Rationale and Evolution of Neoadjuvant Therapy

The concept of adjuvant therapy for rectal cancer dates back nearly one century when gold filtered radon emanation seeds were implanted directly into rectal cancers.[1] Contact radiation with emanation seeds containing radium salts or radon was subsequently suggested as a curative treatment, and surgery was considered a salvage procedure for patients with tumors resistant to radiation.[2] As surgery became safer and the limitations of contact radiation as solitary treatment were appreciated, radiation was considered an adjuvant to be used in only selected patients. Proctectomy alone became standard treatment for rectal cancer until it was eventually realized that the outcomes of surgery alone were often suboptimal with 5-year local recurrence rates of 25-30%.[3],[4],[5] External beam radiotherapy with or without chemotherapy was added to the treatment of these patients following proctectomy to reduce the risk of local recurrence. The National Institutes of Health eventually advocated adjuvant external beam radiotherapy and chemotherapy for patients with stage II and stage III tumors in 1990 when it was demonstrated that adjuvant chemoradiotherapy improved oncologic outcomes.[6] Proctectomy followed by selective postoperative chemoradiotherapy became the regimen recommended for many patients with locally advanced rectal cancer in the United States.

As experience with this adjuvant radiotherapy increased, it was recognized that this treatment was associated with relatively high toxicity and was poorly tolerated by many patients. Accordingly, several centers explored utilizing short-course neoadjuvant radiotherapy or long-course neoadjuvant radiotherapy with or without sensitizing chemotherapy. In general, studies that used higher biologically equivalent radiation doses and a higher number of beams proved to reduce local recurrence in patients treated with preoperative radiation compared to surgery alone. The Swedish Rectal Cancer trial demonstrated that short-course preoperative radiation (25 Gy of radiation delivered in 5 equal doses in 5 consecutive days) improved both local recurrence and overall survival.[4] However, this study was later criticized because TME surgery was not standardized, and the rate of local recurrence in the control arm was considered high for those years’ standards.