Survival and time interval from surgery to the start of chemotherapy for patients with stage II and III colon cancer.

BACKGROUND: Usually adjuvant chemotherapy is started within 12 weeks of surgery, but the evidence on the commencing time is lacking. Our aim was to investigate the association of initiating post-surgery treatment within six weeks vs. six to ten weeks vs. more than ten weeks with survival.
METHODS: We analysed the association of treatment and its timing with survival among patients who were diagnosed and underwent surgery for stage II or III colon cancer from 2012 to 2013 at the National Cancer Institute, Lithuania.
RESULTS: Of the 86 patients, 78% were still alive on December 31, 2013. Patients who received chemotherapy within six weeks after surgery were more likely to survive. However, those who received chemotherapy 6-10 weeks after surgery had better survival (p - 0.014, hazard ratio 0.80, 95% CI 0.60-0.99) than those who began chemotherapy treatment more than ten weeks after surgery (p - 0.173 hazard ratio 0.55, 95% CI 0.12-0.99).
CONCLUSIONS: The results from this study show that optimal timing of adjuvant chemotherapy for patients with resected colon cancer within six weeks and associated with better survival.

INTRODUCTION

In 2013, colon and rectum cancer (CRC) ranked third for cancer incidence and fourth for cancer death worldwide (1) Surgical resection is the primary treatment for localized colon cancer. After curative resection, adjuvant chemotherapy is prescribed to lower the risk of tumour recurrence and metastasis (2, 3, 4, 5). The oncologic benefits of adjuvant chemotherapy have been proven (2), and adjuvant chemotherapy is suggested for stage II or III colon cancer patients in the current National Comprehensive Cancer Network (NCCN) guidelines (6).

One factor that may hamper the benefit of chemotherapy is an excessively long interval between surgery and the commencement of adjuvant therapy, which might give further time to micro-metastases to develop. This has been hardly assessed in CRC and available studies have shown conflicting results (7–9).

We used database of patients with stage II or stage III colon cancer from the National Cancer Institute to investigate the association of the timing of chemotherapy initiation survival.

PATIENTS AND METHODS

The study was approved by the Institutional Review Board.

From January 2012 to December 2013, 86 patients with stage II-III CRC, who had undergone surgical resection, were included in this study. All the patients had histologically proven stage II-III CRC after surgeries: high vascular resection (right-sided hemicolectomies, transverse colon resections, left-sided hemicolectomies, sigmoid resections and rectosigmoid resections) with D3 lymphonodectomy, and had received adjuvant chemotherapy. The medical records of patients were reviewed prospectively. Patients were categorized into three groups representing different times for adjuvant chemotherapy initiation after surgery: group 1 – patients having adjuvant chemotherapy within six weeks, group 2 – 6–10 weeks after surgery, and group 3 – more than 10 weeks after surgery. Patients had chemotherapy intravenously (oxaliplatin, 5-fluorouracil and leucovorin – FOLFOX4; 5-fluorouracil and leucovorin – 5-FU/LV), and orally (capecitabine – Xeloda, tegafur/uracil – UFT). To evaluate the efficacy of adjuvant chemotherapy according to the timing of its initiation, we analyzed and compared 5-year overall survival rates. Overall survival rates were estimated by using the Kaplan-Meier method. Multivariable Cox proportional hazards regression models were then used to analyze the association of treatment and the timing of treatment with mortality in univariate analysis (12). The differences between the groups were assessed using the log-rank test. A two-sided p-value of less than 0.05 was considered to represent statistical significance. All associations were considered to be statistically significant if the two-sided p value was 0.05 or less.

RESULTS

Of the 86 patients included in this study, 45 patients were male and 41 patients were female. The mean age of the patients was 63.3 ± 9.64 years (range from 31 to 75 years). The mean interval from the surgery to the initiation of adjuvant chemotherapy was 47.67 days, with a range of 24 to 206 days. Sixty-eight patients had chemotherapy intravenously (Oxaliplatin 85 mg/m2; Folinic acid 200 mg/m2; Fluorouracil 400–>600 mg/m (FOLFOX4); Leucovorin 200 mg/m2; Fluorouracil 400–>600 mg/m2 (de Gramont)), and 18 patients had it orally (Capecitabine 1250 mg/m2 (Xeloda); tegafur 300 mg/m2/uracil 672 mg/m2 (UFT)) (Table 1). Twenty-two per cent of the patients are known to have died during the five-year study period.

Table 1.

Demographic characteristics of patients in three groups (n = 86)

Characteristic	Value
Age, mean ± SD	63.3 ± 9.64
Sex (male:female)	41:45
Interval between surgery and chemotherapy (day), mean ± SD	47.67 ± 30.45
Regimen of adjuvant chemotherapy
de Gramont or FOLFOX-4 (Group 1/2/3)	47/14/7
capecitabine – Xeloda or tegafur/uracil – UFT (Group 1/2/3)	10/6/2

A total of 57 patients (28 males and 29 females) in group 1 received chemotherapy within six weeks after surgery. The mean age was 60.8 years. A total of 20 patients (11 males and nine females) in group 2 received chemotherapy from six to ten weeks after surgery. The mean age of those patients was 60.5 years. A total of nine patients (five males and four females) in group 3, received chemotherapy more than ten weeks after surgery. The mean age of those patients was 62.3 years. There were no significant differences between the groups (p = 0.0001) (Table 2).

Table 2.

Differences in all three study groups

Variable	Group 1(<6 weeks)	Group 2 (6–10 weeks)	Group 3 (>10 weeks)	p value (<0.05)
Number of patients	57	20	9	–
Age (years), Mean ± SD	60.8 ± 8.27	60.5 ± 12.73	62.3 ± 4.04	0.032
Sex (male:female)	28:29	11:9	5:4	0.0001
TNM (stage II/III)	37/20	9/11	3/6	0.0001

Kaplan-Meier survival analysis showed that the patients who received chemotherapy more than ten weeks after surgery had poorer survival than those whose chemotherapy treatment was started six to ten weeks following the surgery, and the patients who were treated within six weeks after surgery had better survival (Fig. 1).

Fig. 1.

Kaplan-Meier curves depicting 5-year overall survival

DISCUSSION

Numerous clinical factors may affect overall patient survival: stage III diagnosis, older age, and being male were all found to significantly decrease the probability of survival, after adjusting for treatment. Patients with stage III disease were almost twice as likely to die as those with stage II disease (HR 1.98, 95% CI 1.74–2.25). However, after adjusting for these factors, adjuvant chemotherapy was still associated with better survival (10).

Like our results, the results of studies by Kim et al. (9), Czaykowski et al. (11), Klein et al. (12), and Chau et al. (13) support the idea that adjuvant chemotherapy should be started as soon as possible after surgery, within six to eight weeks. A large meta-analysis published by Biagi et al. assessed the impact of delay to initiation of chemotherapy in ten cohorts of patients, involving 15,410 patients (14). The authors demonstrated that each incremental four-week delay in adjuvant chemotherapy resulted in a detriment to overall survival (HR: 1.14; 95% CI: 1.10–1.17) and disease-free survival (HR: 1.14; 95% CI: 1.10–1.18). Des Guetz et al. performed a complimentary meta-analysis of 17,645 patients and demonstrated similar findings, with delays beyond eight weeks associated with inferior overall survival (RR: 1.20; 95% CI: 1.15–1.26) (15).

However, there was a nonsignificant trend toward a higher risk of systemic recurrence when the delay of adjuvant chemotherapy was more than 12 weeks (p = 0.068). Additionally, a significant association was found between age, race, type of hospital, and timeliness of adjuvant chemotherapy (16).

Patients who received chemotherapy after surgery were less likely to die within the period of study. Our study showed that early initiation of chemotherapy may have better result. In summary, the study found that chemotherapy treatment after surgery improves the probability of survival for patients with stage II and III colon cancer. The study found strong evidence that the time interval between surgery and the start of chemotherapy affects survival. Further analysis on the relationship between treatment and survival, doses, durations, and types of chemotherapeutic agents is needed, especially as treatments and technology improve.

Our study obviously has some limitations. First of all, a small sample size and a retrospective nature of the trial. Secondly, we have not differentiated between various prognostic factors (localization of the primary tumour, inseparable left to right side of tumour localization, pathological grading), surgical complications, the number of metastatic lymph nodes. In addition, the age of our groups significantly varied statistically (in patients in the third group are older than in other groups, so they are likely to have more comorbidities).

CONFLICTS OF INTEREST

Authors have no conflicts of interest.

Denis Ganenko, Audrius Dulskas, Žygimantas Kuliešius, Edita Baltruškevičienė, Vincas Urbonas, Eugenijus Stratilatovas