Background and Purpose: Postoperative adjuvant chemotherapy for stage III and high-risk stage II colorectal cancer patients has been recognized by more and more clinicians, but in clinical practice we found that only some patients finally completed six months of adjuvant chemotherapy.The purpose of this study was to analyze the timing of postoperative adjuvant chemotherapy for stage III and high-risk stage II colorectal cancer patients in our hospital and to explore the effect of the timing of postoperative adjuvant chemotherapy for colorectal cancer on the 3-year disease-free survival . METHODS: 276 patients with stage III and high-risk stage II colorectal cancer diagnosed at the Cancer Control Center of Sun Yat-sen University between July 2003 and December 2007 were collected and retrospectively analyzed. All patients underwent radical surgery and received at least 2 courses of postoperative chemotherapy containing 5-FU/CF or siroda or tegafur ± oxaliplatin regimens. RESULTS: 216 of 276 patients received chemotherapy with oxaliplatin and 60 received chemotherapy with either siroda or 5-FU/CF or tegafur. only 49 of 216 patients (22.7%) eventually completed six months of adjuvant chemotherapy. Both univariate and multifactorial analyses showed that the duration of postoperative adjuvant chemotherapy, age, gender, lymph node N stage, and degree of pathological differentiation were independent influencing factors for 3-year disease-free survival (P<0.05). CONCLUSION: The time of postoperative adjuvant chemotherapy in colorectal cancer patients was an independent influencing factor for 3-year disease-free survival.
Keywords: colorectal tumor; adjuvant chemotherapy; disease-free survival
Colorectal cancer is a common malignant tumor that seriously endangers human health, and its incidence is on the rise, with 1.023 million colorectal cancer cases worldwide in 2002. The results of incidence and mortality of malignant tumors in Guangzhou from 2000 to 2002 reported by Cao Kaja et al [1] showed that colon and rectal cancers ranked fourth and sixth in incidence among men and fifth and seventh among women, with annual incidence of 13.5/100,000 and 10.8/100,000 (men) and 13.3/100,000 and 8.2/100,000 (women), respectively. Surgical resection is the main treatment for colorectal cancer, and patients with stage II and III colorectal cancer still have the risk of recurrence and metastasis after surgery, and the 2008 NCCN guidelines recommended that patients with stage III and high-risk stage II colorectal cancer receive six months of adjuvant chemotherapy after surgery [2, 3], but in clinical practice we found that only some patients eventually complete six months of adjuvant chemotherapy, so the factors that affect patients’ adherence to adjuvant chemotherapy are What are the factors affecting patients’ compliance with adjuvant chemotherapy? What is the impact of adjuvant chemotherapy duration on disease-free survival? Do patients who cannot continue oxaliplatin for various reasons (less than six months) benefit from maintenance chemotherapy with 5-fluorouracil (5-FU)/calcium folinate (CF) or siroda until six months? With these questions in mind, we performed this retrospective analysis.
I. Data and methods
1. Clinical data
All patients met the following criteria: 18 years of age or older; pathologically confirmed colorectal cancer; radical surgery; clinical stage III (T1-4, N1-3) or high-risk stage II [3, 4] (high-risk factors include: poor tissue differentiation, T4 lesions, intestinal perforation or intestinal obstruction, peritumoral vascular or lymph node invasion, positive or too close cut margins, and less than 12 lymph node specimens); receiving at least 2 courses of postoperative chemotherapy with a regimen containing 5-FU/CF or siroda or tegafur ± oxaliplatin; and having follow-up information. Patients with rectal cancer who received preoperative neoadjuvant radiotherapy were not included in the final analysis. There were 276 patients available for final analysis, including 151 patients (54.7%) with stage III and 125 patients (45.3%) with stage II. The general information of patients is shown in Table 1.
2.Treatment method
Two hundred and sixteen of the 276 colorectal cancer patients received chemotherapy with oxaliplatin-containing regimens. Among them, 104 cases were treated with mFOLFOX6 regimen alone (2-12 courses, median number of courses was 6). mFOLFOX was administered as follows: oxaliplatin 85-100 mg/m2 intravenously for 3 h, d1; 5-FU 400 mg/m2 intravenously by push, d1; 5-FU 2400-3000 mg/m2 continuously intravenously for 46 h; tetrahydrofolate (CF) 400 mg/m2 intravenously for 2 h, d1; repeated every 14 to 18 d.
The XELOX regimen alone was used in 93 cases (2 to 10 courses, median number of courses was 6.) XELOX dosing: oxaliplatin 100-130 mg/m2 intravenously for 3 h, d1; siroda 1700-2000 mg/m2 divided into morning and evening oral doses for 14 d; repeated every 21-25 d.
Seven patients initially on the mFOLFOX regimen were switched to chemotherapy with the XELOX regimen because of PICC tube dislodgement or infection, and 12 patients originally on the XELOX regimen were later switched to the mFOLFOX6 regimen because of hand-foot syndrome or financial reasons.
Sixty patients received chemotherapy without the oxaliplatin regimen, 39 with high-risk stage IIa, 14 with stage IIb, 6 with stage IIIb, and 1 with stage IIIc. The regimen used included Hirona alone (35 cases, 3 to 8 courses, median number of courses was 6). The administration of Siroda was 1700-2000 mg/m2, divided into morning and evening oral doses for 14 d; it was repeated every 21-28 d.
5FU/CF (9 cases, 3-10 courses, median number of courses 5). 5-FU/CF usage: 5-FU 400 mg/m2 intravenous push, d1; 5-FU 2400-3000 mg/m2 continuous intravenous drip, 46 h; tetrahydrofolate (CF) 400 mg/m2 intravenous drip, 2 h, d1; repeated every 14-18 days.
Tegafur (16 cases, 2-7 courses of treatment, median number of courses 5). Tegafur usage: 200 mg 3 times daily for 4 weeks and then discontinued for 2 weeks and repeated every 42-48 d.
3. Criteria for evaluation of adverse reactions
Toxic and side effects were evaluated according to the description of NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events) 3.0 [5]. The neurotoxicity of oxaliplatin was evaluated with reference to the documentation of the case data and the statements of the patients during the telephone follow-up.
4.Statistical methods
Clinical data were registered and analyzed using SPSS 16.0 statistical software, and Kaplan-Meier method was used for disease-free survival and overall survival, and log-rank was used for analysis of variance. Multi-factor analysis was performed using the Enter model of Cox regression model.
II. Results
The whole group was followed up until October 2008, with a median follow-up time of 36.3 months (2-74.5 months). A total of 15 patients died of tumor progression, and 64 patients developed recurrence or distant metastasis, including 11 cases of recurrence (17.2%) and 53 cases of metastasis (82.8%). The sites of metastasis (including 10 cases of multisite metastasis) included 21 (39.6%) liver metastases, 15 (28.3%) lung metastases, 15 (28.3%) pelvic metastases, 10 (18.9%) retroperitoneal lymph nodes or metastases to abdominal organs other than the liver, and 4 (7.5%) inguinal or supraclavicular lymph node metastases. 3-year disease-free survival rate of 276 patients was 71.2% (see Figure 1), and the overall 5-year survival rate was 86.3% (see Figure 2).
Only 20 (19.2%) of the 104 patients on the mFOLFOX regimen alone completed 12 courses of chemotherapy, and 8 (7.7%) were maintained on 6 to 11 courses of mFOLFOX6 chemotherapy followed by 5FU/CF or siroda for six months because of grade III neurotoxicity (4), grade III-IV myelotoxicity (1), and unknown reasons (3).
Fifteen of the 93 patients (16.1%) treated with XELOX alone completed six months of chemotherapy, while five patients were maintained on two to seven courses of chemotherapy with Herodar for six months because of oxaliplatin allergy (two), grade III neurotoxicity (two), and unknown reasons (one).
Only one of the 19 patients (5.3%) on the mFOLFOX+XELOX regimen was maintained on Siroda until six months for third-degree neurotoxicity after completing three courses of mFOLFOX and three courses of XELOX chemotherapy.
A total of 49 patients completed six months of adjuvant chemotherapy (including those who started with oxaliplatin and were subsequently maintained on only Herodar or 5-FU/CF for six months, 49/216, 22.7%, and only 35 patients completed six months of the oxaliplatin-containing regimen, 35/216, 16.2%). Another 167 of the 216 patients had a median duration of chemotherapy of 4 months, which influenced their completion of Factors affecting the completion of chemotherapy for six months included discontinuation of chemotherapy as prescribed by the physician (102 cases, 61.1%), patients’ unwillingness to continue chemotherapy (non-toxic reactions, 51 cases, 30.5%), neurotoxicity (4 cases, 2.4%), tumor progression (4 cases, 2.4%), hand-foot syndrome (2 cases, 1.2%), III-IV myelotoxicity (1 case, 0.6%), III degree diarrhea (1 case, 0.6 %), and oxaliplatin allergy (2 cases, 1.2%).
The 216 patients who received oxaliplatin-containing regimen chemotherapy were divided into three groups of less than or equal to 2 months, 2 to 4 months (including 4 months), and 4 to 6 months (including 6 months) for the duration of postoperative adjuvant chemotherapy (excluding the duration of single-agent siroda or 5-FU/CF maintenance), and the effect of the duration of postoperative adjuvant chemotherapy on disease-free survival was analyzed by the Kaplan-Meier method. The 3-year disease-free survival rates of the three groups were 57.9%, 65.5%, and 78.6%, respectively, and the difference between the three groups was not statistically significant (P = 0.058), as shown in Figure 3. If the duration of maintenance chemotherapy with Siroda or 5-FU/CF was included in the statistics, the patients were still divided into three groups of less than or equal to 2 months, 2 to 4 months (including 4 months), and 4 to 6 months (including 6 months), and their 3-year disease-free survival rates were 51.5%, 64.0%, and 79.4%, respectively, with statistically significant differences (P=0.01), as shown in Figure 4.
Univariate analysis showed that age, gender, PS score, TNM stage, N stage, degree of tumor differentiation, and duration of postoperative adjuvant chemotherapy (including the duration of single agent maintenance chemotherapy) were the influencing factors for 3-year disease-free survival after colorectal cancer surgery (P values were 0.043, 0.023, <0.001, <0.001, <0.001, 0.001, 0.01, respectively). In contrast, the effects of T stage, tumor site, whether the maximum tumor diameter exceeded 5 cm, tumor tissue CEA immunohistochemical expression, whether preoperative serum CEA was normal, and adjuvant chemotherapy regimen (FOLFOX or XELOX) did not reach statistical significance on the 3-year disease-free survival rate (P>0.05).
The results of multifactorial analysis showed that age, gender, N stage, degree of differentiation, and duration of postoperative adjuvant chemotherapy were independent influences on 3-year disease-free survival (P values <0.001, 0.001, 0.002, 0.043, and 0.032, respectively), as shown in Table 2.
The 3-year disease-free survival rate was 71.0% in 216 patients treated with oxaliplatin-containing regimen chemotherapy and 72.0% in 60 patients treated with oxaliplatin-free regimen chemotherapy, with no statistically significant difference between the two (P=0.925).
Records of neurotoxicity were available in 101 of 216 patients treated with oxaliplatin-containing regimen chemotherapy, with grade 0 in 21 (20.8%), grade I in 34 (33.7%), grade II in 37 (36.6%), and grade III in 9 (8.9%). The median number of chemotherapy sessions with neurotoxicity was 4. At the end of follow-up (median follow-up time of 3 years), 36 patients (35.6%) still had grade I-II numbness in the hands and feet. 16 patients complained of more numbness in the feet than in the hands, and 20 patients felt the same degree of numbness in the hands and feet.
III. Discussion
The issue of postoperative adjuvant chemotherapy for patients with resectable colorectal cancer has been well elaborated in the last decade, and the results of the MOSAIC clinical trial in 2004 established the status of the six-month FOLFOX regimen in postoperative adjuvant chemotherapy for patients with stage III colon cancer [6], and the results of the QUASAR trial recommended that patients with high-risk stage II colon cancer receive adjuvant chemotherapy after surgery [7]. Information on postoperative adjuvant chemotherapy for rectal cancer is less available, mostly with reference to colon cancer.
The duration of adjuvant chemotherapy after surgery for bowel cancer was 1 year until 1998, and in 1998 two major organizations, the NCCTG (North Central Cancer Treatment Group) and NCI (National Cancer Institute of Canada), evaluated the effectiveness of the duration of adjuvant chemotherapy at 6 and 12 months after surgery and showed that 12 months of adjuvant chemotherapy was not better than 6 months [8]. Later Saini [9] had compared 12 weeks (3 months) of continuous intravenous drip 5FU
and 6-month Mayo regimens in adjuvant chemotherapy in patients with Dukes’ B and C stage colorectal cancer, and showed that the 12-week regimen was superior to the 6-month Mayo regimen in terms of recurrence-free survival. Moreover, the incidence of grade III neutropenia, diarrhea, stomatitis and alopecia was higher with 6-month chemotherapy than with 12-week. Although the results appear encouraging, its small sample size (716 cases) limits its further use in the clinic, while the 6-month duration of adjuvant chemotherapy remains a goal pursued by clinicians.
A comprehensive analysis of several studies showed a linear correlation between 3-year disease-free survival and 5-year overall survival in patients with colon cancer, and 3-year disease-free survival could be used to predict 5-year overall survival, which facilitates early observation of the effect of the drug [10]. Therefore, we used 3-year disease-free survival as an observational index in this retrospective analysis.
In this study, 216 patients received chemotherapy containing oxaliplatin regimen, and we classified the duration of adjuvant chemotherapy received as less than or equal to 2 months, 2 to 4 months (including 4 months), and 4 to 6 months (including 6 months). Both univariate and multifactorial analyses showed that the duration of adjuvant chemotherapy was an influential factor in the 3-year disease-free survival of patients with colorectal cancer, with a 3-year disease-free survival rate of 79.4% in the 4 to 6 months (including 6 months) group, comparable to the results of the MOSAIC trial [6].
The records of grade I-III neurotoxicity of oxaliplatin in our data were less than the results of the MOSAIC trial [6], and since this was a retrospective analysis, some patients could not recall the neurotoxicity, but analyzing from our results and the results of the MOSAIC trial [5], the grade III neurotoxicity of oxaliplatin was around 10% and was not the main influence on the patients’ completion of six months of adjuvant chemotherapy reason.
In this retrospective analysis we found that only 22.7% of patients completed six months of adjuvant chemotherapy, and an even smaller percentage, 16.2%, completed six months of chemotherapy containing oxaliplatin regimens. More than 60% of patients discontinued adjuvant chemotherapy after six courses of FOLFOX or XELOX as prescribed by their physicians, and only 6.5% failed to complete six months of adjuvant chemotherapy due to toxic side effects or progression. It is therefore particularly important for clinicians to be aware of the impact of the duration of adjuvant chemotherapy on 3-year disease-free survival.
In our data, some patients were unable to continue oxaliplatin for various reasons and were maintained on Siroda or 5-FU until six months. For this group of patients, if the duration of their subsequent maintenance chemotherapy is not considered and only the duration of chemotherapy containing oxaliplatin is calculated, the results show that the difference in disease-free survival is not statistically significant among the three groups of patients, but when the duration of single-agent maintenance chemotherapy is included in the duration of adjuvant chemotherapy, a significant difference in disease-free survival is seen among the three groups of patients, and because the number of cases in the subgroup analysis was too small, the number of patients who could not tolerate oxaliplatin was not analyzed Patients continued with siroda or 5FU maintenance on disease-free survival, but the results from the above analysis indirectly reflect the effect of siroda or 5FU maintenance chemotherapy on improving 3-year disease-free survival in patients who could not tolerate oxaliplatin chemotherapy.
In univariate and multifactorial analyses, in addition to the duration of adjuvant chemotherapy, age, gender, N stage and degree of differentiation were also factors influencing disease-free survival, which was longer in female patients than in men, and an analysis of factors influencing the prognosis of disease-free survival after preoperative radiotherapy for rectal cancer also showed that men were poor prognostic factors [11], but the mechanisms involved are still unclear, and whether they are related to the protective effect of estrogen effect needs further investigation, and whether men should be one of the high-risk factors for the need to receive adjuvant chemotherapy after surgery in stage II patients needs to be clarified by clinical trials. In addition, the 3-year disease-free survival rate was not statistically different between patients with oxaliplatin-containing chemotherapy and those without oxaliplatin, but the proportion of stage II patients who did not receive oxaliplatin chemotherapy was 88.3% (53/60) compared with 33.4% of patients with oxaliplatin-containing chemotherapy. Despite the small number of cases, we can recommend chemotherapy with either the Hirona or 5-FU/CF or tegafur regimens for patients with stage II colorectal cancer.
This retrospective analysis showed that the duration of postoperative adjuvant chemotherapy in patients with colorectal cancer was an independent influence on 3-year disease-free survival, with longer 3-year disease-free survival obtained by receiving 4 to 6 months of adjuvant chemotherapy than by those receiving less than or equal to 4 months.