Treatment Strategy for Rectal Submucosal Cancer
Surgical management and chemoradiotherapy of T1 rectal cancer
Corresponding: Hirotoshi Kobayashi, Center for Minimally Invasive Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Email: firstname.lastname@example.org
T1 rectal cancer can be treated using various strategies. Endoscopic or transanal resection is the first choice of treatment when tumors are not associated with risk for lymph node metastasis. However, transabdominal resection with lymphadenectomy is recommended for tumors that do confer risk of lymph node metastasis. The prognosis after transabdominal resection is satisfactory, but various dysfunctions impair the postoperative quality of life. The standard treatment for T3–T4 rectal cancer is total mesorectal excision with preoperative chemoradiotherapy in Western countries and total mesorectal excision with laterallymph node dissection in Japan. Previous reports indicate that preoperative radiotherapy contributes to a lower rate of local recurrence, although overall survival is not affected. In addition, radiotherapy increases the prevalence of sexual dysfunction and fecal incontinence. The effect of perioperative chemoradiotherapy for T1–T2 rectal cancer remains unclear.
The prognosis is worse for patients with rectal cancer than for those with colon cancer, because of its higher local recurrence rate. Total mesorectal excision (TME) has been proposed to solve this problem. Preoperative chemoradiotherapy before rectal surgery is the gold standard in Western countries, whereas lateral lymph nodes have been dissected to prevent local recurrence of rectal cancer in Japan since the 1970s.[3, 4] Because a high frequency of genitourinary dysfunction was initially important in Japan, autonomic nerve-preserving rectal surgery prevailed. However, Sugihara et al. demonstrated the limited effectiveness of lateral lymph node dissection for rectal cancer. Therefore, a multicenter study investigated indications for lateral lymph node dissection for rectal cancer and found that the optimal indication for lateral lymph node dissection was T3–T4 tumors with a distal edge located below the peritoneal reflection and mesorectal lymph node metastasis.
Miles described abdominoperineal resection in 1908 and this procedure became a standard procedure for treating rectal cancer. As a matter of course, abdominoperineal resection is still carried out for some patients with rectal cancer today. Thereafter, low anterior resection prevailed since Knight and Griffen described the double-stapling technique in 1980. However, the disadvantages associated with low anterior resection include frequent defecation and urgency.
Although the outcomes of surgery for T1 rectal cancer are relatively good, postoperative urgency and frequent defecation persist after radical low anterior resection. Abdominoperineal resection might be suitable for some patients. From this standpoint, transanal excision (TAE) or endoscopic resection can be used to treat T1 rectal cancer in patients with a low risk of lymph node metastasis.[9, 10] However, additional transabdominal resection is recommended after pathological assessment because of the risk of lymph node metastasis or a positive margin. Some patients refuse to undergo additional transabdominal resection because of postoperative dysfunction. Whether or not adjuvant chemotherapy or radiotherapy is useful after endoscopic resection or TAE for T1 rectal cancer in patients with a risk of lymph node metastasis remains undefined. The present study reviews various guidelines, surgical management and chemoradiotherapy for T1 rectal cancer as well as adverse events after chemoradiotherapy and the findings of a recent trial for T2 rectal cancer (ACOSOG Z6041).
Guidelines for T1 Rectal Cancer
National Comprehensive Cancer Network (NCCN) guidelines
The National Comprehensive Cancer Network (NCCN) guidelines recommend the following for T1 rectal cancer. TAE is indicated for clinical stage T1 rectal cancer without evidence of lymph node metastasis on magnetic resonance (MR) or endorectal ultrasonography (ERUS) images. Transabdominal resection is recommended if a pathological assessment uncovers high-risk features of lymph node metastasis. The NCCN guidelines define high-risk features as positive margins, lymphovascular invasion, poorly differentiated tumors or sm3 invasion.
Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines
The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines consider curative resection with lymph node dissection for patients with T1 rectal cancer and the risk factors for lymph node metastasis of a positive vertical margin, a depth of SM invasion of ≥1000 μm, poorly differentiated adenocarcinoma, signet-ring cell or mucinous carcinoma and grade 2 or 3 budding at the site of deepest invasion.
Surgical Management of T1 Rectal Cancer
T1 rectal cancer that is not associated with risk for lymph node metastasis is usually treated by TAE or endoscopic resection such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).[9, 10, 13, 14] However, patients with risk factors for lymph node metastasis are usually treated by transabdominal resection with lymphadenectomy. The JSCCR guidelines recommend D2 lymph node dissection for T1 colorectal cancer. The frequency of abdominoperineal resection of T1 rectal cancer has decreased because intersphincteric resection has prevailed[15, 16] and some institutions have adopted a laparoscopic approach.
Lymph Node Metastasis in T1 Rectal Cancer
A recent study has demonstrated 9.6%, 12.0% and 13.6% rates of lymph node metastasis associated with T1 cancer of the colon, upper and lower rectum, respectively. Another study found that 8.6% and 0.99% rates of lymph node metastasis were associated with T1 distal rectal cancer and with T1 well-differentiated adenocarcinoma in males, respectively. In contrast, that in female patients with T1 cancer other than well-differentiated adenocarcinoma was 30.4%. Preoperative evaluation of risk for lymph node metastasis is important when considering treatment for T1 rectal cancer.
Chemoradiotherapy for Rectal Cancer
Table 1 shows the results of preoperative radiotherapy for rectal cancer. The high local recurrence rate after surgery for rectal cancer has been problematic. The current standard therapy for T3–T4 rectal cancer in most developed counties is TME with preoperative chemoradiotherapy. A Swedish trial of preoperative radiotherapy for rectal cancer found that the incidence of local recurrence decreased and both cancer-specific and overall survival were improved. However, other trials did not identify a survival benefit of radiotherapy in the treatment of rectal cancer. A Dutch randomized phase III trial with twice as many registered patients as the Swedish trial found that preoperative radiotherapy significantly reduced local recurrence rates, but did not confer a survival benefit.
Table 1. Preoperative radiotherapy for rectal cancer
|Swedish rectal cancer trial|| || || || || || || |
|Preoperative RT||454||11|| ||74|| ||58|| |
|Dutch trial|| || || || || || || |
|Preoperative RT||897||5.6|| || || ||64.2|| |
|Surgery alone||908||10.9||<0.001|| || ||63.5||0.902|
Table 2 shows the results of preoperative chemoradiotherapy for rectal cancer. Concomitant chemotherapy with preoperative radiotherapy decreases local recurrence compared with preoperative radiotherapy alone. The EORTC 22921 trial reported by Bosset et al. found local recurrence rates of 17.1% and 8.7% in patients who had undergone preoperative radiotherapy and chemoradiotherapy, respectively, but no difference in overall survival between the two groups. The results of the FFCD trial reported by Gerard et al. were similar to those of the EORTC 22921 trial. The local recurrence rates of concomitant chemotherapy and preoperative radiotherapy reduced recurrence rates from 16.5% to 8.1%, but the overall survival rates of the two groups remained essentially identical.
Table 2. Preoperative chemoradiotherapy for rectal cancer
|EORTC 22921|| || || || || || |
|RT||505||5.3||17.1|| ||64.8|| |
|FFCD 9203|| || || || || || |
|RT||367||3.7||16.5|| ||67.9|| |
Preoperative versus postoperative chemoradiotherapy
Table 3 shows the results of neoadjuvant versus adjuvant therapy for rectal cancer. A German trial found a lower local recurrence rate after preoperative than after postoperative chemoradiotherapy, although neither disease-free nor overall survival significantly differed between the two groups. In contrast, the NSABP R-03 trial found no difference in local recurrence rates between patients who had undergone preoperative and postoperative chemoradiotherapy. However, preoperative chemoradiotherapy led to better disease-free survival. The 5-year overall survival rates of patients who had received preoperative or postoperative chemoradiotherapy in the NSABP R-03 study were 75% and 66%, respectively, although the difference did not reach statistical significance.
Table 3. Neoadjuvant vs adjuvant therapy for rectal cancer
|German rectal cancer study (RT+FU)|| || || || || || || |
|Preoperative||421||6|| ||68|| ||76|| |
|NSABP R-03 (RT+FU+LV)|| || || || || || || |
|Preoperative||1223||11|| ||65|| ||75|| |
Addition of oxaliplatin
Table 4 shows the results of oxaliplatin plus chemotherapy for rectal cancer. A recent study found that preoperative chemoradiotherapy with and without oxaliplatin for rectal cancer led to complete response rates of 17% and 13%, respectively. However, two other trials found that oxaliplatin regimens led to a higher incidence of grade 3 and 4 toxicity.[27, 28] The long-term results of local control and survival benefits will be disclosed in the future.
Table 4. Oxaliplatin plus chemoradiotherapy for rectal cancer
|STAR-1|| || || || || || || || |
|FU group||379|| ||8|| ||16|| ||80|| |
|ACCORD 12/0405 PRODIGE 2|| || || || || || || || |
|FU group||299|| ||11|| ||14|| ||75|| |
|German CAO/ARO/AIO-04 trial|| || || || || || || || |
|FU group||623|| ||20|| ||13|| ||76|| |
|L-OHP group||613||50.4||23|| ||17||0.038||75|| |
Adverse Events after Chemoradiotherapy for Rectal Cancer
Urinary dysfunction is a major issue after rectal surgery. Long-term urinary incontinence has been identified in 38.1% of patients, among whom 72.0% had normal preoperative function. However, Lange et al. reported that the main reason for urinary dysfunction was autonomic nerve damage caused by the surgical procedure. Another study found no difference in voiding function between groups with and without radiotherapy before rectal surgery.
Several studies have revealed radiotherapy as a risk factor for sexual dysfunction after rectal surgery.[30, 31] Lange et al. reported that 70–80% of patients experienced sexual dysfunction after rectal surgery after preoperative radiotherapy. Women can also develop sexual dysfunction after rectal surgery, with the major symptoms being pain during intercourse and decreased sexual satisfaction.
Recent studies have also demonstrated that late fecal incontinence is a problem after pelvic radiotherapy for prostate cancer.[33, 34]
Radiotherapy and Chemotherapy for T1–T2 Rectal Cancer
Little is known about the effects of chemoradiotherapy on T1–T2 rectal cancer. Chakravarti et al. described the outcomes of patients with T1–T2 rectal cancer managed by local excision with and without adjuvant irradiation. They found that adjuvant irradiation significantly improved 5-year outcomes in patients with high-risk pathological features such as lymphovascular invasion, poorly differentiated tumors or tumor invasion to the muscularis propria. Curative resection with lymphadenectomy is usually recommended for patients who develop adverse pathological features after local excision or endoscopic resection. However, postoperative chemoradiotherapy could be considered for compromised general conditions or if patients refuse to undergo surgery.[35, 36] The ACOSOG Z6041 trial has investigated the effects of chemoradiotherapy before local excision for T2 rectal cancer. Only short-term outcomes are presently available. Radiotherapy with chemotherapy including capecitabine with oxaliplatin has led to a complete response rate of 44%. However, 39% of patients developed grade ≥3 complications.
We reviewed surgical approaches and chemoradiotherapy for treating rectal cancer. Preoperative chemoradiotherapy followed by TME is a standard treatment for T3–T4 rectal cancer in Western countries, whereas TME with lateral lymph node dissection is the standard in Japan. Further studies are required to define the outcomes of chemoradiotherapy for T1–T2 rectal cancer.
Conflict of Interests
Authors declare no conflict of interests for this article.