Rationale and Evolution of Rectal Cancer Chemotherapy and Radiation Therapy

The concept of adjuvant therapy for rectal cancer dates back more than a 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 were better appreciated, radiation was considered an adjunct to be used in selected patients.

Proctectomy alone became standard treatment for rectal cancer until the 1980s. It later became clear that the outcomes of surgery alone were 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.[6] Proctectomy followed by selective postoperative chemoradiotherapy (CRT) became the common regimen in the United States after the National Institutes of Health, in 1990, advocated for adjuvant external beam radiotherapy and chemotherapy for patients with stage II and stage III rectal cancer, with resulting improved local disease control.[7]

As experience with 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 using higher radiation doses and more beams were shown 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 five equal doses in 5 consecutive days) improved both local recurrence and overall survival.[4] However, this study was later criticized because total mesorectal excision (TME) was not standardized, and the rate of local recurrence in the control arm was considered high for that time period.[8]