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There is growing belief that neoadjuvant therapy plays an important role in the cancer armamentarium. Neoadjuvant therapy involves the use of chemotherapy, radiation treatment (RT), and/or molecular targeted therapy before surgery with curative intent. The goal of neoadjuvant therapy is to improve locoregional control, thereby facilitating margin-negative resections, which may, in turn, result in less radical resections, tissue preservation, and improved survival.

Neoadjuvant therapy may have the advantage of increased antineoplastic effect, since the tumor and surrounding tissues have not been disturbed by surgery. Tolerance of therapy may be improved, since recovery from surgery and delays from operative complications are avoided. Neoadjuvant therapy may also allow early treatment of micrometastases. Furthermore, prognostic information may be gained based on clinical and pathologic response. However, neoadjuvant therapy can have certain disadvantages, including cost as well as delay of tumor control if neoadjuvant therapy is ineffective or causes toxicity. In addition, response to neoadjuvant treatment may also make tumor pathologic staging more difficult to interpret.

Historically, neoadjuvant therapy showed early promise in the treatment of squamous cell carcinoma of the anus. Early on, abdominoperineal resection (APR) was performed after preoperative chemoradiation therapy allowed locoregional tumor control. Several randomized trials established the role of 5-fluorouracil (5-FU), mitomycin C, and radiation therapy in the treatment of this disease. Currently, however, surgery is reserved only for salvage treatment of patients with persistent local disease 6 months after chemoradiotherapy, with recurrent local or inguinal disease, or with perineal septic symptoms.

Neoadjuvant therapy is routinely used in most centers for rectal cancer. The use of neoadjuvant therapy has been the standard of care for almost a decade for patients with T3/T4, locally advanced, or unresectable rectal cancer. Many randomized and nonrandomized trials have shown an increase in resectability rates and pathological responses in patients who received combined preoperative chemoradiation. Sphincter preservation rates appear to be increased as well. Almost all trials have shown a decrease in local recurrence, but there is no consistent evidence that neoadjuvant chemoradiation improves survival. Thus, patients with locally advanced or unresectable rectal cancer should receive neoadjuvant radiation therapy with 5-FU/leucovorin as standard therapy.

Neoadjuvant therapy has also contributed to clinical downstaging in locally advanced breast cancer and in some soft tissue sarcomas. For more than a decade, neoadjuvant chemotherapy has been the standard of care for patients with locally advanced breast cancer (LABC) (T3, T4, N2-regional disease) and it is a potential treatment for patients with T1 and T2 disease. Many large randomized and nonrandomized clinical trials have correlated tumor downstaging with response to chemotherapy. Common findings from the trials were that pathological complete response (pCR) increased with sequential neoadjuvant treatment, and pCR led to improved disease-free survival. Also, the addition of taxane to doxorubicin-based regimens has shown similar or better pCR with increased breast conservation. Therefore, at the present time, the neoadjuvant chemotherapy regimen consisting of an anthracycline, cyclophosphamide, and taxane should be the treatment of choice for patients with LABC.

In soft tissue sarcomas of the extremities, preoperative radiation conferred a survival advantage, but has been complicated by worsened wound healing. On the other hand, patients treated with preoperative chemotherapy (with radiation postoperatively) did not have worsened wound complications, but also did not have a survival advantage. As plastic and tissue transfer surgical techniques evolve, there will be fewer restrictions on the use of preoperative radiation therapy for patients with extremity soft tissue sarcoma.

Tumors in which the benefit of neoadjuvant therapy has been suggested, but has not been clearly validated in randomized trials, include esophageal, gastric, and pancreatic carcinoma, non-small cell lung cancer, and other soft tissue sarcomas.

Neoadjuvant treatment with systemic and local agents has been evaluated extensively for respectable esophageal cancer due to the high risk of locoregional spread and recurrence following surgery alone. Although cisplatin-based chemotherapy, with or without radiation, fails to confer a significant improvement in overall survival, patients who respond favorably to these treatments have a significant survival advantage. On the other hand, non-responders fare much worse than patients who undergo surgery alone, and they face the costs and toxicities of the preoperative treatment without any benefit, as well as delay before surgical resection. Unfortunately, it is difficult to predict which patients will respond to preoperative treatment. Due to this inability to determine, before treatment, which patients will have a complete pathologic response, and the survival advantage that accompanies it, there is some bias within the medical community that, although statistically unproven, neoadjuvant chemoradiation, followed by surgical therapy, should be the standard of care. Further investigations to determine the optimal preoperative regimen, as well as improving means to predict patient response, are needed.

There is also currently insufficient evidence to recommend neoadjuvant chemotherapy for gastric adenocarcinoma, outside the context of a clinical trial. It is not appropriate for patients with early gastric cancer (T1NX). However, neoadjuvant therapy does show promise over surgery followed by adjuvant therapy in patients with locally advanced gastric adenocarcinoma, but this needs to be validated in prospective trials.

Neoadjuvant therapy does offer a survival benefit in patients with pancreatic adenocarcinoma who undergo a complete resection that is comparable to patients receiving surgery and adjuvant therapy treatment. However, neither therapeutic option has been shown to be superior to the other. At the present time, due to the absence of effective regimens in pancreatic cancer, neoadjuvant therapy cannot be recommended as standard treatment and controversy regarding the appropriate components of neoadjuvant and adjuvant therapy continues to plague our treatment decisions.

A few studies have shown a modest improvement in overall survival with neoadjuvant therapy in small studies of stage I-II non-small cell lung cancer (NSCLC); however, the evidence is not definitive that a neoadjuvant cisplatin-based regimen should be the standard of care for patients with early stage NSCLC. Surgery still remains the accepted form of definitive therapy. For patients who suffer from stage III disease, surgery alone is no longer the standard of care. A preoperative cisplatin-based regimen, with or without radiation before surgery, should be utilized. For patients with stage III disease, the present published evidence does not provide conclusive evidence which is better: neoadjuvant chemotherapy or chemoradiation. The published trials to date, however, do show increased resectability rates and overall survival rates in patients who received preoperative regimens when compared to patients who received surgery only.

For retroperitoneal soft tissue sarcoma, although surgery remains the standard of care, evidence is mounting that neoadjuvant chemotherapy with doxorubicin and ifosfamide, with concurrent radiation, has acceptable toxicity profiles, and decreased local failure rates. A randomized study comparing neoadjuvant radiation therapy to surgery alone in retroperitoneal sarcomas is under way through the American College of Surgeons Oncology Group (ACOSOG). For gastrointestinal stromal tumors (GIST), treatment with the molecular targeted therapy, imatinib, has shown promise in locally advanced or unresectable tumors.

Further evaluation of neoadjuvant treatment for solid tumors must be continued in the context of multicenter, randomized controlled trials, which can be conducted in larger numbers of patients. In addition, new chemotherapeutic agents, as well as combined modalities, should be evaluated. Identification of molecular targets may allow development of tumor-specific neoadjuvant treatment for solid tumors in the future.