Abstract
Background/Aim: Preoperative chemoradiotherapy followed by total mesorectal excision (TME) is the standard treatment for stage III lower rectal cancer worldwide. However, in Japan, the standard treatment is TME with lateral pelvic lymph node dissection (LPLD) followed by adjuvant chemotherapy. We examined the safety and efficacy of adjuvant therapy with oxaliplatin, leucovorin, and 5-fluorouracil (modified FOLFOX6) after TME with LPLD. Patients and Methods: This retrospective study included 33 patients who received modified FOLFOX6 after TME with LPLD for stage III lower rectal cancer. Results: The overall completion rate of 12 cycles of adjuvant modified FOLFOX6 was 76%. Grade 3 or 4 neutropenia was observed in eight patients (24%). Sensory neuropathy was observed in 32 patients (97%) with 4 (12%) having a grade 3 event. The disease-free survival (DFS) rate was 45% at 3 years. Conclusion: Adjuvant modified FOLFOX6 was feasible in patients with stage III lower rectal cancer after TME with LPLD.
Preoperative fluorouracil-based chemoradiotherapy followed by a total mesorectal excision (TME) and post-operative adjuvant chemotherapy is standard treatment in rectal cancer in North America (1). However, TME with lateral pelvic lymph node dissection (LPLD) without preoperative chemoradiotherapy but with postoperative adjuvant chemo therapy is standard practice for patients with advanced lower rectal cancer in Japan (2-4), because it has a low rate of local recurrence and a high rate of patient survival. Preoperative chemoradiotherapy is used by choosing the patients' characteristics, such as tumor invasion of the adjacent organs (5). In fact, TME with LPLD had similar efficacy compared to TME followed by adjuvant chemoradiotherapy (6).
As for adjuvant chemotherapy, the National Surgical Adjuvant Study-Colorectal Cancer 01 trial (NSAS-CC 01) showed that patients with stage III rectal cancer who received uracil and tegafur (UFT; Taiho Pharmaceutical Ltd., Tokyo, Japan) had significantly longer relapse-free survival and better overall survival (OS) rates than patients who received surgery-alone (7, 8). UFT-alone has been a standard adjuvant therapy for patients with stage III lower rectal cancer; however, after the introduction of leucovorin in the 2000s (9), UFT plus leucovorin or intraveneous 5-fluorouracil (5-FU) plus leucovorin (RPMI) became standard practice. In 2004, the multicenter international study of oxaliplatin/5-FU/leucovorin (FOLFOX) in the adjuvant treatment of colon cancer (the MOSAIC trial) reported that adding oxaliplatin to 5-FU provided 23% further improvement in relative disease-free survival (DFS) and 4% absolute improvement in 6-year OS (68.7% vs. 72.9%) in stage III colon cancer (10, 11). A Japanese phase III study (JCOG0205) of UFT plus leucovorin, compared to the RPMI regimen in stage III colon cancer demonstrated a 5-year OS of 88% (12). Considering the excellent OS in JCOG0205, Japanese physicians made a choice between 5-FU alone (UFT plus leucovorin or RPMI) and oxaliplatin-based adjuvant chemotherapy. Therefore, TME with LPLD as local control treatment followed by adjuvant chemotherapy as systemic control became a standard treatment in patients with advanced rectal cancer in Japan.
Patients' characteristics.
Among rectal cancer patients, those with lateral pelvic lymph node metastases had a poor OS of 40% (13-16). More intensive oxaliplatin-based chemotherapy was selected for those patients. Nevertheless, the benefits of adjuvant oxaliplatin-based chemotherapy without radiation after TME with LPLD for stage III lower rectal cancer remain unclear. Moreover, we need to understand the adverse events of adjuvant oxaliplatin-based chemotherapy because TME with LPLD have some effect on bowel and bladder functions.
In the present study, we aimed to assess whether adjuvant modified FOLFOX6 was tolerated and was effective after TME with LPLD for stage III lower rectal cancer.
Patients and Methods
Patients. Patients with histologically-confirmed pathological stage III lower rectal cancer were eligible for this retrospective study. The other principal inclusion criteria were as follows: Main tumor lesion located in the rectum with the lower tumor margin below the peritoneal reflection; the patient underwent TME with LPLD; received adjuvant modified FOLFOX6; had ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2; sufficient bone marrow function; and normal liver and renal function. Modified FOLFOX6 consisted of a 2-h infusion of leucovorin isomers at 200 mg/m2, followed by a bolus of 5-FU at 400 mg/m2 plus a 46-h infusion of 5-FU at 2,400 mg/m2 every 2 weeks with oxaliplatin, 85 mg/m2, as a 2-h infusion on day 1.
Adverse events.
Evaluation of treatment. Medical history and drug safety and efficacy were determined from Hospital medical records. Toxicity was evaluated by using the Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0) (17).
Statistical analysis. DFS was measured from the date of surgery to the date of second cancer occurrence, cancer recurrence or death from any cause. OS was measured from the date of surgery to the date of death or the final date of confirmed survival. Time-to-event analyses were performed according to the Kaplan-Meier method. IBM SPSS Statistics, version 20 (IBM SPSS, Inc., Chicago, IL, USA), was used for the abovementioned statistical analyses.
Results
Patients' characteristics. A total of 33 patients who had received adjuvant modified FOLFOX6 after TME with LPLD for stage III lower rectal cancer were registered at seven Institutions between March 2008 and August 2012 (Table I). The distribution of disease stages was stage IIIa, 3 patients (9%) and stage IIIb, 30 patients (91%) according to the 8th edition of the Japanese Classification of Colorectal Carcinoma.
Treatment results. The median number of cycles of chemotherapy received was 12 (range=6-12). The overall completion rates of 6, 9 and 12 cycles of modified FOLFOX6 were 100%, 88%, and 76%, respectively, whether oxaliplatin was discontinued or not. The completion rates of 6, 9 and 12 cycles of modified FOLFOX6 without interruption of oxaliplatin were 97%, 82% and 58%, respectively. Chemotherapy was discontinued in 8 patients (24%) because of adverse events (n=4; gastrointestinal toxicity in 2, allergic reaction in 1 and sensory neuropathy in 1), recurrence (n=3) or social issues (n=1). Twelve patients (36%) required 5-FU bolus dose reduction or interruption because of neutropenia (n=9), diarrhea (n=2) or mucositis (n=1). Eight patients (24%) required 5-FU infusion dose reduction because of neutropenia (n=4), diarrhea (n=3) or hand-foot syndrome (n=1). Ten patients (30%) underwent oxaliplatin dose reductions or interruptions because of sensory neuropathy (n=9) or grade 2 anorexia (n=1). The median cumulative dose of oxaliplatin received was 960 mg/m2 (range=340-1.020 mg/m2). The median relative dose intensities of 5-FU bolus, 5-FU infusion and oxaliplatin were 82%, 83% and 78%, respectively. The average relative dose intensities of 5-FU bolus, 5-FU infusion and oxaliplatin were 76%, 80% and 76%, respectively.
Kaplan-Meier estimates of disease-free survival for patients.
Efficacy. Thirteen out of the 33 patients developed recurrences. Nine patients had distant recurrences, three had only local recurrences and one had both local and distant recurrences. The median DFS time was 30.8 months (95% confidence interval (CI)=23.9-37.7 months) (Figure 1). The DFS rate was 88% at 1 year and 45% at 3 years. After a median follow-up of 27.5 months (range=7.5-62.9 months), four patients had died of tumor progression; the other 29 patients remained alive. The median survival time data were immature (Figure 2).
Toxicity. Grade 3 or 4 neutropenia was observed in eight patients (24%), although no febrile neutropenia was observed (Table II). Sensory neuropathy was observed in 32 patients (97%); the majority of these (n=28) had grade 1 or 2 and four patients (12%) had grade 3. Two patients experienced allergic reactions (one of grade 1 and the other of grade 2), which resolved following discontinuation of oxaliplatin; chemotherapy was not restarted in the grade 2 patient. Other grade 3 or 4 non-hematological toxicities included nausea (3%), vomiting (3%) and diarrhea (3%). No treatment-related deaths were observed.
Kaplan-Meier estimates of overall survival for patients.
Discussion
We evaluated the efficacy and safety of modified FOLFOX6 in stage III lower rectal cancer patients after TME with LPLD. To our knowledge, this is the first report to evaluate adjuvant modified FOLFOX6 after TME with LPLD for stage III lower rectal cancer.
The overall rate of completion of 12 cycles of adjuvant treatment was 76%, although the rate in patients in whom oxaliplatin treatment was not interrupted was lower, at 58%. Our overall completion rate of adjuvant treatment was similar to those in previous prospective studies of colon cancer, such as the MOSAIC study (74.7%). Our patients' rate of grade 3 sensory neuropathy (12%) was also similar to that in the MOSAIC study (12.4%). Our frequency (3%) of grade 3 or 4 diarrhea was lower than that observed in previous prospective studies (18.9% in patients treated with capecitabine plus oxaliplatin (XELOX), 10.8% in patients treated with FOLFOX4 and 9.7% in patients treated with modified FOLFOX6); we may have underestimated the grade of diarrhea because the retrospective nature of the study made it difficult to differentiate the causes. It is possible that one of the reasons for the underestimation was the difficulty in determining the diarrhea count in patients who underwent surgery with colostomy; we had no detailed information on colostomy in our study. Sphincter dysfunction after TME with LPLD is a common problem (18) and diarrhea is also a potential problem in adjuvant 5-FU-based treatment. As for the combination therapy with 5-FU plus oxaliplatin, XELOX was more frequently accompanied by grade 3 or 4 diarrhea than was FOLFOX (19). From this perspective, the FOLFOX regimen is a more feasible adjuvant treatment after TME for lower rectal cancer.
The benefits of adjuvant modified FOLFOX6 for advanced lower rectal cancer have remained controversial. In Japan, based on the results of the MOSAIC study, adjuvant modified FOLFOX6 has been used as common practice in patients at high-risk for recurrence with lateral pelvic lymph node metastasis or many mesenteric lymph node metastases after TME with LPLD without preoperative chemoradio therapy. In Germany, the CAO/ARO/AIO-04 study did not show a benefit in OS for adjuvant modified FOLFOX6 compared with 5-FU alone after preoperative chemoradiotherapy followed by TME, although the CAO/ARO/AIO-04 and ADORE studies demonstrated a significant benefit in DFS (20, 21).
Use of radiation is also associated with the potential for substantial short-term toxicity and long-term morbidity, including infertility and sexual dysfunction, abdominal fibrosis, autonomic nerve injury resulting in abnormal bowel and bladder functions, increased risk of pelvic fracture and decreased bone marrow reserve (22-24). Therefore, it is logical to question whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy. With better local control, an increasing percentage of patients with rectal cancer will experience relapse at a systemic level providing a rationale for the investigation of oxaliplatin-based chemotherapy without radiotherapy in patients at increased risk for distant recurrence-specifically those with locally advanced disease or those with lateral pelvic lymph node metastasis who undergo TME with LPLD.
In our study in the adjuvant setting, the 44.8% of 3-year DFS was unsatisfactory over this short follow-up period. Fujita et al. reported a 5-year DFS rate of 27% in rectal cancer patients with lateral pelvic lymph node metastasis (14). The prognosis of those patients was poor and the 5-year survival rate was about 40%. The NSAS-CC 01 trial showed that the rate of distant metastasis was higher than that of local recurrence (8). Therefore, more intensive systemic chemotherapy is required to improve the control of micro-metastatic disease and prognosis. Schrag et al. reported that neoadjuvant FOLFOX for locally advanced rectal cancer gave a pathological complete response of 25% and a 4-year DFS rate of 84% (25). On the basis of these promising data, a randomized phase II/III NCCTG N1048 trial to evaluate the utility of neoadjuvant modified FOLFOX6 without routine use of radiation is ongoing. This study had some limitations. First, the efficacy results cannot be judged accurately because of the short follow-up period. The treatment period was short because the use of oxaliplatin in an adjuvant setting was not approved in Japan until September 2008. However, our short-term follow-up results revealed that adjuvant FOLFOX6 was not sufficiently effective because of the low 3-year DFS rate (44.8%). Second, the patients enrolled in our study had many factors placing them at high risk for recurrence, such as many lymph node metastases, positive lateral pelvic lymph node metastasis and T4. Surgical and medical oncologists had, therefore, likely recommended aggressive adjuvant therapy with an oxaliplatin-containing regimen because of these patients' high-risk stage III lower rectal cancers. Third, the small sample size is another limitation.
In conclusion, adjuvant modified FOLFOX6 treatment had an acceptable toxicity profile in patients with stage III lower rectal cancer after TME with LPLD. However, the short-term follow-up results showed that adjuvant modified FOLFOX6 was not sufficiently effective. Nevertheless, the potential for improved control of micro-metastatic disease suggests that there is a rationale for the continued investigation of oxaliplatin in rectal cancer, potentially in the context of neoadjuvant chemotherapy.
Acknowledgements
This study was supported in part by the National Cancer Center Research and Development Fund 23-A-19.
- Received November 22, 2014.
- Revision received December 2, 2014.
- Accepted December 4, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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