Reevaluation of Oral Adjuvant Chemotherapy for T3 Lower Rectal Cancer: A Multicenter Collaborative Retrospective Cohort Study

Aim: This study aimed to evaluate the usefulness of oral adjuvant chemotherapy (OAC) for T3 lower rectal cancers without lateral lymph node metastasis. Methods: Between 2010 and 2014, 110 patients with T3 lower rectal cancer without lateral lymph node metastasis, 80 years of age or younger, who underwent curative resection at four Jikei University Hospitals were enrolled in this retrospective study. Of these, 94 patients underwent neither preoperative chemoradiotherapy (CRT) nor intensive chemotherapy after surgery: 47 patients who did not receive OAC for a pathological diagnosis of stage II cancer and 47 patients who did receive OAC for a pathological diagnosis of stage III cancer. The remaining 16 patients received intensive oxaliplatin-based combination chemotherapy after surgery without preoperative CRT. Results: The 5-year disease-free survival (DFS) of the 47 patients in stage II was 82.6%, whereas that of the 63 patients in stage III was 63.1% (p=0.033). The 5-year DFS of the 16 patients who received intensive chemotherapy after surgery was 81.3%, which was similar to the DFS of stage II patients, whereas that of the 47 patients with OAC alone was 58.2% (p=0.048). Conclusion: Intensive oxaliplatin-based combination chemotherapy after surgery was better for 5-year DFS than OAC among stage III patients. OAC is not suitable as adjuvant chemotherapy for patients with stage III lower rectal cancer even if no lateral lymph node metastasis is detected.


Introduction
Postoperative adjuvant chemotherapy is systemic chemotherapy that is performed after surgery to prevent recurrence and improve the prognosis of patients who have undergone R0 resection [1]. In the Japanese Society for Cancer of the Colon and Rectum Guidelines 2010 [2], the indications for systemic adjuvant chemotherapy are as follows: (1) stage III colorectal cancer (colon and rectal cancer) for which R0 resection has been performed; (2) maintenance of the function of major organs, bone marrow, liver function, and renal function; and (3) patients who have stage II colorectal cancer with a high risk of recurrence. Recommended therapies covered by Japanese National Health Insurance are as follows: (1) 5-uorouracil (5-FU) + levofolinate calcium (l-LV), (2) tegafur uracil (UFT) + calcium folinate (LV), (3) capecitabine, and (4) infusional 5-uorouracil and folinic acid plus oxaliplatin (FOLFOX4 or mFOLFOX6). In principle, the recommended administration period is 6 months. In our institutions, patients with T3 rectal cancer undergo adjuvant chemotherapy according to the guidelines. However, the usefulness of oral adjuvant chemotherapy (OAC) for T3 lower rectal cancers without lateral lymph node metastasis has not been elucidated.  (Table I). All patients (n=110) underwent total mesorectal excision (TME) with bilateral autonomic nerve preservation without lateral pelvic lymph node dissection. Disease-free survival (DFS) and the received treatments were retrospectively compared between groups. The medical records of all patients were reviewed and classi ed according to the Japanese Classi cation of Colorectal Carcinoma [3]. According to this classi cation, T3 corresponds to invasion of the subserosa.

Treatment schedule
All patients were followed for 5 years; during this period, physical examinations, routine blood analyses, and serum CEA measurements were conducted every two months after surgery. CT was performed every 6 months or when a patient's serum CEA value was higher than the normal level of 5.0 ng/ml. Colonoscopy was performed every year or when a stool sample was positive for blood. Positron emission tomography (PET) or PET/CT was occasionally employed to detect occult metastasis for patients who had equivocal conventional imaging studies.

Statistical analysis
Continuous variables are expressed as the mean and range. The Wilcoxon rank-sum test was used for the comparison of continuous variables, and a chi-squared test was used for the comparison of categorical data. DFS after surgery was examined by the Kaplan-Meier method and by log-rank analysis. Variables affecting postoperative recurrence were analyzed using the Cox proportional hazards regression. A pvalue of less than 0.05 indicated signi cance. All data were analyzed with IBM SPSS Statistics, version 24.0 (IBM Japan, Ltd, Tokyo, Japan).

Results
Signi cant differences were identi ed in only lymphatic invasion ( Table 2). The 5-year DFS of the 47 patients in stage II was 82.6%, whereas that of the 63 patients in stage III was 63.1% (p=0.033) ( Figure 1).

Comparison of DFS between the intensive and oral adjuvant chemotherapy groups
Signi cant differences were identi ed in only the recurrence sites (Table 3). Local recurrence and lymph node metastasis after surgery were not identi ed in the intensive chemotherapy group, whereas 6 patients with local recurrence (13%) and 2 patients with lymph node metastasis (4%) were found in the OAC group postoperatively. The 5-year DFS of the 16 patients who received intensive chemotherapy after surgery was 81.3%, which was similar to the DFS of stage II rectal cancer, whereas that of the 47 patients who received oral adjuvant chemotherapy after surgery was 58.2%, (p=0.048) (Figure 2).

Cox proportional hazards regression for postoperative recurrence
To determine the variables affecting postoperative recurrence, 5 variables (age, gender, type of adjuvant chemotherapy, number of lymph node metastases, and surgical approach) were analyzed using Cox proportional hazards regression. Only type of adjuvant chemotherapy was identi ed independent contributing factors to postoperative recurrence (p=0.049). The intensive chemotherapy reduced the postoperative recurrence risk to approximately 40% of the hazard ratio in the OAC group (Table 4).

Discussion
Between 1990 and 2004, postoperative chemotherapy with leucovorin (LV)-modulated 5-uorouracil (5-FU + l-LV) was the standard of care for stage III colon cancer, based on a 26% relative reduction in mortality with respect to that of surgery alone [4]. The oral uoropyrimidine capecitabine and S-1 can be effective alternatives to 5-FU + l-LV as adjuvant chemotherapy. In a randomized phase III study of capecitabine vs bolus 5-FU + l-LV (Mayo Clinic regimen), capecitabine showed an equivalent DFS to 5-FU + l-LV and was associated with signi cantly fewer adverse events [5]. UFT + LV and capecitabine showed non-inferiority to 5-FU + 1-LV [6]. S-1 showed non-inferiority to UFT + LV [7]. Thus, OAC has been considered the gold standard of care as adjuvant chemotherapy for stage III colorectal cancer in Japan since then. SOX, and CapeOX have been considered the gold standard care as adjuvant chemotherapy for stage III colorectal cancer in Japan since 2004. However, the usefulness of OAC for T3 lower rectal cancers without lateral lymph node metastasis has not been elucidated.
In this study, the 5-year DFS of the intensive oxaliplatin-based combination chemotherapy group after surgery was 81.3%, which was similar to the DFS of patients with stage II rectal cancer who received no adjuvant chemotherapy. Meanwhile the 5-year DFS of the OAC group after surgery was 58.2%. Signi cant differences were found between the two groups (p = 0.048). Furthermore, intensive chemotherapy reduced the postoperative recurrence risk to approximately 40% of the hazard ratio in the OAC group according to Cox proportional hazards regression analysis. Some large-scale randomized controlled trials have reported that oxaliplatin-based combination therapy for patients with stage III colon cancer was associated with a signi cant reduction in the risk of recurrence and an improved prognosis compared with those of 5-FU + l-LV, which was comparable to OAC [9, 10].
The most adverse event among patients who receive oxaliplatin combination therapy is the greater incidence of sensory peripheral neuropathy than that for OAC. The incidence of sensory peripheral neuropathy was signi cantly lower in a 3-month administration group than in the 6-month administration group [11]. In the ACHIEVE trial, the postoperative recurrence rate of a 3-month CapeOX-administered group was similar to that of the 6-month administered group, especially in patients with a low risk of recurrence. The 3-year DFS of the 3-month and 6-month administration groups were also similar [12]. The optimal oxaliplatin administration period as adjuvant therapy is still debated.
In conclusion, oxaliplatin combination intensive chemotherapy after surgery was better for 5-year DFS than OAC in stage III colorectal cancer. OAC is not suitable as adjuvant chemotherapy for patients with stage III lower rectal cancer even if no lateral lymph node metastasis is detected.

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