Irradiation of Very Locally Advanced and Recurrent Rectal Cancer

Adjuvant therapy with chemoradiation or short-course radiation in addition to improvements in surgical technique has led to improved outcomes for patients with locally advanced rectal cancer. Local recurrence rates of less than 10% and 5-year survival rate of 60% or higher is expected. However, for patients with very locally advanced primary or locally recurrent disease in whom surgical resection is likely to be associated with incomplete resection, survival and disease control rates are poor and standard doses of adjuvant radiation or chemoradiation are relatively ineffective. Dose-escalation approaches with intraoperative radiation (IORT) have been explored in both the primary and recurrent setting. Although high-level evidence is lacking, available data suggest improvements in local and distant control leading to improved survival with IORT approaches. This review summarizes the evidence for dose-escalation approaches with IORT for patients with very locally advanced and recurrent rectal cancer.

Introduction

Worldwide, colorectal cancer is diagnosed in more than 1 million people and results in more than 600,000 deaths per year. Colorectal cancer is the fifth leading cause of cancer death in the world.¹ Rectal cancer accounts for about one-third of colorectal cancers with nearly 40,000 new cases in the United States in 2015.² The incidence and mortality of colorectal cancer in the United States has been declining since the mid-1980s, but it remains the third leading cause of cancer deaths in the United States. A significant increase in screening over the last decade is likely the largest contributing factor to recent declines.²

Approximately 80% of new patients with rectal cancer have disease confined to the pelvis at initial diagnosis.² Patients with early-stage disease are curable with surgical resection alone, but those with more advanced locoregional disease have improved outcomes with the addition of radiation and chemotherapy to surgical resection. Controversy exists as to the definition of locally advanced disease. Some investigators include any patient with T3-T4 disease or regional lymph node involvement in the locally advanced category. Others would include only patients with T3N0 disease with threatened circumferential margin in the locally advanced category. In a detailed pooled analysis of 3 North American phase III randomized trials, a relatively favorable subset of patients with only one risk factor for relapse was defined. For patients with T3N0 or T1-2N1 disease, the 5-year survival rate was in the range of 74%-81% with local recurrence rates less than 10% and distant relapse rates of 15%-20%.³ In addition, investigators from Mayo Clinic have reported excellent results with surgery without radiotherapy for selected patients with stage III rectal cancer with a local recurrence rate of 5%, suggesting that not all patients with stage II and III disease need to be classified as those in locally advanced category.⁴

Historically, surgical resection alone was the only option for curative therapy of rectal cancer. Before the 1990s, local relapse was observed following complete resection in 5%-10% of patients with stage I disease, 25%-30% of patients with stage II disease, and 50% or more of patients with stage III disease.⁵ Survival and local disease control for patients with stage II and stage III rectal cancer with surgery alone in randomized trials are presented in Table 1. Survival and local control rates with surgery alone are significantly higher in patients with stage II disease than in patients with stage III disease. Among patients with stage III disease, survival with surgery alone is also correlated with extent of lymph node involvement. In the NSABP R-01 study, survival rate at 5 years with surgery alone was 63% in patients with N0 disease, 41% in patients with N1 disease, and 22% in patients with N2 disease.¹⁵

Numerous studies have been conducted evaluating either preoperative or postoperative radiation alone as adjuvant therapy for rectal cancer.7, 13, 14, 16, 17 The most consistent finding from these studies is a 50% reduction in local relapse risk without significant effect on survival. The Swedish trial is an exception with a survival benefit seen in addition to local control improvement with 25 Gy in 5 fractions followed by surgery within 1 week compared to surgery alone.¹³ Preoperative radiation with 25.5 Gy in 5 fractions was compared to 60 Gy postoperative radiation in another Swedish trial. Local recurrence was observed in 21% of patients treated postoperatively compared to 12% with short-course preoperative radiation (P = 0.02), but there was no significant difference in survival.¹⁸

In contrast to the results seen with adjuvant radiotherapy alone, concomitant chemotherapy and radiation in the adjuvant setting has been associated with improved local control and survival.6, 12 An early small randomized trial at the Mayo Clinic suggested that the addition of 5-fluorouracil (5-FU) to radiation in patients with unresectable colorectal cancer might prolong survival.¹⁹ This led to a series of trials evaluating chemotherapy, radiation, and concomitant chemotherapy and radiation therapy as surgical adjuvant therapy. The GITSG 7175 study compared surgery alone to surgery followed by radiation alone (40 Gy or 48 Gy in 180-200 cGy fractions) or chemotherapy with 5-FU and methyl CCNU or chemotherapy with concomitant bolus 5-FU. The survival rate at 5 years was 50% in both single-modality adjuvant arms and not significantly different from the 45% survival rate observed in the surgery alone arm. Local recurrence rate in the radiation alone arm was 20% vs 27% with chemotherapy and 24% with observation. However, in the combined-modality adjuvant arm local relapse rate was reduced to 11% and survival rate increased to 60%.⁶ A subsequent Mayo-NCCTG study confirmed improved survival and local control with concomitant chemoradiation as compared to radiation alone.²⁰ The NSABP R-01 study compared surgery alone with postoperative radiation or postoperative chemotherapy and found improved survival with chemotherapy (5-FU, methyl CCNU, and vincristine) and improved local control with radiation therapy.⁷ The results of these trials led to a 1990 National Institutes of Health consensus conference recommendation that postoperative chemoradiation be considered for all patients with stage II and III rectal cancer.²¹

In the adjuvant setting, improved results were observed with continuous infusion rather than bolus 5-FU during radiation therapy. In NCCTG study 87-47-51, the reported 4-year survival rate was 70% with continuous infusion 5-FU vs 60% with bolus 5-FU.²² A subsequent German study demonstrated that preoperative chemoradiation with 5-FU was less toxic and associated with better local control than postoperative chemoradiation with a reduction in local relapse rate from 13%-6% (P = 0.006). There was no difference in overall survival rate.²³