Naohito Beppu

Feasibility of modified short-course radiotherapy combined with a chemoradiosensitizer for T3 rectal cancer.

BACKGROUND: 5-Fluorouracil-based chemotherapy is considered to be a radiosensitizer; however, conventional short-course radiotherapy combined with chemotherapy is generally thought to not be feasible because of the prevalence of side effects. OBJECTIVE: The aim of this study was to evaluate the feasibility of modified short-course radiotherapy combined with a chemoradiosensitizer for T3 rectal cancer. DESIGN AND SETTINGS: This study was retrospective in nature and used a prospectively collected database. PATIENTS: Patients with T3 rectal cancer located below the peritoneum reflection were selected. INTERVENTIONS: A total dose of 25 Gy of radiotherapy was administered in 10 fractions of 2.5 Gy each for 5 days. Radiotherapy was performed with S-1 as a radiosensitizer from day 1 to day 10. Surgery was targeted to be performed 4 weeks after radiotherapy. MAIN OUTCOME MEASUREMENTS: The morbidity, sphincter-preserving rate, anal function, and long-term outcomes were assessed. RESULTS: All patients (n = 170) completed the radiotherapy regimen and 166 (97.6%) completed the combination regimen with chemotherapy. A total of 149 patients (87.6%) had sphincter-preserving surgery (double stapling technique (DST), 58 patients; intersphincteric resection (ISR), 91 patients), and postoperative complications were relatively mild (anastomotic leakage, 15.4%; intra-abdominal infection, 8.2%). Among those undergoing sphincter preserving surgery, the 5-year local relapse-free survival rate was 94.3% in the DST group, and 89.8% in the ISR group. With respect to the anal function, the Wexner score the first year after stoma closure for the double-stapling technique group was 6 and that for intersphincteric resection was 15; however, the score for the intersphincteric resection group was improved to 8 at 4 years after stoma closure. LIMITATIONS: This study had limitations because it was an uncontrolled, 1-arm, retrospective review with a small sample size. CONCLUSIONS: Modified short-course radiotherapy combined with chemoradiosensitizer is a feasible approach for treating T3 rectal cancer. With the use of the short-course approach, efforts to reduce the incidence of side effects by appropriately prolonging the waiting period enable the administration of combination treatment with short-course radiotherapy and chemotherapy.

Neoadjuvant short-course hyperfractionated accelerated radiotherapy (SC-HART) combined with S-1 for locally advanced rectal cancer

The purpose of this study was to examine the safety and feasibility of a novel protocol of neoadjuvant short-course hyperfractionated accelerated radiotherapy (SC-HART) combined with S-1 for locally advanced rectal cancer. A total of 56 patients with lower rectal cancer of cT3N1M0 (Stage III b) was treated with SC-HART followed by radical surgery, and were analyzed in the present study. SC-HART was performed with a dose of 2.5 Gy twice daily, with an interval of at least 6 hours between fractions, up to a total dose of 25 Gy (25 Gy in 10 fractions for 5 days) combined with S-1 for 10 days. Radical surgery was performed within three weeks following the end of the SC-HART. The median age was 64.6 (range, 39–85) years. The median follow-up term was 16.3 (range, 2–53) months. Of the 56 patients, 53 (94.4%) had no apparent adverse events before surgery; 55 (98.2%) completed the full course of neoadjuvant therapy, while one patient stopped chemotherapy because of Grade 3 gastrointestinal toxicity (CTCAE v.3). The sphincter preservation rate was 94.6%. Downstaging was observed in 45 patients (80.4%). Adjuvant chemotherapy was administered to 43 patients (76.8%). The local control rate, disease-free survival rate and disease-specific survival rate were 100%, 91.1% and 100%, respectively. To conclude, SC-HART combined with S-1 for locally advanced rectal cancer was well tolerated and produced good short-term outcomes. SC-HART therefore appeared to have a good feasibility for use in further clinical trials.

Short-course radiotherapy with delayed surgery versus conventional chemoradiotherapy: A comparison of the short- and long-term outcomes in patients with T3 rectal cancer.

INTRODUCTION The aim of this study was to compare the short- and long-term outcomes between short-course radiotherapy with delayed surgery (SRT-delay) and a standard conventional chemoradiotherapy (CRT) regimen. METHODS Two collaborating institutions adopted different regimens; the SRT-delay regimen was selected by Meiwa Hospital and the CRT regimen was selected by Hyogo College of Medicine. The inclusion criteria were T3 middle and low rectal cancer patients treated with radical surgery after preoperative therapy. The median follow-up period was 44 months (range, 12-85). RESULTS From 2007 to 2013, 104 patients were treated using the SRT-delay regimen and 61 patients were treated using the CRT regimen. The pretreatment characteristics of the 2 groups were not significantly different. The sphincter-preserving rate (93.3%, 85.2%), T downstaging (37.5%, 37.7%), ypN(-) (74.0%, 67.2%), postoperative complications and the bowel, and urinary and sexual functioning of the SRT-delay regimen were noninferior to those of the CRT regimen. The 3-year local recurrence-free survival, recurrence-free survival, and overall survival in the SRT-delay and CRT groups were 90.6% and 90.6% (P = .764), 83.8% and 78.3% (P = .687) and 96.0% and 92.8% (P = .833), respectively. CONCLUSION The SRT-delay regimen was noninferior in terms of the downstaging effect, and oncologic and functional outcomes compared with the CRT regimen for T3 middle and low rectal cancer.

Pathologic evaluation of the response of mesorectal positive nodes to preoperative chemoradiotherapy in patients with rectal cancer

BACKGROUND The response of positive mesorectal lymph nodes to chemoradiotherapy remains largely unstudied in patients with rectal cancer. The aim of this study was to investigate the requirements of the total regression of positive nodes treated with chemoradiotherapy. METHODS The response of the primary tumor was evaluated according to the tumor regression grade (TRG 0-4) in resected specimens, and positive lymph nodes were assessed according to the lymph node regression grade (LRG 1-3), with TRG 4 and LRG 3 indicating total regression. We investigated the relationships among TRG, LRG, and the sizes of positive lymph nodes. RESULTS Among 178 patients, 68 (38.2%) had 200 positive lymph nodes. We first investigated the relationship of positive nodes to TRG and LRG and found that the response of the primary tumor to chemoradiotherapy correlated with the response of positive nodes. Next, we investigated the correlation between LRG and the size of positive nodes. At TRG 1 and 2, LRG score was not correlated with the positive node size. In contrast, at TRG 3, LRG score was correlated with the size of positive nodes. Next, our assessment of the relationship between the sizes of positive nodes and complete degeneration to LRG 3 showed that the most accurate cut-off score on receiver-operator-characteristics curve analysis was 6 mm in maximum diameter for TRG 3. CONCLUSION The requirements of the total regression of positive nodes are 1) degeneration of the primary tumor to TRG 3 and 2) a positive node diameter of <6 mm.

Long-Term Functional Outcomes of Total Mesorectal Excision Following Chemoradiotherapy for Lower Rectal Cancer: Stapled Anastomosis versus Intersphincteric Resection

Aims: To compare the long-term functional outcomes of total mesorectal excision following chemoradiotherapy for lower rectal cancer between stapled anastomosis and intersphincteric resection (ISR). Methods: A total of 105 of 170 sphincter-preserving patients found to be disease-free and anal functional patients were assessed at 6.5 years (range 2.4-13.0 years) of follow-up after surgery. Of these subjects, 87 (double stapling technique [DST]: 41; ISR: 46) of the 105 patients (82.9%) responded to the questionnaire on the low anterior resection syndrome score (LARS score). Results: The total LARS scores in the DST and ISR groups were not significantly different (Major/Minor/No LARS = 23/14/4 and 31/10/5, p = 0.431). When considering each item of the LARS, ISR was associated with poorer incontinence scores than DST. Conversely, the scores for the frequency of bowel movement, clustering and urgency were not different between the 2 groups. In addition, in the multivariate analysis, the tumor distance from the anal verge and postoperative period was independently associated with Major LARS. Conclusion: In this study, we demonstrate the long-term functional outcomes of irradiated lower rectal cancer reconstructed with DST and ISR. Bowel function improves over time; therefore, long-term patient follow-up is important.

Laparoscopic intersphincteric resection and J-pouch reconstruction without laparotomy

In some cases, a J-pouch is not created after laparoscopic intersphincteric resection (Lap-ISR), because this procedure usually does not involve laparotomy. This study aimed to develop a new technique for Lap-ISR and J-pouch reconstruction without laparotomy and to assess the short- and long-term outcomes of this technique. After a rectal specimen is excised using the transanal approach, the reconstructed intestine is reinserted into the intra-abdominal space. To create the J-shape, the reconstructed intestine is looped back using Allis forceps, and the septum of the J-shape is divided using a surgical stapler. We performed 20 surgeries using the new technique. Although three patients developed pelvic infections, no J-pouch-related complications were noted. Intestinal continuity could be maintained in all patients who received a diverting stoma.

The impact of the radiation-induced regression of positive nodes on survival in patients with rectal cancer treated with chemoradiotherapy

BACKGROUND Although preoperative chemoradiotherapy exerts a destructive effect on positive lymph nodes, microscopic examination reveals different degrees of tumor regression. The aim of the present study is to investigate the impact of the radiation‐induced regression of positive nodes on survival in patients with rectal cancer treated with preoperative chemoradiotherapy. METHODS From 2001 to 2015, 229 patients with T3 rectal cancer underwent total mesorectal excision after preoperative chemoradiotherapy. The patients were classified into 3 groups according to their lymph node status: residual cancer cells in positive nodes (Group A), total regression of positive nodes after preoperative chemoradiotherapy with complete fibrosis (Group B), and the entire lymph node filled with lymph nodules and the absence of fibrosis (Group C). The survival of the 3 groups was compared, and a Cox model was used to evaluate the prognostic value of the regression of the positive nodes by preoperative chemoradiotherapy. RESULTS Groups A, B, and C included 57, 18, and 154 patients, respectively. Group B showed significantly better overall survival than Group A (P = .041) and similar outcomes to Group C (P = .383). Among the patients with positive lymph nodes prior to treatment (Groups A and B), the total regression of the positive nodes after preoperative chemoradiotherapy was the only independent factor to be associated with good overall survival (hazard ratio; 6.26, 95% confidence interval; 1.28–113.0, P = .020). CONCLUSION Total regression of positive nodes by preoperative chemoradiotherapy improves the prognosis of patients with rectal cancer with positive lymph nodes prior to treatment.

Functional Outcomes of Patients Treated with Intensive Medications for Bowel and Pain Control for Low-Lying Rectal Cancer Who Received Preoperative Chemoradiotherapy

Purpose: The aim of this study was to assess the functional outcomes of patients treated with intensive medications for bowel and pain control for low-lying rectal cancer who received preoperative chemoradiotherapy (CRT). Methods: The inclusion criterion was sphincter-preserving surgery following CRT for T3 middle and low rectal cancer. Postoperative defecation control was conducted using calcium polycarbophil and loperamide, and anal pain control was conducted using oxycodone hydrochloride hydrate. The functional outcomes were determined by an annual questionnaire after stoma closure. Results: Of 64 patients evaluated, 33 were reconstructed using the double stapling technique (DST) and 31 were reconstructed using the intersphincteric resection (ISR) technique. The median Visual Analogue Scale at ISR was improved from 7 to 1.5 at 1 year after surgery. The median Wexner scores were 6.0, 6.0, 5.0 and 5.0 for DST and 14.5, 12.0, 10.0 and 8.0 for ISR for the first 4 years, respectively. The only independent predictor of a poor bowel function (Wexner score >10) according to a multivariate analyses was pelvic infection (OR 3.994, 95% CI 1.235-13.52, p = 0.021), while ISR was not a predictor. Conclusions: Anal pain following ISR can be controlled with oxycodone hydrochloride hydrate therapy. ISR is feasible following CRT for low-lying rectal cancer.

A review of preoperative chemoradiotherapy for lower rectal cancer

In Western countries, rectal cancer has been treated by chemoradiotherapy (CRT) for several decades now, and good local control has been reported. However, Japanese guidelines did not strongly recommend CRT, because CRT is only useful for achieving local control and imbues no survival benefit. For this reason, CRT was rarely used to treat rectal cancer in Japan. However, in the 2000s, several studies involving CRT began to be reported from Western countries, such as “correlation between pathological complete response and survival,” “induction chemotherapy followed by CRT,” and “watch-and-wait policies.” These studies were directly correlated with survival of and benefits to the patients. Given these findings, Japanese institutions have recently begun to introduce CRT for rectal cancer. Therefore, in the present study, we reviewed several topics regarding CRT for rectal cancer.

Early results of a phase-II study of modified short-course radiotherapy combined with capecitabine and delayed surgery for T3M0 lower rectal cancer

Strong evidence of short-course 5 5Gy radiotherapy (SRT) for rectal cancer has been published [1,2], and recently, the Stockholm III trial demonstrated the feasibility of an experimental regimen involving short-course 5 5Gy radiotherapy with delayed surgery (SRT-delay) [3]. However, these regimens might still have some limitations. First, there exist concerns regarding the toxicity of the high 5-Gy fractions, even if only five fractions are administered, resulting in a comparably low total dose of 25 Gy. Second, long-course settings combined with chemotherapy improves local control, especially in highly advanced groups; however, no evidence is available regarding the combined use of chemotherapy and the short-course regimen. Thus, we proposed a modified SRT-delay regimen, which involves two modifications from the original regimen. The first is that 5Gy of each fraction is divided into two fractions (2.5Gy/fraction 2 fractions/day) to reduce each fraction dose. The second is that capecitabine, a radiosensitizer, was administered with radiotherapy to improve the treatment response. The aim of the present phase-II study was to evaluate the efficacy, tolerability and feasibility of this modified SRT-delay with concomitant use of capecitabine for T3 lower rectal cancer. The primary endpoint was response rate (total and major regression: Grade 2 and 3), and the secondary endpoints were safety (incidence of adverse events and complications), curative resection (R0) rate, downstaging and sphincter preservation.