Rectal Adenocarcinoma: proposal for a model based on pretreatment prognostic factors.
Identifying which are the most important prognostic factors in rectal cancer would allow selection of patients with unfavorable features for whom the newer chemotherapy regimens may be of greater benefit, at the same time sparing those with favorable prognostic features from the toxicity of the newer combinations. Numerous studies have assessed the prognostic factors in colorectal carcinoma but few have focused exclusively on rectal cancer (16-58). Therefore, it is not clear whether the prognostic factors of colon and rectal cancer are equivalent. There are some data which suggest that adenocarcinoma of the rectum is biologically different from that arising in colon (59). Furthermore, the small number of studies that have examined the prognostic factors in rectal cancer separately from colon cancer have emphasized those features observed after neoadjuvant chemoradiation therapy has been completed rather than prior to such therapy (10, 34, 37, 49). However, information regarding the relevant preoperative prognostic features is needed when faced with the decision as to what type of neoadjuvant chemotherapy regimen might be preferable. Thus, the aim of this study was to assess the association between pretreatment prognostic factors and unfavorable outcomes in rectal cancer.
A retrospective review of 123 patients with rectal cancer operated at the Auxilio Mutuo Hospital, San Juan, Puerto Rico, and San Pablo Hospital, Bayamon, Puerto Rico from January 2000 through January 2007 was performed. The study population included all patients operated by two of the authors (IAE, GQ), both experienced colorectal surgeons. Of the 123 cases, 7 presented either with stage IV disease or with unresectable T4 tumors and were excluded from this analysis. Seventeen cases had missing data for carcinoembryonic antigen (CEA) levels. Thus, the study group consisted of 99 rectal adenocarcinoma cases with stage I-III presentations. The study was approved by the Institutional Review Board of Auxilio Mutuo Hospital.
The following data were collected and analyzed as potential pretreatment prognostic factors: gender, age (as a continuous variable), histologic grade (well-, moderately-, or poorly differentiated), mucinous histology (yes or no), clinical stage (I, II, or III), preoperative carcinoembryonic antigen (CEA) level (<5 or [greater than or equal to] 5 ng/ml), and lymphovascular invasion (yes or no). The level of the primary tumor within the rectum was calculated mostly by rigid proctoscopy and/or digital rectal examination and expressed as the distance from the anal verge. Low rectum was defined as 0-5 cm from the anal verge, mid-rectum as 6-10 cm and high rectum as 11-15 cm. The type of surgery performed (abdomenoperineal resection [APR], low anterior resection [LAR], local or transanal excision or others [pelvic exenteration, subtotal colectomy]) was also evaluated.
Computed tomography (CT) scans of abdomen and pelvis as well as chest x-rays or CT of chest was performed to determine preoperative clinical staging in all cases. Preoperative endorectal ultrasound (EUS) and digital rectal exam were performed for local staging in 47 cases of rectal cancer. Preoperative EUS was not done on 52 cases due to the following reasons: 27 cases had tumors in the upper part of the rectum, 2 had occlusion of rectal lumen, 2 had a preoperative diagnosis of benign polyps, and 21 for various other reasons. Preoperative local staging was performed with digital rectal exam and CT scans in the 52 patients who did not have a preoperative EUS. Evaluation for systemic disease was carried out with CT scans.
A low anterior resection was performed in patients in whom it was possible to save the sphincter; otherwise, an abdominoperineal resection was done. The surgical technique used was total mesorectal excision (TME) except in those cases that had a local excision. Highly selected cases with low rectal lesions were managed with full thickness local transanal excision.
Finally, chemoradiation was utilized preoperatively essentially for all T3 lesions with low and mid-rectal presentations. The type of chemotherapy used consisted primarily of 5-FU in varying schedules. All patients who started chemoradiation were able to proceed to surgery.
Descriptive statistics were used to portray the study group using the mean (standard deviation, SD) or median (25th and 75th percentiles) for continuous data; frequencies and proportions were used for categorical data. A comparison of selected pretreatment prognostic factors between rectal and colon cases was performed using Student's t test (or Mann-Whitney-Wilcoxon test if appropriate) and the Pearson chi-square statistic (or Fisher's exact test if applicable).
Failure free survival was defined as the length of time from surgery to first evidence of relapse or lethal toxicity from treatment. Data were censored at the last follow-up date (January 31, 2007) if no events occurred. Age-adjusted survival curves were estimated from the Cox model. To generate the age-adjusted failure free survival curves, age was categorized as < 65 years or [greater than or equal to] 65 years of age. Three statistical models were generated for the predictor variables: 1) a bivariate (crude) model for all predictors, 2) an age-adjusted model for all predictors, and 3) a multivariate model. A p <0.10 in bivariate analysis was used as the criteria for inclusion of predictors in the multivariate Cox proportional hazards regression models to assess the effect of pretreatment prognostic factors on failure free survival. No significant age group (<65 vs. [greater than or equal to] 65 years of age) interaction effect (p>0.05) with the other predictors was found; thus, age-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were computed. Due to the limited data available, it was not possible to run an interaction model with all the predictors; however, an evaluation for the possible interaction effect between the clinical stage (I vs. II & III) with the other predictors in the model was carried out and no significant interactions were observed (p>0.05); thus, multivariate HR and (95%CI) were calculated. The evaluation of the proportional hazards assumption was assessed prior to the selection of the final regression model. All statistical analyses were performed using STATA version 11 (STATA Corp., College Station, TX).
Table 1 summarizes the demographic and clinical characteristics of cancer patients. Proportion of males and female cases was 54% vs. 46%, respectively. The mean age [+ or -] SD was 62.2 [+ or -] 10.4. Among the 99 with rectal adenocarcinoma, 52.4% were moderately to poorly differentiated carcinomas, and 13.1% were mucin producing tumors. Preoperative CEA level [greater than or equal to] 5ng/ml was observed in 11.1%. Preoperative clinical stages of the cases were as follow: 33.3% stage I, 45.5% stage II, and 21.2% stage III. Male patients presented with a statistically significant higher rate of clinical stage II-III presentations compared to female patients (65.6% vs. 34.3%, respectively; p-value<0.01) (data not shown).
Preoperative chemotherapy and radiotherapy was used in 70.7% of the rectal cases. Of the 29 cases who did not receive preoperative chemoradiation, 26 (90%) presented with preoperative stage I, while 63 (90%) of the 70 cases who did receive preoperative chemoradiation presented with preoperative stage II or III. Thus, the use of preoperative chemoradiation was heavily weighted in favor of those who had more advanced preoperative stages. Low rectal presentation was seen in 45.5% of the patients, and the median distance from the anal verge was 9 cm.
EUS was performed primarily in the low and mid cases 25/36 (69%) and 19/45 (40%) respectively while only 3/11 (27%) of the high rectal cases had this study performed. By EUS criteria, 26 (55%) of the 47 patients who underwent this procedure were found to have localized disease (uN0) and the remaining 21 (45%) had uN1-2 disease. With the additional use of CT scans, another patient was found to have ctN1-2 disease for a total of 22/47 (47%).
In a comparison analysis of selected pretreatment factors for patients with rectal adenocarcinomas (n=99) or colon adenocarcinomas treated by the same surgeons (n=76), a higher proportion of preoperative CEA level [greater than or equal to] 5 ng/ml was observed among colon patients compared to rectal cases (p<0.01) whereas a trend for a higher percentage of male patients was observed among rectal cases compared to colon cancer cases (56% vs. 44%, p=0.07) (data not shown). Both groups were similar in other selected pretreatment factors such as age, histologic grade and mucin-producing tumors.
Failure free survival analysis
Of the 99 rectal adenocarcinoma patients, 18 (18.2%) relapsed. The median follow-up time of non-relapsed patients was 36.3 months (range, 0.4 to 82.1 months). Of relapsed patients, 6 (27%) were local failures (two of whom simultaneously relapsed systemically) and the remainder were exclusively systemic. The local failure rate was 5.1%. The median failure free survival time was 31.6 months.
Figure 1 shows the age-adjusted failure free survival estimates of selected pretreatment predictors. Failure free survival was significantly different for gender (p=0.01), mucin producing tumors (p=0.02), clinical stage (p=0.02) (Figure 1; A, B and C). A marginal difference was observed in the Kaplan-Meier failure free survival estimates for CEA level (p= 0.14) (Figure 1, D).
Table 2 shows the bivariate, age-adjusted and multivariate Cox proportional hazards regression models for rectal adenocarcinoma failure free survival. In bivariate analysis, male gender (HR [95% CI]: 3.61 [1.18-10.98]), mucinous type (HR [95% CI]: 3.19 [1.11-9.13]), and clinical stages II & III (HR [95% Ci]: 9.30 [1.24-69.94]) were associated with poorer failure free survival. There was a marginal trend towards a poor failure free survival in patients with CEA levels [greater than or equal to] 5 ng/ml (HR [95% CI]: 3.08 [1.00-9.53]; p=0.05). The preoperative factors age, histologic grade, lymphovascular invasion, distance from the anal verge, and type of surgery performed were not associated with a poor failure free survival. In age-adjusted analysis, a significant association was maintained for male gender (HR [95CI%]: 3.32 [1.09-10.13]), mucin producing tumors (HR [95CI%]: 3.67 [1.25-10.77]), and clinical stage (HR [95CI%]: 8.19 [1.08-62.08]). A tendency towards a poorer prognosis among patients with preoperative CEA levels [greater than or equal to] 5 ng/ml was observed although the differences were not statistically significant [HR (95%CI): 2.46 (0.77-7.83). In age-adjusted multivariate Cox regression analysis, a tendency towards a poor prognosis was observed for male gender (HR: 2.60), mucinous type carcinoma (HR: 3.67), clinical stages II & III (HR: 4.96), and CEA levels [greater than or equal to] 5 ng/ml (HR=2.55) was observed.
[FIGURE 1 OMITTED]
Recent case series reveal that the majority of patients with rectal cancer can be cured (11, 60-62). The chemotherapy regimen most commonly used as part of the chemoradiation strategy is single agent 5-FU. The toxicity associated with this drug is relatively low when compared with more recent and more effective combination regimens such as FOLFOX and FOLFIRI (12-13). Consequently it is undesirable to use these more toxic regimens to treat all patients with rectal cancer. Individualization of therapy would entail the accurate selection of those cases with poor prognostic features at diagnosis. The choice of chemotherapy regimen in rectal cancer is made prior to surgery whereas in colon cancer it is made postoperatively after the pathological stage has been determined. Thus, it is crucial to identify the pertinent pretreatment prognostic factors in rectal cancer in order to appropriately select the chemotherapy regimen. Most studies that have examined prognostic factors in rectal cancer have included postoperative factors such as the pathological response to chemoradiation. Several other studies have also recognized preoperative CEA level, gender, preoperative clinical stage, and mucinous histology as having prognostic importance. Yet, to the best of our knowledge, no studies have examined these factors using multivariable analysis strictly in the preoperative setting. Neither have any studies looked at all these prognostic factors considering rectal carcinomas separately from colon cancers. Mucinous histology has been identified as an adverse factor in some series but not in others (29, 38, 46-47, 52, 63). Our data suggest that perhaps some of the conflicting results are due to the fact that in the majority of the published literature, colon and rectal carcinomas were analyzed together without considering them as different entities thus leading to this confusion. Du et al examined the importance of mucinous histology in rectal carcinomas separately from colon (46) and their findings and conclusions are in accordance with ours in the sense that mucinous histology has an adverse impact on outcome in rectal but not in colon adenocarcinomas.
The importance of a preoperative CEA level > 5 has been shown before by several investigators and no conflicting data exist in this regard (16-17, 19, 22, 24, 30, 39, 44-45, 64-65). The explanation for this finding could be related to the biology of colorectal tumors. Human colorectal carcinomas with a preoperative CEA > 5 have a higher tumorigenic capability than those with a low CEA. This has been shown in a study using nude mice transplanted with human colorectal carcinomas derived from patients with as well as without elevated CEA preoperatively (66).
An intriguing finding from this study is the favorable outcome of females with rectal cancer. This appears to be at least in part related to the more advanced presentation seen in male patients. Preoperative stage II-III presentation was more common in males than in females. This, however, does not fully explain the inferiority in failure free survival seen in males because the multivariate Cox regression analysis still selected gender as a prognostic factor independent of preoperative clinical stage. Another possible explanation for their poor outcome is the narrower male pelvis which makes the operation more difficult. However, if that is the case, then we would expect more local relapses in males but the vast majority of failures in our series were systemic and not local, thus making this a less likely explanation for the unfavorable outcome of males. Finally, we find it intriguing that the importance of gender as a prognostic factor in rectal cancer was not observed in 126 patients with colon cancer operated by the same surgeons (data not shown).
Limitations of this study include the retrospective nature of the study design and the relatively small numbers. On the basis of our results, we recommend that further studies be conducted to assess these correlations in a larger number of patients.
In summary, our results suggest that three simple and readily available factors, CEA levels [greater than or equal to] 5 ng/ml, male gender, and clinical stage, potentially could be used to identify patients whose predicted outcome is unfavorable. We could identify these patients preoperatively and within the setting of a clinical trial treat them with a potentially more effective experimental chemoradiation regimen. However, our conclusions are derived from a multivariate model that has not been confirmed yet in an independent population of patients with rectal cancer. Until that is done, our findings have to be considered as preliminary. In addition, even though the model is robust with a highly significant p value, it is derived from a relatively small population.
Fundings provided by the National Center for Research Resources (U54 RR 026139-01A1) and the National Institute on Minority Health and Health Disparities (8U54MD007587-03) from the National Institutes of Health.
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Fernando Cabanillas, MD *; Mariely Nieves-Plaza, MS [[dagger]]; Gerardo Quevedo, MD [[double dagger]]; Ignacio A. Echenique, MD *
* University of Puerto Rico School of Medicine, San Juan, Puerto Rico; UTMD Anderson Cancer Center, Houston, Texas, United States of America; Moffitt Cancer Center, Tampa, Florida, United States of America; [[dagger]] Puerto Rico Clinical and Translational Research Consortium, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico; [[double dagger]] Private practice, San Juan, Puerto Rico
The authors have no conflicts of interest to disclose.
Address correspondence to: Fernando Cabanillas, MD, Auxilio Centro de Cancer, Ave. Ponce de Leon # 715- Piso 4. San Juan, PR 00919. E-mail: email@example.com
Table 1. Demographical and clinical characteristics of rectal cancer cases (n=99). Pre-treatment factors n (%) Gender Female 46 (46.5) Male 53 (53.5) Age, years Mean (SD) 62.2 (10.4) Median 65.0 25th-, 75th -percentiles 57, 73 Histology n=91 Well differentiated 43 (47.2) Moderately differentiated 44 (48.4) Poorly differentiated 4 (4.4) Mucin producing Yes 13 (13.1) Preoperative clinical stage I 33 (33.3) II 45 (45.5) III 21 (21.2) Preoperative CEA level, ng/ml [greater than or equal to] 5 11 (11.1) <5 88 (88.9) Lymphovascular invasion n=69 Yes 19 (27.5) Level in rectum ([dagger]) High (11-15cm) 18 (18.2) Mid (6-10cm) 36 (36.3) Low (0-5 cm) 45 (45.5) Distance from anal verge, cm Mean (SD) 7.3 (3.4) Median 7.0 Minimum-Maximum 1.0-15.0 Type of surgery APR 27 (27.3) LAR 64 (64.7) Other ([double dagger]) 8 (8.1) Preoperative chemotherapy + radiotherapy Yes 70 (70.7) Values are frequency "n" (percentages, "%") unless otherwise stated; SD: standard deviation; CEA: carcinoembryonic antigen; APR: abdominoperineal resection; LAR: lower anterior resection; ([dagger]) Measured from anal verge; ([double dagger]) Other types of surgery included pelvic exanteration, subtotal colectomy Table 2. Hazard ratios estimates and 95% confidence intervals for pretreatment factors associated with poor outcomes in rectal adenocarcinoma (N=99). Predictors Bivariate model Age-adjusted HR (95% CI) model HR (95% CI) Gender (Male) 3.61 (1.18-10.98) 3.32 (1.09-10.13) Histologic grade (moderately to poorly differentiated) 2.36 (0.83-6.73) 2.02 (0.71-5.79) Mucinous type 3.19 (1.11-9.13) 3.67 (1.25-10.77) Clinical stage (Stages II & III) 9.30 (1.24-69.94) 8.19 (1.08-62.08) Preoperative CEA [greater 3.08 (1.00-9.53) 2.46 (0.77-7.83) than or equal to] 5 ng/ml Lymphovascular invasion 1.43 (0.87-2.35) 1.38 (0.84-2.26) Distance from anal 1.28 (0.73-2.25) 1.32 (0.74-2.38) verge (>5cm) Type of surgery performed 0.70 (0.31-1.60) 0.73 (0.31-1.72) (APR) Predictors Multivariate model ([dagger]) HR (95% CI) Gender (Male) 2.60 (0.80-8.40) Histologic grade (moderately to poorly differentiated) -- Mucinous type 2.96 (0.97-8.98) Clinical stage (Stages II & III) 4.96 (0.62-39.95) Preoperative CEA [greater 2.55 (0.75-8.62) than or equal to] 5 ng/ml Lymphovascular invasion -- Distance from anal -- verge (>5cm) Type of surgery performed -- (APR) * Multivariate model was age-adjusted, model R2: 0.13; HR: Hazard ratio; CI: Confidence interval; CEA: carcinoembryonic antigen; APR: abdominoperineal resection