the primary endpoint. This approach makes it possible for studies to enroll a significantly smaller number of patients and to attain results in a much shorter time frame. The old trials of large numbers of patients treated in the adjuvant setting and followed for years for cancer events has been replaced by smaller studies in the neoadjuvant setting with quicker impact on drug development and clinical practice. Additionally, neoadjuvant studies allow assessment of the drug’s effects on the target tumor in the patient and development of biomarkers of response. Evaluation of residual disease after neoadjuvant chemotherapy can provide information on mechanisms of resistance to therapy.

In May 2012, the U.S. Food and Drug Administration (FDA) announced that pCR to neoadjuvant chemotherapy may be used as a surrogate endpoint as a component for accelerated approval of drugs.12 The FDA’s accelerated approval program allows patients to have access to these drugs while the confirmatory clinical trials are being conducted. In September 2013, the drug Pertuzumab was granted accelerated approval as part of the treatment regimen in the neoadjuvant setting for patients with early-stage breast cancer.13 Pertuzumab is the first FDA-approved drug for the neoadjuvant treatment of breast cancer based on pCR as the primary outcome. Improvement in survival is still required for regular approval.

One of the best ways to improve our knowledge of cancer therapy is through neoadjuvant clinical trials. Surgeons have the unique opportunity to discuss the concept of neoadjuvant therapy and the option of enrolling newly diagnosed cancer patients in a clinical trial. Responsiveness to a cancer therapy is understood more quickly through neoadjuvant therapy than through adjuvant therapy trials. Additionally, evaluation of the extent of surgery after neoadjuvant systemic therapy for optimal local control is the focus of several trials, and it is critical to inform clinical management of patients receiving neoadjuvant therapy.

The clinical trials through the Alliance of Clinical Trials in Oncology can be viewed on their website at http://www.allianceforclinicaltrialsinoncology.org. There are Alliance clinical trials available for patients who are appropriate candidates for neoadjuvant therapy. These trials include breast, gastrointestinal, genitourinary, and respiratory cancers. Information on how your institution can become a member of the Alliance also can be found on the website. Membership in any of the cooperative groups will enable surgeons to participate in these trials. Please consider offering these trials to your patients so we can learn today the best way to care for our patients tomorrow.

Alliance clinical trials involving neoadjuvant therapy

Breast cancer

  • Alliance A011202: A Randomized Phase III Trial Evaluating the Role of Axillary Lymph Node Dissection in Breast Cancer Patients (cT1‐3N1) Who Have Positive Sentinel Lymph Node Disease after Neoadjuvant Chemotherapy. Evaluates the best therapy for local control in women with residual nodal involvement after they have completed neoadjuvant chemotherapy. This study compares axillary lymph node dissection to axillary radiation for patients with positive sentinel node(s) after chemotherapy.
  • Cancer and Leukemia Group B (CALGB) 40903: Phase II Study Neoadjuvant Letrozole for Postmenopausal Women with Estrogen Receptor Positive Ductal Carcinoma in Situ (DCIS). This study is designed to evaluate how well letrozole works in DCIS by evaluating the change in tumor volume on magnetic resonance imaging after three to six months of neoadjuvant letrozole for estrogen receptor-positive DCIS.

Gastrointestinal cancers

  • American College of Surgeons Oncology Group (ACOSOG) Z5041: A Phase II Study of Preoperative Gemcitabine and Erlotinib Plus Pancreatectomy and Postoperative Gemcitabine and Erlotinib for Patients with Operable Pancreatic Adenocarcinoma. This study assesses the two-year survival rate in patients with pancreatic cancer treated with neoadjuvant and adjuvant gemcitabine and erlotinib.
  • North Center Cancer Treatment Group (NCCTG) N1048: A Phase II/III trial of Neoadjuvant FOLFOX with Selective Use of Combination Radiation with Locally Advanced Rectal Cancer. This study compares chemotherapy to chemotherapy and radiation therapy in the neoadjuvant setting for rectal cancer with primary endpoints of R0 resection, disease-free survival, and time to local recurrence.

Genitourinary cancers

  • CALGB 90203: This randomized phase III study examines neoadjuvant docetaxel and androgen deprivation prior to radical prostatectomy versus immediate radical prostatectomy in patients with high-risk, clinically localized prostate cancer. This study compares neoadjuvant therapy with surgery first in terms of biochemical progression-free survival in patients with high-risk, clinically localized prostate cancer.

Respiratory cancers

  • CALGB 31102: Phase I study of accelerated hypofractionated radiation therapy with concomitant chemotherapy for unresectable stage III non-small cell lung cancer. This study is designed to determine the side effects and response of specialized radiation together with chemotherapy in unresectable stage III non-small cell lung cancer.

References

  1. National Cancer Institute. NCI dictionary of cancer terms. Available at: http://www.cancer.gov/dictionary?CdrID=45800. Accessed April 25, 2014.
  2. Ke TW, Liao YM, Chiang HC, et al. Effectiveness of neoadjuvant concurrent chemoradiotherapy versus up-front proctectomy in clinical stage II-III rectal cancer: A populations-based study. Asia Pac J Clin Oncol. 2014 Jan 24. [Epub ahead of print].
  3. Makowiec F, Baier P, Kulemann B, et al. Improved long-term survival after esophagectomy for esophageal cancer: Influence of epidemiologic shift and neoadjuvant therapy. J Gastrointest Surg. 2013;17(7):1193-1201.
  4. McClaine RJ, Lowy AM, Sussman JJ, Schmulewitz N, Grisell DL, Ahmad SA. Neoadjuvant therapy may lead to successful surgical resection and improved survival in patients with borderline resectable pancreatic cancer. HPB(Oxford). 2010;12(1):73-79.
  5. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small cell lung cancer: A systematic review and meta-analysis of individual participant data. The Lancet. 2014;383(9928):1561-1571.
  6. Hertz R, Li MC, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med. 1956;93(2):361-366.
  7. Li MC, Hertz R, Bergenstal DM. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N Engl J Med. 1958;259(2):66-74.
  8. Fisher B, Ravdin RG, Ausman RK, Slack NH, Moore GE, Noer RJ. Surgical adjuvant chemotherapy in cancer of the breast: Results of a decade of cooperative investigation. Ann Surg. 1968;168(3):337-56.
  9. Smith DE, Muff NS, Shetabi H. Combined preoperative neoadjuvant radiotherapy and chemotherapy for anal and rectal cancer. Am J Surg. 1986;151(5):577-580.
  10. Weese JL, Nussbaum ML, Paul AR, Engstrom PF, Solin LJ, Kawalynshyn MJ, Hoffman JP. Increased resectability of locally advanced pancreatic and periampullary carcinoma with neoadjuvant chemoradiotherapy. Int J Pancreatol. 1990;7(1-3):177-185.
  11. Buchholz TA, Hunt KK, Whitman GJ, Sahin AA, Hortobagyi GN. Neoadjuvant chemotherapy for breast cancer. Multidisciplinary considerations of benefits and risks. Cancer. 2003;98(6):1150-1160.
  12. U.S. Department of Health and Human Services. U.S. Food and Drug Administration. Guidance for industry pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: Use as an endpoint to support accelerated approval. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf. Accessed April 25, 2014.
  13. U.S. Department of Health and Human Services. U.S. Food and Drug Administration (FDA). FDA approves Perjeta for neoadjuvant breast cancer treatment. Press release. September 30, 2013. Available at: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm370393.htm. Accessed April 25, 2014.

Tagged as: , , ,

Contact

Bulletin of the American College of Surgeons
633 N. Saint Clair St.
Chicago, IL 60611

Archives

Download the Bulletin App


Get it on Google Play