Abstract
Until now, it remains unclear how to best use the histological subtype in clinical practice. This study aimed to compare differences in the efficacy of postoperative chemotherapy among different histological subtypes of colon adenocarcinomas. Using the Surveillance, Epidemiology, and End Results‐Medicare database, 51,200 patients with stage II or III primary colon carcinomas who underwent resection for curative intent between 1992 and 2008 were included. The survival benefit was evaluated using a Cox proportional hazards model, interaction analyses, and propensity score‐matched techniques. There was no significant difference in survival for low‐risk stage II mucinous adenocarcinoma (MA) or nonmucinous adenocarcinoma (NMA) between 5‐FU and oxaliplatin‐treated groups (P = 0.387 for MA, P = 0.629 for NMA). Patients with high‐risk stage II NMA who received the oxaliplatin chemotherapy regimen had significantly improved cancer‐specific survival (CSS) compared with the 5‐FU group (P = 0.004), while those with MA saw no improvement (P = 0.690). For stage III tumors, patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS compared with the 5‐FU group (P < 0.001), while those with MA saw no improvement (P = 0.300). There were significant interactions between chemotherapy regimen and histological subtype. For patients with resected colon cancer who received 5‐FU‐based postoperative chemotherapy, oxaliplatin chemotherapy prolongs CSS for stage III and high‐risk stage II NMA. Conversely, there was no similar improvement with addition of oxaliplatin for patients with stage III or stage II MA.
Keywords: Chemotherapy, colon neoplasms, mucinous adenocarcinoma, nonmucinous adenocarcinoma, SEER program
Introduction
The use of histological subtype as a classification system for colorectal cancer was introduced by the World Health Organization in 1979. Carcinomas are categorized as traditional adenocarcinomas, mucinous adenocarcinomas (MA), signet‐ring cell carcinomas (SC), and other, more infrequent, types 1, 2. MA is a histological subtype of colon cancer in which the neoplastic cells secrete extensive extracellular mucins that form more than 50% of the tumor volume 3. SC tumors are comprised of more than 50% signet‐ring cells in which the nucleus is pushed to the periphery by intracytoplasmic mucins of colon cancer 4. This classification of histological subtype is routinely carried out during the postoperative pathological examination of colon cancer. However, how to this histological subtyping should best be used to aid in the clinical practice remains unclear.
In clinical practice, decision making regarding whether give or which regimen give adjuvant therapy to patients with stage II tumors remains controversial 5, 6. For patients with stage III disease, although the preferred treatment options are FOLFOX or CapeOx, the side effects of oxaliplatin are indisputable. It has been reported that oxaliplatin might not be applicable for all patients, specifically the elderly population 7, 8. Thus, it is important to find prognostic and predictive features to help assist with selecting appropriate and beneficial adjuvant therapy for patients considered. Histological subtype is not considered in the decision making for colon cancer adjuvant therapy in either the National Comprehensive Cancer Network (NCCN) 9 or the European Society for Medical Oncology (ESMO) 10. In addition, no research has proposed that histological subtype could have an influence on chemotherapeutic effects in colorectal cancer patients. As for other types of cancer, Sugawa et al. 11 found a difference in chemotherapy effects between different histological subtypes in cervical cancer, and Itaya et al. 12 found histology‐dependent differences of chemosensitivity in nonsmall cell lung cancer.
The aim of this study was to compare the efficacy of postoperative chemotherapy among different histological subtypes of colon cancer. We then tried to find the most suitable postoperative chemotherapy regimens for both major histological subtypes of colonic adenocarcinoma.
Materials and Methods
Data source
This study was a retrospective analysis of data collected from the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. This study was conducted in accordance with a SEER‐Medicare data use agreement, and a study protocol approval was also granted by the First Hospital of China Medical University Institutional Review Board.
SEER data contain information on patient demographics, tumor and disease characteristics, course of treatment, use of cancer‐directed operative and medical therapy, survival, and cause of death for individuals diagnosed with cancer. It is a population‐based cancer registry covering approximately 28% of the US population across several disparate geographic regions 13. Medicare is the primary health insurer for approximately 97% of the US population aged ≥65 years 14. The unmentioned details of the database appeared elsewhere 15.
Patient selection
All Medicare‐registered patients diagnosed with incident malignant primary colon cancer (SEER cancer site codes: 18.0, 18.2–18.9) between 1992 and 2008 in a SEER area were considered for study inclusion. The study contained two histological types defined by WHO International Classification of Diseases for Oncology, 3rd edition (ICD‐O‐3), codes: MA (8480) and nonmucinous adenocarcinomas (NMA) (8010, 8020–8022, 8140–8141, 8144–8145, 8210–8211, 8220–8221, 8230–8231, 8260–8263).
Patients were selected who underwent primary tumor resection with likely curative intent within 180 days of diagnosis. The No‐chemo group was designated as no claim of postoperative chemotherapy within 9 months after operation. The 5‐FU group consisted of patients who only received 5‐FU/capecitabine chemotherapy within 9 months of surgery. The oxaliplatin group comprised patients with any record of oxaliplatin plus 5‐FU/capecitabine within 9 months of surgery.
Patients were eliminated from the study population if they (1) received any preoperative adjuvant treatment; (2) received postoperative radiotherapy; (3) had prior noncolon cancer; (4) had incomplete histological subtype or pathological stage entries; (5) died within 30 days after tumor resection; (6) had stage I or stage IV tumors; (7) histological subtype was signet‐ring cell carcinoma, as this population represented too small a sample size (0.9%).
Variables
Subjects were categorized by age at diagnosis, year of diagnosis, gender, race, marital status, residence (rural or urban), median household income, level of education (percentage of people aged >25 years with <12 years of education), and the type of hospital in which they received care (teaching or nonteaching). To control for the effects of comorbidities, analyses were adjusted by the Centers for Medicare and Medicaid Services Hierarchical Condition Category (HCC) based on Medicare outpatient and inpatient claims for miscellaneous comorbidities within the 12 months before colon cancer diagnosis. The HCC risk score summarizes the healthcare problems and forecasts the future healthcare cost of a population compared with the average Medicare beneficiary 16.
Postoperative pathological stage was designated via the seventh edition of the Union for International Cancer Control (UICC) tumor‐node‐metastasis (TNM) staging system 17. Other covariates included histological grade, histological subtype, intestinal obstruction, intestinal perforation, and the number of lymph nodes examined.
Statistical analysis
The chi‐square test was used to compare demographics and tumor characteristics between the different groups. In the univariate survival analysis, cancer‐specific survival (CSS) was analyzed by the Kaplan–Meier method. Comparison of survival curves was carried out using the log‐rank test. Because treatment choice estimates are likely confounded by factors related to treatment selection, a propensity score (PS)‐matched analysis was performed to compare the effect of treatment on survival among patients of similar risk profiles as assessed by measured known confounders 18, 19. Propensity score matching is a statistical procedure for reducing this bias by assembling a sample in which confounding factors are balanced between treatment groups. Univariate logistic regression was used to find factors related to treatment selection (P < 0.05). Multivariate logistic regression was used to estimate the propensity scores in each group (Table 1). The propensity score‐matched sample would then be constructed using “psmatch2” software package in STATA 14.0. A Cox proportional hazards model was also used in the adjusted analysis. The covariates included all variables that were identified to be significantly related to survival in the univariate analysis.
Table 1.
Main effect variables in propensity score models
| NMA Patients in low‐risk stage II | |
| Variables that significantly related to the patients’ probability of receiving 5‐FU compared with No‐chemo | Gender, age at diagnosis, year at diagnosis, HCC risk score, race, marital status |
| MA Patients in low‐risk stage II | |
| Variables that significantly related to the patients’ probability of receiving 5‐FU compared with No‐chemo | Gender, age at diagnosis, year at diagnosis |
| NMA Patients in high‐risk stage II | |
| Variables that significantly related to the patients’ probability of receiving 5‐FU compared with No‐chemo | Gender, age at diagnosis, year at diagnosis, histological grade, pT category, intestinal obstruction, HCC risk score, number of examined lymph node, level of education, marital status, residence location |
| Variables that significantly related to the patients’ probability of receiving 5‐FU plus oxaliplatin compared with 5‐FU alone | Age at diagnosis, year at diagnosis, pT category, number of examined lymph node, median income, marital status |
| MA Patients in high‐risk stage II | |
| Variables that significantly related to the patients’ probability of receiving 5‐FU compared with No‐chemo | Gender, age at diagnosis, year at diagnosis, pT category, intestinal obstruction, HCC risk score, marital status, profit hospital |
| Variables that significantly related to the patients’ probability of receiving 5‐FU plus oxaliplatin compared with 5‐FU alone | Year at diagnosis, pT category, number of examined lymph node, profit hospital |
| NMA Patients in stage III | |
| Variables that significantly related to the patients’ probability of receiving 5‐FU compared with No‐chemo | Gender, age at diagnosis, year at diagnosis, pT category, pN category, intestinal obstruction, HCC risk score, level of education, median income, race, marital status, residence location |
| Variables that significantly related to the patients’ probability of receiving 5‐FU plus oxaliplatin compared with 5‐FU alone | Age at diagnosis, year at diagnosis, pN category, number of examined lymph node, level of education, median income, marital status |
| MA Patients in stage III | |
| Variables that significantly related to the patients’ probability of receiving 5‐FU compared with No‐chemo | Gender, age at diagnosis, year at diagnosis, pT category, intestinal obstruction, HCC risk score, marital status |
| Variables that significantly related to the patients’ probability of receiving 5‐FU plus oxaliplatin compared with 5‐FU alone | Gender, age at diagnosis, year at diagnosis, pN category, number of examined lymph node, median income, marital status |
MA, mucinous adenocarcinoma; NMA, nonmucinous adenocarcinoma; HCC, hierarchical condition categories; 5‐FU, 5‐fluorouracil.
All statistical analyses and graphics were performed using SAS 9.4 (SAS Institute, Cary, NC), STATA 14.0 software (STATA, College Station, TX), and PASW Statistics 20.0 software (SPSS, Inc., Somers, NY). For all analyses, a P value < 0.05 was considered statistically significant.
Results
Patient characteristics
Selected 51,200 individuals were stratified into two analysis groups: NMA (n = 43,998) and MA (n = 7202). Demographic characteristics of patients are depicted in Table 2. Compared with NMA, MA was more common in women (P < 0.001), individuals aged >80 years (P = 0.018), year at diagnosis before 2004 (P < 0.001), well histological grade (P < 0.001), T1–T3 category (P < 0.001), N2 category (P < 0.001), nonintestinal obstruction (P < 0.001), number of examined lymph nodes ≥12 (P < 0.001), white race (P < 0.001), widowed (P = 0.006). Stage II patients were further divided into low‐risk stage II and high‐risk stage II groups. We designated the cohort of patients with high‐risk stage II using features of poor prognosis referred to in the NCCN 9, including T4 tumors, poorly differentiated histology, bowel obstruction, bowel perforation, and inadequate sampled nodes (<12 lymph nodes). The number of patients and the results of each analysis and treatment chemotherapy effect analysis are summarized in Table 3.
Table 2.
Clinicopathologic features of patients with different histological subtype
| NMA | MA | P | |
|---|---|---|---|
| n (%) | n (%) | ||
| Gender | <0.001 | ||
| Male | 18,479 (42.0%) | 2665 (37.0%) | |
| Female | 25,519 (58.0%) | 4537 (63.0%) | |
| Age at diagnosis, years | 0.018 | ||
| <70 | 6712 (15.3%) | 1027 (14.3%) | |
| 70–74 | 8840 (20.1%) | 1411 (19.6%) | |
| 75–79 | 10,066 (22.9%) | 1610 (22.4%) | |
| 80–84 | 9205 (20.9%) | 1563 (21.7%) | |
| >84 | 9175 (20.9%) | 1591 (22.1%) | |
| Year at diagnosis | 0.001 | ||
| 1992–1996 | 8818 (20.0%) | 1472 (20.4%) | |
| 1997–2000 | 8393 (19.1%) | 1421 (19.7%) | |
| 2001–2004 | 14,410 (32.8%) | 2452 (34.0%) | |
| 2005–2008 | 12,377 (28.1%) | 1857 (25.8%) | |
| Histological grade | <0.001 | ||
| Well | 2695 (6.1%) | 658 (9.1%) | |
| Moderate | 30,354 (69.0%) | 4470 (62.1%) | |
| Poor | 9707 (22.1%) | 1475 (20.5%) | |
| Undifferentiated | 503 (1.1%) | 77 (1.1%) | |
| Unknown | 739 (1.7%) | 522 (7.2%) | |
| Postoperative chemotherapy | 0.396 | ||
| No | 28,104 (63.9%) | 4563 (63.4%) | |
| Yes | 15,894 (36.1%) | 2639 (36.6%) | |
| pT category | <0.001 | ||
| T1 | 612 (1.4%) | 57 (0.8%) | |
| T2 | 1504 (3.4%) | 197 (2.7%) | |
| T3 | 35,209 (80.0%) | 5661 (78.6%) | |
| T4a | 4134 (9.4%) | 787 (10.9%) | |
| T4b | 2539 (5.8%) | 500 (6.9%) | |
| pN category | <0.001 | ||
| N0 | 24,869 (56.5%) | 4105 (57.0%) | |
| N1a | 6852 (15.6%) | 1016 (14.1%) | |
| N1b | 6422 (14.6%) | 992 (13.8%) | |
| N2a | 3652 (8.3%) | 604 (8.4%) | |
| N2b | 2203 (5.0%) | 485 (6.7%) | |
| Intestinal obstruction | <0.001 | ||
| No | 34,677 (78.8%) | 5910 (82.1%) | |
| Yes | 9321 (21.2%) | 1292 (17.9%) | |
| Intestinal perforation | 0.463 | ||
| No | 43,401 (98.6%) | 7112 (98.8%) | |
| Yes | 597 (1.4%) | 90 (1.2%) | |
| HCC risk score | 0.001 | ||
| 1st quartile | 11,575 (26.3%) | 1974 (27.4%) | |
| 2nd quartile | 10,846 (24.7%) | 1707 (23.7%) | |
| 3rd quartile | 10,892 (24.8%) | 1671 (23.2%) | |
| 4th quartile | 10,685 (24.3%) | 1850 (25.7%) | |
| Number of examined lymph node | <0.001 | ||
| <12 | 20,747 (47.2%) | 3164 (43.9%) | |
| ≥12 | 23,251 (52.8%) | 4038 (56.1%) | |
| Level of education | 0.712 | ||
| 1st quartile | 11,129 (25.3%) | 1845 (25.6%) | |
| 2nd quartile | 11,088 (25.2%) | 1828 (25.4%) | |
| 3rd quartile | 10,974 (24.9%) | 1772 (24.6%) | |
| 4th quartile | 8899 (20.2%) | 1426 (19.8%) | |
| Unknown | 1908 (4.3%) | 331 (4.6%) | |
| Median income | 0.061 | ||
| 1st quartile | 10,858 (24.7%) | 1815 (25.2%) | |
| 2nd quartile | 11,072 (25.2%) | 1698 (23.6%) | |
| 3rd quartile | 11,063 (25.1%) | 1828 (25.4%) | |
| 4th quartile | 9097 (20.7%) | 1530 (21.2%) | |
| Unknown | 1908 (4.3%) | 331 (4.6%) | |
| Race | <0.001 | ||
| White | 37,285 (84.7%) | 6279 (87.2%) | |
| Black | 3859 (8.8%) | 560 (7.8%) | |
| Asian | 1303 (3.0%) | 149 (2.1%) | |
| Others | 1551 (3.5%) | 214 (3.0%) | |
| Marital status | 0.006 | ||
| Single | 4042 (9.2%) | 636 (8.8%) | |
| Married | 20,997 (47.7%) | 3341 (46.4%) | |
| Widowed | 17,487 (39.7%) | 3011 (41.8%) | |
| Others | 1472 (3.3%) | 214 (3.0%) | |
| Residence locationa | 0.127 | ||
| Big Metro | 23,585 (53.6%) | 3938 (54.7%) | |
| Metro or Urban | 15,298 (34.8%) | 2416 (33.5%) | |
| Less Urban or Rural | 5113 (11.6%) | 848 (11.8%) | |
| Profit hospitala | 0.006 | ||
| Nonprofit hospital | 21,362 (49.4%) | 3620 (51.1%) | |
| For‐profit hospital | 15,938 (36.9%) | 2586 (36.5%) | |
| Public hospital | 5924 (13.7%) | 885 (12.5%) | |
| Number of bedsa | 0.076 | ||
| 1st quartile | 10,653 (24.6%) | 1772 (25.0%) | |
| 2nd quartile | 10,795 (25.0%) | 1823 (25.7%) | |
| 3rd quartile | 10,819 (25.0%) | 1800 (25.4%) | |
| 4th quartile | 10,957 (25.3%) | 1696 (23.9%) | |
| Teaching hospitala | 0.941 | ||
| Yes | 22,604 (52.7%) | 3699 (52.6%) | |
| No | 20,304 (47.3%) | 3329 (47.4%) | |
HCC, hierarchical condition categories; NMA, nonmucinous adenocarcinomas; MA, mucinous adenocarcinomas.
Variables have missing data.
Table 3.
Results of patients subjected to different chemotherapy regimens
| Number of patients | HR | 95% CI | P | |||
|---|---|---|---|---|---|---|
| No‐chemo | 5‐FU | Oxaliplatin | ||||
| Low‐risk stage II | ||||||
| No‐PSM‐NMA (No‐ chemo vs. 5‐FU) | 5958 | 961 | – | 0.735 | 0.604–0.893 | 0.002 |
| No‐PSM‐NMA (5‐FU vs. oxaliplatin) | – | 961 | 94 | 0.462 | 0.146–1.465 | 0.179 |
| No‐PSM‐MA (No‐ chemo vs. 5‐FU) | 1025 | 178 | – | 0.934 | 0.582–1.496 | 0.775 |
| No‐PSM‐MA (5‐FU vs. oxaliplatin) | – | 178 | 13 | 0.045 | 0.001–843.46 | 0.346 |
| PSM‐NMA (No‐chemo vs. 5‐FU) | 961 | 961 | – | 0.939 | 0.726–1.214 | 0.629 |
| PSM‐MA (No‐chemo vs. 5‐FU) | 176 | 176 | – | 1.399 | 0.690–2.598 | 0.387 |
| High‐risk stage II | ||||||
| No‐PSM‐NMA (No‐chemo vs. 5‐FU) | 13,951 | 2664 | – | 0.826 | 0.758–0.901 | <0.001 |
| No‐PSM‐NMA (5‐FU vs. oxaliplatin) | – | 2664 | 260 | 0.529 | 0.348–0.804 | 0.002 |
| No‐PSM‐MA (No‐chemo vs. 5‐FU) | 2028 | 443 | – | 0.749 | 0.598–0.938 | 0.011 |
| No‐PSM‐MA (5‐FU vs. oxaliplatin) | – | 443 | 37 | 0.792 | 0.289–2.172 | 0.649 |
| PSM‐NMA (No‐chemo vs. 5‐FU) | 2662 | 2662 | – | 1.003 | 0.894–1.125 | 0.961 |
| PSM‐NMA (5‐FU vs. oxaliplatin) | – | 260 | 260 | 0.529 | 0.348–0.804 | 0.004 |
| PSM‐MA (No‐chemo vs. 5‐FU) | 436 | 436 | – | 1.049 | 0.778–1.415 | 0.754 |
| PSM‐MA (5‐FU vs. oxaliplatin) | – | 29 | 29 | 0.792 | 0.289–2.172 | 0.690 |
| Stage III | ||||||
| No‐PSM‐NMA (No‐chemo vs. 5‐FU) | 7843 | 8188 | – | 0.551 | 0.525–0.578 | <0.001 |
| No‐PSM‐NMA (5‐FU vs. oxaliplatin) | – | 8188 | 1826 | 0.583 | 0.522–0.625 | <0.001 |
| No‐PSM‐MA (No‐chemo vs. 5‐FU) | 1287 | 1360 | – | 0.566 | 0.503–0.637 | <0.001 |
| No‐PSM‐MA (5‐FU vs. oxaliplatin) | – | 1360 | 258 | 0.74 | 0.569–0.962 | 0.023 |
| PSM‐NMA (No‐chemo vs. 5‐FU) | 7841 | 7841 | – | 0.554 | 0.527–0.581 | <0.001 |
| PSM‐NMA (5‐FU vs. oxaliplatin) | – | 1819 | 1819 | 0.621 | 0.543–0.710 | <0.001 |
| PSM‐MA (No‐chemo vs. 5‐FU) | 1287 | 1287 | – | 0.567 | 0.502–0.639 | <0.001 |
| PSM‐MA (5‐FU vs. oxaliplatin) | – | 252 | 252 | 0.837 | 0.598–1.173 | 0.300 |
PSM, propensity score matched; MA, mucinous adenocarcinoma; NMA, nonmucinous adenocarcinoma; HR, hazard ratio; CI, confidential intervals; 5‐FU, 5‐fluorouracil; No‐chemo, without postoperative chemotherapy.
CSS in low‐risk stage II adenocarcinoma
There was a significant difference in survival for NMA patients with low‐risk stage II cancer between the no‐chemo and 5‐FU groups (P = 0.002, Fig. 1A), while those with MA saw no difference (P = 0.775, Fig. 1B). There was no significant difference in NMA and MA patients with low‐risk stage II cancer between the 5‐FU and oxaliplatin groups (Fig. 1C and D).
Figure 1.
Kaplan–Meier comparison of cancer‐specific survival among patients who received different postoperative treatment stratified by histological subtype. (A) NMA in low‐risk stage II (No‐chemo vs. 5‐FU); (B) MA in low‐risk stage II (No‐chemo vs. 5‐FU); (C) NMA in low‐risk stage II (5‐FU vs. oxaliplatin); (D) MA in low‐risk stage II (5‐FU vs. oxaliplatin); (E) NMA in low‐risk stage II after PS‐matched (No‐chemo vs. 5‐FU); (F) MA in low‐risk stage II after PS‐matched (No‐chemo vs. 5‐FU).
A PS‐matched cohort was generated using related variables which may interfere with the chemotherapy decision (Table 1). The aforementioned general results were recalculated in the PS‐match cohorts. There was no significant difference in survival for patients with low‐risk stage II NMA between the no‐chemo and 5‐FU groups (P = 0.629, Fig. 1E), while those with MA again saw no difference (P = 0.387, Fig. 1F). Another PS‐matched cohort was generated using related variables which may interfere with the choice of chemotherapy regimen. However, its sample size is too small to recalculate aforementioned results.
CSS in high‐risk stage II adenocarcinoma
There was a significant difference in survival for patients with high‐risk stage II NMA between the no‐chemo and 5‐FU groups (P < 0.001, Fig. 2A), while those with MA again saw a difference (P = 0.011, Fig. 2B). Patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS (P = 0.002, Fig. 2C) compared with the 5‐FU group, while those with MA saw no improvement (P = 0.649, Fig. 2D).
Figure 2.
Kaplan–Meier comparison of cancer‐specific survival among patients who received different postoperative treatment stratified by histological subtype. (A) NMA in high‐risk stage II (No‐chemo vs. 5‐FU); (B) MA in high‐risk stage II (No‐chemo vs. 5‐FU); (C) NMA in high‐risk stage II (5‐FU vs. oxaliplatin); (D) MA in high‐risk stage II (5‐FU vs. oxaliplatin).
Then, we used the PS‐match cohorts to recalculate the aforementioned general results. There was no significant difference in survival for patients with high‐risk stage II NMA between the no‐chemo and 5‐FU groups (P = 0.961, Fig. 3A), while those with MA again saw no difference (P = 0.754, Fig. 3B). Patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS (P = 0.004, Fig. 3C) compared with the 5‐FU group, while those with MA saw no improvement (P = 0.690, Fig. 3D). This result was also verified by a Cox proportional hazards model (Table 4 and 5).
Figure 3.
After PS‐matched, Kaplan–Meier comparison of cancer‐specific survival among patients who received different postoperative treatment stratified by histological subtype. (A) NMA in high‐risk stage II (No‐chemo vs. 5‐FU); (B) MA in high‐risk stage II (No‐chemo vs. 5‐FU); (C) NMA in high‐risk stage II (5‐FU vs. oxaliplatin); (D) MA in high‐risk stage II (5‐FU vs. oxaliplatin).
Table 4.
Cox proportional hazards model for patients in high‐risk stage II stratified by histological subtype
| HR | 95% CI | P | |
|---|---|---|---|
| NMA | |||
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.867 | 0.564–0.366 | 0.009 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 2.165 | 1.449‐0.970 | 0.070 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.619 | 1.356–1.135 | 0.001 |
| Number of examined lymph node | |||
| <12 | 1 | ||
| ≥12 | 0.817 | 0.681–0.568 | <0.001 |
| HCC risk score | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.584 | 1.227–0.950 | 0.118 |
| 3rd quartile | 1.679 | 1.303–1.010 | 0.041 |
| 4th quartile | 1.692 | 1.289–0.982 | 0.068 |
| Race | |||
| White | 1 | ||
| Black | 2.025 | 1.504–1.116 | 0.007 |
| Asian | 0.863 | 0.472–0.258 | 0.015 |
| Others | 1.167 | 0.715–0.438 | 0.179 |
| pT category | |||
| T3 | 1 | ||
| T4a | 1.739 | 1.383–1.100 | 0.005 |
| T4b | 3.419 | 2.763–2.233 | <0.001 |
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 1.653 | 1.311–1.039 | 0.022 |
| 75–79 | 1.947 | 1.543–1.222 | <0.001 |
| 80–84 | 2.533 | 1.917–1.450 | <0.001 |
| >84 | 5.814 | 3.870–2.577 | <0.001 |
| Marital status | |||
| Single | 1 | ||
| Married | 1.028 | 0.780–0.591 | 0.078 |
| Widowed | 1.343 | 1.005–0.752 | 0.973 |
| Others | 1.460 | 0.851–0.496 | 0.557 |
| Level of education | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.259 | 1.002–0.798 | 0.984 |
| 3rd quartile | 1.134 | 0.903–0.719 | 0.380 |
| 4th quartile | 1.266 | 0.995–0.782 | 0.969 |
| Gender | |||
| Male | 1 | ||
| Female | 1.133 | 0.938–0.777 | 0.507 |
| MA | |||
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.622 | 0.224–1.732 | 0.364 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 1.827 | 0.712–4.683 | 0.210 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.050 | 0.634–1.738 | 0.851 |
| pT category | |||
| T3 | 1 | ||
| T4a | 1.543 | 0.910–2.616 | 0.108 |
| T4b | 3.666 | 2.244–5.990 | <0.001 |
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 0.870 | 0.500–1.513 | 0.622 |
| 75–79 | 0.985 | 0.550–1.762 | 0.959 |
| 80–84 | 1.816 | 0.912–3.615 | 0.090 |
| >84 | 2.731 | 1.204–6.199 | 0.016 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.563 | 0.292–1.088 | 0.087 |
| Widowed | 0.517 | 0.253–1.060 | 0.072 |
| Others | 0.227 | 0.028–1.837 | 0.165 |
MA, mucinous adenocarcinoma; NMA, nonmucinous adenocarcinoma; HCC, hierarchical condition categories; HR, hazard ratio; CI, confidential intervals; 5‐FU, 5‐fluorouracil.
Table 5.
Univariate prognostic analysis stratified by histological subtype
| HR | 95% CI | P | |
|---|---|---|---|
| NMA in stage III | |||
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 1.070 | 0.991–1.155 | 0.082 |
| 75–79 | 1.217 | 1.130–1.311 | <0.001 |
| 80–84 | 1.468 | 1.361–1.583 | <0.001 |
| >84 | 2.021 | 1.875–2.179 | <0.001 |
| Year at diagnosis | |||
| 1992–1996 | 1 | ||
| 1997–2000 | 1.000 | 0.934–1.070 | 0.989 |
| 2001–2004 | 0.925 | 0.870–0.984 | 0.014 |
| 2005–2008 | 0.850 | 0.794–0.910 | <0.001 |
| HCC risk score | |||
| 1st quartile | 1 | ||
| 2nd quartile | 0.838 | 0.787–0.891 | <0.001 |
| 3rd quartile | 0.905 | 0.850–0.964 | 0.002 |
| 4th quartile | 1.117 | 1.050–1.189 | <0.001 |
| Number of examined lymph node | |||
| <12 | 1 | ||
| ≥12 | 0.890 | 0.851–0.930 | <0.001 |
| pT category | |||
| T1 | 1 | ||
| T2 | 1.240 | 0.994–1.547 | 0.057 |
| T3 | 2.804 | 2.311–3.401 | <0.001 |
| T4a | 4.124 | 3.375–5.039 | <0.001 |
| T4b | 7.451 | 6.087–9.120 | <0.001 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 2.259 | 1.928–2.648 | <0.001 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.549 | 1.473–1.629 | <0.001 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.793 | 0.733–0.858 | <0.001 |
| Widowed | 1.007 | 0.930–1.091 | 0.864 |
| Others | 0.926 | 0.802–1.070 | 0.299 |
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.583 | 0.522–0.652 | <0.001 |
| Histological grade | |||
| Well | 1 | ||
| Moderate | 1.264 | 1.123–1.422 | <0.001 |
| Poor | 1.801 | 1.595–2.034 | <0.001 |
| Undifferentiated | 1.902 | 1.550–2.334 | <0.001 |
| Unknown | 1.223 | 0.993–1.507 | 0.059 |
| Median income | |||
| 1st quartile | 1 | ||
| 2nd quartile | 0.938 | 0.881–0.997 | 0.041 |
| 3rd quartile | 0.905 | 0.850–0.963 | 0.002 |
| 4th quartile | 0.858 | 0.803–0.918 | <0.001 |
| Unknown | 1.027 | 0.919–1.148 | 0.639 |
| pN category | |||
| N1a | 1 | ||
| N1b | 1.417 | 1.337–1.503 | <0.001 |
| N2a | 2.000 | 1.877–2.131 | <0.001 |
| N2b | 3.272 | 3.056–3.503 | <0.001 |
| Race | |||
| White | 1 | ||
| Black | 1.066 | 0.988–1.149 | 0.098 |
| Asian | 0.750 | 0.653–0.86 | <0.001 |
| Others | 0.945 | 0.843–1.06 | 0.338 |
| Level of education | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.091 | 1.024–1.163 | 0.007 |
| 3rd quartile | 1.140 | 1.069–1.215 | <0.001 |
| 4th quartile | 1.195 | 1.118–1.278 | <0.001 |
| Unknown | 1.219 | 1.090–1.364 | 0.001 |
| Gender | |||
| Male | 1 | ||
| Female | 1.069 | 1.022–1.119 | 0.004 |
| MA in stage III | |||
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 1.037 | 0.857–1.256 | 0.706 |
| 75–79 | 1.216 | 1.011–1.464 | 0.038 |
| 80–84 | 1.405 | 1.164–1.696 | <0.001 |
| >84 | 1.692 | 1.401–2.045 | <0.001 |
| Year at diagnosis | |||
| 1992–1996 | 1 | ||
| 1997–2000 | 1.040 | 0.881–1.227 | 0.643 |
| 2001–2004 | 1.032 | 0.889–1.198 | 0.677 |
| 2005–2008 | 0.826 | 0.694–0.983 | 0.032 |
| HCC risk score | |||
| 1st quartile | 1 | ||
| 2nd quartile | 0.847 | 0.724–0.991 | 0.038 |
| 3rd quartile | 0.986 | 0.844–1.151 | 0.854 |
| 4th quartile | 1.203 | 1.037–1.396 | 0.015 |
| Number of examined lymph node | |||
| <12 | 1 | ||
| ≥12 | 0.792 | 0.710–0.884 | <0.001 |
| pT category | |||
| T1 | 1 | ||
| T2 | 0.841 | 0.445–1.590 | 0.595 |
| T3 | 2.214 | 1.280–3.828 | 0.004 |
| T4a | 3.590 | 2.048–6.295 | <0.001 |
| T4b | 5.753 | 3.270–10.122 | <0.001 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.634 | 1.436–1.859 | <0.001 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.776 | 0.636–0.948 | 0.013 |
| Widowed | 0.941 | 0.770–1.151 | 0.555 |
| Others | 1.089 | 0.780–1.520 | 0.618 |
| pN category | |||
| N1a | 1 | ||
| N1b | 1.208 | 1.040–1.402 | 0.013 |
| N2a | 1.905 | 1.628–2.228 | <0.001 |
| N2b | 2.752 | 2.344–3.231 | <0.001 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 1.915 | 1.151–3.188 | 0.012 |
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.740 | 0.569–0.962 | 0.025 |
| Histological grade | |||
| Well | 1 | ||
| Moderate | 0.955 | 0.763–1.197 | 0.692 |
| Poor | 1.332 | 1.053–1.685 | 0.017 |
| Undifferentiated | 1.701 | 1.073–2.697 | 0.024 |
| Unknown | 1.129 | 0.847–1.503 | 0.407 |
| NMA in high‐risk stage II | |||
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 2.666 | 2.249–3.161 | <0.001 |
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.529 | 0.348–0.804 | 0.003 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.510 | 1.413–1.613 | <0.001 |
| Number of examined lymph node | |||
| <12 | 1 | ||
| ≥12 | 0.921 | 0.859–0.987 | 0.020 |
| HCC risk score | |||
| 1st quartile | 1 | ||
| 2nd quartile | 0.925 | 0.847–1.011 | 0.087 |
| 3rd quartile | 1.045 | 0.958–1.141 | 0.321 |
| 4th quartile | 1.286 | 1.178–1.404 | <0.001 |
| Race | |||
| White | 1 | ||
| Black | 1.424 | 1.284–1.580 | <0.001 |
| Asian | 0.698 | 0.560–0.870 | 0.001 |
| Others | 1.033 | 0.863–1.235 | 0.726 |
| pT category | |||
| T3 | 1 | ||
| T4a | 1.357 | 1.238–1.489 | <0.001 |
| T4b | 2.589 | 2.348–2.855 | <0.001 |
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 0.969 | 0.858–1.094 | 0.612 |
| 75–79 | 1.210 | 1.079–1.358 | 0.001 |
| 80–84 | 1.416 | 1.262–1.588 | <0.001 |
| >84 | 2.026 | 1.813–2.265 | <0.001 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.652 | 0.586–0.727 | <0.001 |
| Widowed | 0.881 | 0.792–0.980 | 0.020 |
| Others | 0.693 | 0.562–0.854 | 0.001 |
| Level of education | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.038 | 0.946–1.139 | 0.432 |
| 3rd quartile | 1.107 | 1.012–1.211 | 0.027 |
| 4th quartile | 1.218 | 1.108–1.338 | <0.001 |
| Unknown | 1.148 | 0.971–1.356 | 0.106 |
| Gender | |||
| Male | 1 | ||
| Female | 0.935 | 0.877–0.996 | 0.038 |
| MA in high‐risk stage II | |||
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.792 | 0.289–2.172 | 0.650 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 2.439 | 1.577–3.773 | <0.001 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.500 | 1.252–1.796 | <0.001 |
| pT category | |||
| T3 | 1 | ||
| T4a | 1.585 | 1.276–1.968 | <0.001 |
| T4b | 2.610 | 2.055–3.314 | <0.001 |
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 1.061 | 0.773–1.456 | 0.713 |
| 75–79 | 1.102 | 0.808–1.504 | 0.538 |
| 80–84 | 1.198 | 0.882–1.628 | 0.248 |
| >84 | 2.013 | 1.507–2.690 | <0.001 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.638 | 0.480–0.847 | 0.002 |
| Widowed | 0.876 | 0.663–1.158 | 0.351 |
| Others | 0.716 | 0.393–1.303 | 0.274 |
MA, mucinous adenocarcinomas; NMA, nonmucinous adenocarcinomas; HCC, hierarchical condition categories; 5‐FU, 5‐fluorouracil; HR, hazard ratio; CI, confidential intervals.
An interaction analysis was performed between chemotherapy regimen (5‐FU or oxaliplatin) and histological type for patients with high‐risk stage II adenocarcinoma. No significant interaction effects were found in the test (P = 0.750).
CSS in stage III adenocarcinoma
The prognosis for patients with stage III NMA in the no‐chemo group was significantly worse than the 5‐FU group (P < 0.001, Fig. 4A). Similar results were also found for MA patients (P < 0.001, Fig. 4B). Patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS (P < 0.001, Fig. 4C) compared with the 5‐FU group. Likewise, we found a survival benefit for patients with stage III MA receiving oxaliplatin compared to the 5‐FU group (P = 0.023, Fig. 4D).
Figure 4.
Kaplan–Meier comparison of cancer‐specific survival among patients who received different postoperative treatment stratified by histological subtype. (A) NMA in stage III (No‐chemo vs. 5‐FU); (B) MA in stage III (No‐chemo vs. 5‐FU); (C) NMA in stage III (5‐FU vs. oxaliplatin); (D) MA in stage III (5‐FU vs. oxaliplatin).
The aforementioned results were recalculated in the PS‐matched cohorts. The prognosis of patients with stage III NMA in the no‐chemo group was significantly worse than in the 5‐FU group (P < 0.001, Fig. 5A). Similar results were also seen for MA patients (P < 0.001, Fig. 5B). Patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS (P < 0.001, Fig. 5C) compared with the 5‐FU group. However, we did not find a similar survival benefit for patients with stage III MA between the oxaliplatin and 5‐FU groups (P = 0.300, Fig. 5D). This result was also verified by a Cox proportional hazards model (Table 5 and 6). The result of the interaction analysis showed that there was a significant interaction effect seen in the test (P = 0.040).
Figure 5.
After PS‐matched, Kaplan–Meier comparison of cancer‐specific survival among patients who received different postoperative treatment stratified by histological subtype. (A) NMA in stage III (No‐chemo vs. 5‐FU); (B) MA in stage III (No‐chemo vs. 5‐FU); (C) NMA in stage III (5‐FU vs. oxaliplatin); (D) MA in stage III (5‐FU vs. oxaliplatin).
Table 6.
Cox proportional hazards model for patients in stage III stratified by histological subtype
| HR | 95% CI | P | |
|---|---|---|---|
| NMA | |||
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.601 | 0.525–0.687 | <0.001 |
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 0.986 | 0.896–1.086 | 0.781 |
| 75–79 | 1.013 | 0.917–1.119 | 0.795 |
| 80–84 | 1.294 | 1.158–1.445 | <0.001 |
| >84 | 1.627 | 1.393–1.901 | <0.001 |
| Year at diagnosis | |||
| 1992–1996 | 1 | ||
| 1997–2000 | 0.905 | 0.822–0.997 | 0.044 |
| 2001–2004 | 0.766 | 0.698–0.840 | <0.001 |
| 2005–2008 | 0.794 | 0.698–0.903 | <0.001 |
| HCC risk score | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.048 | 0.944–1.163 | 0.381 |
| 3rd quartile | 1.111 | 0.999–1.234 | 0.051 |
| 4th quartile | 1.245 | 1.116–1.388 | <0.001 |
| Number of examined lymph node | |||
| <12 | 1 | ||
| ≥12 | 0.791 | 0.738–0.848 | <0.001 |
| pT category | |||
| T1 | 1 | ||
| T2 | 0.965 | 0.718–1.298 | 0.815 |
| T3 | 1.961 | 1.523–2.525 | <0.001 |
| T4a | 2.691 | 2.062–3.510 | <0.001 |
| T4b | 4.094 | 3.112–5.385 | <0.001 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 1.856 | 1.391–2.477 | <0.001 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.307 | 1.207–1.415 | <0.001 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.884 | 0.782–1.000 | 0.049 |
| Widowed | 0.980 | 0.862–1.114 | 0.754 |
| Others | 0.949 | 0.759–1.185 | 0.642 |
| Histological grade | |||
| Well | 1 | ||
| Moderate | 1.160 | 0.975–1.381 | 0.094 |
| Poor | 1.461 | 1.221–1.749 | <0.001 |
| Undifferentiated | 1.575 | 1.143–2.172 | 0.006 |
| Unknown | 1.209 | 0.887–1.649 | 0.231 |
| Median income | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.085 | 0.982–1.199 | 0.107 |
| 3rd quartile | 1.150 | 1.028–1.286 | 0.014 |
| 4th quartile | 1.155 | 1.006–1.326 | 0.041 |
| pN category | |||
| N1a | 1 | ||
| N1b | 1.360 | 1.244–1.486 | <0.001 |
| N2a | 1.962 | 1.783–2.159 | <0.001 |
| N2b | 3.624 | 3.259–4.029 | <0.001 |
| Race | |||
| White | 1 | ||
| Black | 1.076 | 0.952–1.215 | 0.240 |
| Asian | 0.806 | 0.664–0.977 | 0.028 |
| Others | 0.975 | 0.821–1.157 | 0.771 |
| Level of education | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.041 | 0.939–1.154 | 0.445 |
| 3rd quartile | 1.148 | 1.025–1.286 | 0.017 |
| 4th quartile | 1.270 | 1.111–1.452 | <0.001 |
| Gender | |||
| Male | 1 | ||
| Female | 0.970 | 0.897–1.049 | 0.445 |
| MA | |||
| Chemotherapy regimen | |||
| 5‐FU | 1 | ||
| Oxaliplatin | 0.851 | 0.611–1.185 | 0.340 |
| Age at diagnosis, years | |||
| <70 | 1 | ||
| 70–74 | 1.136 | 0.890–1.450 | 0.306 |
| 75–79 | 1.243 | 0.975–1.586 | 0.079 |
| 80–84 | 1.602 | 1.226–2.094 | 0.001 |
| >84 | 1.326 | 0.865–2.033 | 0.195 |
| Year at diagnosis | |||
| 1992–1996 | 1 | ||
| 1997–2000 | 0.867 | 0.685–1.098 | 0.236 |
| 2001–2004 | 0.939 | 0.755–1.167 | 0.570 |
| 2005–2008 | 0.707 | 0.510–0.981 | 0.038 |
| HCC risk score | |||
| 1st quartile | 1 | ||
| 2nd quartile | 1.114 | 0.876–1.417 | 0.378 |
| 3rd quartile | 1.297 | 1.026–1.639 | 0.030 |
| 4th quartile | 1.316 | 1.029–1.683 | 0.029 |
| Number of examined lymph node | |||
| <12 | 1 | ||
| ≥12 | 0.705 | 0.596–0.834 | <0.001 |
| pT category | |||
| T1 | 1 | ||
| T2 | 1.066 | 0.476–2.386 | 0.876 |
| T3 | 2.038 | 1.048–3.965 | 0.036 |
| T4a | 3.166 | 1.589–6.308 | 0.001 |
| T4b | 4.793 | 2.358–9.742 | <0.001 |
| Intestinal obstruction | |||
| No | 1 | ||
| Yes | 1.258 | 1.021–1.549 | 0.031 |
| Marital status | |||
| Single | 1 | ||
| Married | 0.846 | 0.624–1.148 | 0.284 |
| Widowed | 0.888 | 0.645–1.222 | 0.465 |
| Others | 1.561 | 0.951–2.560 | 0.078 |
| pN category | |||
| N1a | 1 | ||
| N1b | 1.286 | 1.025–1.614 | 0.030 |
| N2a | 2.176 | 1.718–2.756 | <0.001 |
| N2b | 3.046 | 2.381–3.897 | <0.001 |
| Intestinal perforation | |||
| No | 1 | ||
| Yes | 1.443 | 0.705–2.955 | 0.316 |
| Histological grade | |||
| Well | 1 | ||
| Moderate | 0.974 | 0.688–1.378 | 0.882 |
| Poor | 1.141 | 0.794–1.640 | 0.474 |
| Undifferentiated | 1.250 | 0.577–2.709 | 0.572 |
| Unknown | 0.864 | 0.555–1.345 | 0.517 |
HCC, Hierarchical condition categories; HR, hazard ratio; CI, confidential intervals; MA, mucinous adenocarcinoma; NMA, nonmucinous adenocarcinoma; 5‐FU, 5‐fluorouracil.
FOLFOX versus CapeOx
We found no difference in survival between the FOLFOX and CapeOx group for NMA (HR: 0.817, 95% CI: 0.190–3.518, P = 0.786) and MA (HR: 0.042, 95% CI: 0.001–92710.202, P = 0.512) in high‐risk stage II patients. Similar results were found for NMA (HR: 1.128, 95% CI: 0.750–1.695, P = 0.562) and MA (HR: 0.746, 95% CI: 0.234–2.382, P = 0.618) in stage III patients. Detailed information is shown in Table 7.
Table 7.
Univariate prognostic analysis between the FOLFOX and CapeOx groups
| HR | 95% CI | P | |
|---|---|---|---|
| NMA in low‐risk stage II | 0.044 | 0.001–38913059 | 0.065 |
| NMA in high‐risk stage II | 0.817 | 0.190–3.518 | 0.786 |
| NMA in stage III | 1.128 | 0.750–1.695 | 0.562 |
| MA in low‐risk stage II | – | – | – |
| MA in high‐risk stage II | 0.042 | 0.001–92710.202 | 0.512 |
| MA in stage III | 0.746 | 0.234–2.382 | 0.618 |
MA, mucinous adenocarcinoma; NMA, nonmucinous adenocarcinoma; HR, hazard ratio; CI, confidential intervals.
Discussion
Mucinous adenocarcinoma is a relatively common histological subtype of colon adenocarcinoma, yet the clinical significance of its histological designation remains unclear. The rate of MA was 14.1% in our study and 20–30% in previous studies 20, 21. Moreover, other studies reported that MA occurred in 10–20% cases of colon cancer 22, 23. The reason may be that the definition of MA has not been consistent across studies 24. In our study, MA was defined according to the MORPHOLOGY CODE of SEER (ICD‐O‐3: 8480). Most previous studies demonstrated worse survival in MA patients compared with NMA 25, 26. However, this is contradicted by other research 22. MA is more often discovered in the proximal colon 27, and in females 23, and it generally has a more advanced stage at presentation 27. Whether MA should be considered as an independent prognostic factor is still controversial. To the best of our knowledge, there is no difference in treatment prescribed between NMA and MA. At present, the main treatment for locally advanced colon cancer is curative resection plus chemotherapy.
Most of the benefit of postoperative chemotherapy is reported in the patients with stage III disease. The benefit of chemotherapy for stage II disease is very controversial. In our study, there was no significant difference in survival for NMA and MA patients with stage II cancer between the no‐chemo and 5‐FU groups. For patients with stage III, adjuvant chemotherapy after primary surgical treatment is usually recommended 28. As would be expected, we found a survival benefit for MA and NMA patients with stage III receiving 5‐FU compared to the no‐chemo group.
Oxaliplatin is a platinum analogue that blocks DNA replication and transcription. It has been permitted in the European Union since 1999 and in the United States since 2002 29, 30. FOLFOX had proven to be highly efficient in treatment of gastrointestinal cancer, which had enabled significant progress in clinical oncology in recent years 31. Studies have found that the 10‐year OS of patients with stage III disease receiving FOLFOX was significantly increased compared with those receiving 5‐FU alone 32. However, oxaliplatin causes severe side effects which should not be ignored. These include peripheral neuropathy and gastrointestinal side effects. The primary safety concern with oxaliplatin use is peripheral neuropathy, a cumulative dose‐related toxicity which affects 90% of all treated patients 33. Incidence of grade 3 peripheral sensory neuropathy was 12.4% for patients receiving FOLFOX and only 0.2% for patients receiving 5‐FU. Moreover, Andre et al. 34 found that neuropathy was still present in 15.4% of examined patients at 4 years post‐treatment, suggesting that oxaliplatin‐induced neuropathy may not be completely reversible in some patients.
It is quite important to identify which patients could optimally benefit from oxaliplatin treatment. This study found that patients with locally advanced colon cancer whose histological type is NMA can benefit from oxaliplatin, while those with MA cannot. We compared the prognosis of patients stratified by histological type between the 5‐FU and oxaliplatin groups. We found that in stage III and high‐risk stage II MA, adding oxaliplatin to 5‐FU in the adjuvant setting did not prolong CSS. On the contrary, the oxaliplatin regimen improved CSS in NMA patients compared with the 5‐FU regimen. The results of the PS‐match and Cox proportional hazards models in high‐risk stage II and stage III patients confirmed these findings, as do the results of the interaction analysis in stage III patients. Moreover, there were a relatively small number of patients in subgroup analyses, and therefore, more studies with a larger sample size are necessary.
In spite of this, we still could not clearly define a reason for our findings. However, we elaborated upon this phenomenon to provide some preliminary data for markers identifying the efficiency of oxaliplatin in MA, and it is important to continue researching its specific mechanism in future studies.
Our findings should be interpreted in the context of several limitations. The information on perineural, vascular, and lymphatic invasion was not available in the SEER‐Medicare database. To the best of our best knowledge, no studies to date evaluated the impact of perineural, vascular, and lymphatic invasion on the sensitivity of oxaliplatin, and no definite conclusions could be made because of limited data. Therefore, more studies are necessary to address this problem more conclusively.
The nonavailability of the microsatellite instability (MSI) status in the SEER‐Medicare database was a major limitation. It was reported that 27% of MA patients were in MSI‐H status and only 12% of NMA patients were in the MSI‐H status 35. In addition, Kim reported the prognosis of MA associated with the MSI‐H status 36. It is well known that patients with MSI‐H stage II colon cancer do not benefit from 5‐FU therapy in survival 9. In contrast, whether the MSI status can affect FOLFOX efficacy in stage III patients remains controversial. A previous study found no difference between pMMR and dMMR in survival of patients with stage III colon cancer undergoing FOLFOX adjuvant chemotherapy 37. In contrast, another study indicated that survival was significantly higher in patients undergoing FOLFOX with dMMR tumors compared to those with pMMR tumors 38. Whether the MSI status interacted with the influence of MA on the efficacy of FOLFOX needs to be better studied.
In addition, few patients were aged <65 years at the time of diagnosis in our study (3.2%), which may limit the application of these findings to younger patients with colon cancer. It was reported that the efficacy of oxaliplatin was poor for older adults 8. Therefore, we took age into account when recruiting the population for the PS‐Match analysis. Moreover, it could be also a major confounding point, in that MSI and mucinous patients seem more frequent in older population. Since that, it is important to continue researching this problem in future studies.
Finally, although both a PS‐matched technique and a Cox proportional hazards model were used to eliminate known relevant confounders, the potential for confounding based on patients selection could not be eliminated completely, as it was a retrospective exploratory study. Further prospective study was needed to verify our findings in future.
In summary, for patients with resected colon cancer who received 5‐FU‐based postoperative chemotherapy, oxaliplatin chemotherapy prolongs CSS for patients with stage III and high‐risk stage II NMA. Conversely, adding oxaliplatin to 5‐FU in postoperative chemotherapy did not improve CSS for patients with stage III or high‐risk stage II MA.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Consent
The manuscript was approved by SEER‐Medicare for anonymity prior to submission for publication. Because the SEER‐Medicare data are de‐identified and are based on registry data, no prior informed consent was required.
Acknowledgments
This work was supported by National Science Foundation of China (No. 81372549, 81402520) and Clinical Capability Construction Project for Liaoning Provincial Hospitals (LNCCC‐A01‐2014).
References
- 1. Bosman, F. T. , Carneiro F., Hruban R. H., and Theise N. D.. 2010. WHO classification of tumours of the digestive system. IARC Press, Lyon. [Google Scholar]
- 2. Morson, B. C. , and Sobin L. H.. 1976. Histological typing of intestinal tumours (International histological classification of tumours, No. 15), 1st ed World Health Organization, Geneva. [Google Scholar]
- 3. Hamilton, S. R. , and Aaltonen L. A.. 2000. Pathology and genetics of tumours of the digestive system. IARC press, Lyon. [Google Scholar]
- 4. Tung, S. Y. , Wu C. S., and Chen P. C.. 1996. Primary signet ring cell carcinoma of colorectum: an age‐ and sex‐matched controlled study. Am. J. Gastroenterol. 91:2195–2199. [PubMed] [Google Scholar]
- 5. Benson, A. B. 3rd , Schrag D., Somerfield M. R., Cohen A. M., Figueredo A. T., Flynn P. J., et al. 2004. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J. Clin. Oncol. 22:3408–3419. [DOI] [PubMed] [Google Scholar]
- 6. O'Connor, E. S. , Greenblatt D. Y., LoConte N. K., Gangnon R. E., Liou J. I., Heise C. P., et al. 2011. Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J. Clin. Oncol. 29:3381–3388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Huang, X. Z. , Gao P., Song Y. X., Sun J. X., Chen X. W., Zhao J. H., et al. 2016. Impact of age on efficacy of postoperative oxaliplatin‐based chemotherapy in patients with rectal cancer after neoadjuvant chemoradiotherapy. Oncotarget 7:19643–19653. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. McCleary, N. J. , Meyerhardt J. A., Green E., Yothers G., de Gramont A., Van Cutsem E., et al. 2013. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database. J. Clin. Oncol. 31:2600–2606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Colon cancer 2017 NCCN Clinical Practice Guidelines in Oncology. www.nccn.org/patients. 2017.
- 10. Labianca, R. , Nordlinger B., Beretta G. D., Brouquet A., Cervantes A., and Group EGW . 2010. Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow‐up. Ann. Oncol. 21(Suppl 5):v70–v77. [DOI] [PubMed] [Google Scholar]
- 11. Sugawa, T. , and Yamagata S.. 1986. Differing progress patterns in cancer of the uterine cervix and variant effects of adjuvant chemotherapy based on histological type. Gan To Kagaku Ryoho 13:210–215. [PubMed] [Google Scholar]
- 12. Itaya, T. , Yamaoto N., Ando M., Ebisawa M., Nakamura Y., Murakami H., et al. 2007. Influence of histological type, smoking history and chemotherapy on survival after first‐line therapy in patients with advanced non‐small cell lung cancer. Cancer Sci. 98:226–230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. National Cancer Institute . Surveillance epidemiology and end results. Available at: http://seer.cancer.gov/index.html.
- 14. Potosky, A. L. , Riley G. F., Lubitz J. D., Mentnech R. M., and Kessler L. G.. 1993. Potential for cancer related health services research using a linked Medicare‐tumor registry database. Med. Care 31:732–748. [PubMed] [Google Scholar]
- 15. SEER‐Medicare: About the data files. Available at: http://appliedresearch.cancer.gov/seermedicare/aboutdata/.
- 16. Ash, A. S. , Ellis R. P., Pope G. C., Ayanian J. Z., Bates D. W., Burstin H., et al. 2000. Using diagnoses to describe populations and predict costs. Health Care Financ. Rev. 21:7–28. [PMC free article] [PubMed] [Google Scholar]
- 17. Sobin, L. H. , Gospodarowicz M. K., and Wittekind C.. 2009. UICC: TNM classification of malignant tumours, 7th ed Wiley‐Blackwell, Oxford. [Google Scholar]
- 18. Rubin, D. B. 1997. Estimating causal effects from large data sets using propensity scores. Ann. Intern. Med. 127:757–763. [DOI] [PubMed] [Google Scholar]
- 19. Leuven, E. , and Sianesi B.. 2015. PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing. Statistical Software Components.
- 20. Papadopoulos, V. N. , Michalopoulos A., Netta S., Basdanis G., Paramythiotis D., Zatagias A., et al. 2004. Prognostic significance of mucinous component in colorectal carcinoma. Tech. Coloproctol. 8(Suppl 1):s123–s125. [DOI] [PubMed] [Google Scholar]
- 21. Sultan, I. , Rodriguez‐Galindo C., El‐Taani H., Pastore G., Casanova M., Gallino G., et al. 2010. Distinct features of colorectal cancer in children and adolescents: a population‐based study of 159 cases. Cancer 116:758–765. [DOI] [PubMed] [Google Scholar]
- 22. Catalano, V. , Loupakis F., Graziano F., Bisonni R., Torresi U., Vincenzi B., et al. 2012. Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer. Ann. Oncol. 23:135–141. [DOI] [PubMed] [Google Scholar]
- 23. Hyngstrom, J. R. , Hu C. Y., Xing Y., You Y. N., Feig B. W., Skibber J. M., et al. 2012. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann. Surg. Oncol. 19:2814–2821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Yamaguchi, T. , Taniguchi H., Fujita S., Sekine S., Yamamoto S., Akasu T., et al. 2012. Clinicopathological characteristics and prognostic factors of advanced colorectal mucinous adenocarcinoma. Histopathology 61:162–169. [DOI] [PubMed] [Google Scholar]
- 25. Verhulst, J. , Ferdinande L., Demetter P., and Ceelen W.. 2012. Mucinous subtype as prognostic factor in colorectal cancer: a systematic review and meta‐analysis. J. Clin. Pathol. 65:381–388. [DOI] [PubMed] [Google Scholar]
- 26. Jivapaisarnpong, P. , and Boonthongtho K.. 2011. Clinicopathological characteristics of mucinous and non‐mucinous adenocarcinoma in the colon and rectum in Rajavithi Hospital, Thailand. J. Med. Assoc. Thai. 94(Suppl 2):S41–S45. [PubMed] [Google Scholar]
- 27. Chiang, J. M. , Yeh C. Y., Changchien C. R., Chen J. S., Tang R., and Chen J. R.. 2010. Mucinous adenocarcinoma showing different clinicopathological and molecular characteristics in relation to different colorectal cancer subgroups. Int. J. Colorectal Dis. 25:941–947. [DOI] [PubMed] [Google Scholar]
- 28. Des Guetz, G. , Uzzan B., Morere J. F., Perret G., and Nicolas P.. 2010. Duration of adjuvant chemotherapy for patients with non‐metastatic colorectal cancer. Cochrane Database Syst. Rev.:CD007046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Woynarowski, J. M. , Chapman W. G., Napier C., Herzig M. C., and Juniewicz P.. 1998. Sequence‐ and region‐specificity of oxaliplatin adducts in naked and cellular DNA. Mol. Pharmacol. 54:770–777. [DOI] [PubMed] [Google Scholar]
- 30. Kweekel, D. M. , Gelderblom H., and Guchelaar H. J.. 2005. Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat. Rev. 31:90–105. [DOI] [PubMed] [Google Scholar]
- 31. Huang, C. , Jiang Y., Duan G., Li Z., Chen L., and Wang X.. 2012. Effects of sequential chemotherapy of FOLFIRI/FOLFOX on the endocrine axes of ACTH‐cortisol and renin‐angiotensin‐aldosterone. J. Neurooncol. 108:485–490. [DOI] [PubMed] [Google Scholar]
- 32. Andre, T. , de Gramont A., Vernerey D., Chibaudel B., Bonnetain F., Tijeras‐Raballand A., et al. 2015. Adjuvant fluorouracil, leucovorin, and oxaliplatin in Stage II to III colon cancer: updated 10‐year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J. Clin. Oncol. 33:4176–4187. [DOI] [PubMed] [Google Scholar]
- 33. Raymond, E. , Chaney S. G., Taamma A., and Cvitkovic E.. 1998. Oxaliplatin: a review of preclinical and clinical studies. Ann. Oncol. 9:1053–1071. [DOI] [PubMed] [Google Scholar]
- 34. Andre, T. , Boni C., Navarro M., Tabernero J., Hickish T., Topham C., et al. 2009. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 27:3109–3116. [DOI] [PubMed] [Google Scholar]
- 35. Tanaka, H. , Deng G., Matsuzaki K., Kakar S., Kim G. E., Miura S., et al. 2006. BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non‐mucinous colorectal cancer. Int. J. Cancer 118:2765–2771. [DOI] [PubMed] [Google Scholar]
- 36. Kim, S. H. , Shin S. J., Lee K. Y., Kim H., Kim T. I., Kang D. R., et al. 2013. Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study. Ann. Surg. Oncol. 20:3407–3413. [DOI] [PubMed] [Google Scholar]
- 37. Sinicrope, F. A. , Mahoney M. R., Smyrk T. C., Thibodeau S. N., Warren R. S., Bertagnolli M. M., et al. 2013. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX‐based adjuvant chemotherapy. J. Clin. Oncol. 31:3664–3672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Zaanan, A. , Flejou J. F., Emile J. F., Des G. G., Cuilliere‐Dartigues P., Malka D., et al. 2011. Defective mismatch repair status as a prognostic biomarker of disease‐free survival in stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy. Clin. Cancer Res. 17:7470–7478. [DOI] [PubMed] [Google Scholar]