Research Article
Preoperative Indicators of Poor Outcome in Locally Advanced Rectal Cancer at a County Hospital
Aaron B Parrish1, Brian W Mac Laughlin1, Nicholas C Figueroa2, Gregory R Bryant2, Amy H Kaji3, Patrick C Choi2 and Ravin R Kumar1*
1Department of Surgery, Harbor-UCLA Medical Center, USA
2Department of Radiology, Harbor-UCLA Medical Center, USA
3Department of Emergency Medicine, Harbor-UCLA Medical Center, USA
*Corresponding author: Ravin R Kumar, Department of Surgery, Harbor UCLA Medical Center, 1000 W. Carson St., Bldg. 1 East, Box 25 Torrance, California 90502, USA
Published: 27 Dec, 2016
Cite this article as: Parrish AB, Mac Laughlin BW, Figueroa
NC, Bryant GR, Kaji AH, Choi PC, et
al. Preoperative Indicators of Poor
Outcome in Locally Advanced Rectal
Cancer at a County Hospital. Clin Surg.
2016; 1: 1263.
Abstract
Background: Locally advanced rectal cancer (LARC) is associated with high rates of both local and metastatic recurrence. Preoperative predictors can help determine which patients are at risk for
recurrence.
Methods: A retrospective analysis of LARC patients at a county institution. Patients were grouped
into that disease free at 2 years vs. those with unrepeatability or recurrence. Variables analyzed were
available preoperatively and included demographics, tumor characteristics, and laboratory values.
Results: Out of96 patients, 55 had a successful outcome (SO) and 31 had an unsuccessful outcome
(UO). On univariate analysis, significant predictors of UO were larger tumor size (p=0.002),
extension into levator ani muscles (p=0.001), lower albumin (p=0.006), lower hemoglobin (p=0.02),
and lower MCV (p=0.04). The only significant variable on multivariate analysis was extension into
levators (OR 5.6, CI 1.5-21.1).
Conclusion: LARC patients found to have these high risk characteristics are more likely to have an
unresectable cancer or recurrence. These patients should be considered for additional imaging after
neoadjuvant chemoradiation, as it may lead to a change in the operative plan.
Introduction
The usual method for predicting outcomes in patients with rectal cancer prior to surgery has classically been by local staging with endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI) and distant staging with computed tomography (CT). Studies have shown additional factors available preoperatively can predict worse outcome in rectal cancer, most notably an elevated carcinoembryonic antigen (CEA) and anemia [1-7]. Other predictive factors have included: older age, male sex, clinically positive lymph nodes, tumor histologic grade, CRP, and ca-19-9 [8-13]. Patients with locally advanced rectal cancer (LARC) routinely receive neoadjuvant chemoradiotherapy (CRT) as it decreases local recurrence and improves disease free survival as compared with postoperative CRT [14,15]. However, recurrence is still high with rates of local and metastatic recurrence of 2-7% and 18-33%, respectively [16,17]. While recurrence has been shown to be associated with positive circumferential resection margins (CRM), identifying those at risk for a positive CRM has not been clearly elucidated [18]. Our objective was to assess factors available preoperatively and their ability to predict outcomes in patients with LARC, with the hope that this may change management and improve patient expectations.
Table 1
Table 2
Methods
After institutional review board approval, a retrospective review of medical records and CT
imaging at a county teaching hospital was completed. All patients were operated on for curative
intent with LARC (American Joint committee on Cancer [AJCC] stage II or III) between 2006 and
2014 and had at least two years of follow-up. All patients received preoperative neoadjuvant CRT of
fractionated radiation of 45-50 Gy and either Capecitabin or 5-Fluorouracil.
Patients were initially divided into two groups based on their outcome. Curative resection and
absence of disease at two years is considered a Successful Outcome (SO), while unrepeatability, local
recurrence, and distant metastasis are considered an Unsuccessful Outcome (UO). A secondary
analysis was made between the SO patients and patients with recurrence only (RO).
Variables assessed were available preoperatively and included
demographics, such as age, sex, body mass index (BMI), ethnicity,
smoking/alcohol use, and family history of colorectal cancer. We
also looked at presenting symptoms, tumor characteristics such
as tumor distance from the anal verge, tumor size (measured on
pathology), extension into the levator muscles seen on initial CT,
depth of penetration seen on EUS (clinical T stage), nodal status,
AJCC clinical stage, and histologic degree of differentiation. Finally
we assessed laboratory values; CEA both before and after neoadjuvant
CRT, albumin at diagnosis, hemoglobin at diagnosis, and mean
corpuscular volume (MCV) at diagnosis.
CT scans were analyzed by radiologists at the time of data
collection and included only CT scans obtained prior to neoadjuvant
CRT. Levator ani extension was defined as soft tissue density or fat
stranding extending from the suspected rectal mass into these muscles.
The lack of a clear fat plane was considered invasion. On multiplanar
evaluation, if the fat planes were homogeneous and similar in
Hounsfield Units to adjacent perirectal fat, it was considered negative.
Instances of involvement within 2mm of the levator ani muscle were
considered involved.
The data were entered and maintained in a Microsoft Excel
(Excel; Microsoft Corp, Redmond, WA) worksheet and were then
exported and translated into native SAS (SAS Institute, Cary, NC)
format. Data were then analyzed using SAS 9.4. A univariate analysis
was performed to compare the SO and the UO cohorts, as well as
the SO to the RO cohort. Categorical characteristics (e.g. gender,
smoking, etc.) are described as proportions or percentages, and
proportional differences are described as odds ratios with 95%CI.
Chi-squared or Fisher’s exact p-values are described, as appropriate.
Continuous variables (e.g., age, distance from anal verge, etc.) are
described as medians and interquartile ranges, and the differences
between the cohorts are described as median differences with the
associated 95% CI. The reported p-values are derived from the nonparametric
Wilcox on rank sum test, used to describe the difference
between non-normally distributed continuous variables. There was
no correction made for multiple testing. A multivariable analysis
incorporating significant univariate factors was also performed to
identify independent predictors of UO.
Table 3
Results
There were a total of 96 patients with LARC operated on for
curative intent. Ten patients were excluded due to having less than
2 years of follow-up. Fifty-five patients had a successful outcome and
31 patients had an unsuccessful outcome. Of the 31 patients with an
unsuccessful outcome, 10 patients were found to be unresectable at
the time of surgery, 11 patients developed local recurrence, and 10
patients developed distant metastasis. The mean time to diagnosis of
the recurrence was 1.25 years.
There were several significant indicators for an unsuccessful
outcome on univariate analysis seen in table 1. These included tumor
size both as a continuous variable (p=0.002) and when dichotomized
to >/=3 cm (p=0.02), extension into levator ani muscles (p=0.001),
albumin at diagnosis (p=0.006), hemoglobin at diagnosis (p=0.02),
and MCV at diagnosis (p=0.04). Multivariate analysis (Table 2)
including the five variables found to be significant on univariate
analysis, identified that extension into the levator ani muscles was
the only independent predictor of UO (OR 5.6, CI, 1.5-21.1). Table 3
shows the UO patients with extension into levator ani muscles: 6 of 11
patients had a positive resection margin, 5 corresponding to positive
CRM. Of the 10 patients with SO and extension into levator muscles,
9 of 10 underwent abdominoperineal resection (APR) and one had a
positive CRM.
When comparing SO with RO patients, univariate analysis of the
same variables yielded significance for extension into the levator ani
muscles 23.8% SO vs. 64.7% RO (p=0.003), and tumor size 2.0 (1.2-
3.2) SO vs. 3.0(2.2-4.5) RO, (p=0.02).
Discussion
The goal of this study was to identify characteristics that may
be identified preoperatively that are associated with unrepeatability
or local recurrence. This could result in a decrease in unnecessary
operations for those that are unresectable, or an opportunity to
provide tailored treatment (i.e. additional chemotherapy, extended
resection margin) for patients with high risk features.
This study found various predictors that can identify patients at
high risk for unrepeatability or recurrence. The strongest predictor
of poor outcome was levator ani extension identified on preneoadjuvant
CRT CT scan. On review of these CT scans, 26 out of the
67 CT scans reviewed had this finding and 62% of these patients had
a poor outcome. This shows that a majority of patients with tumor
extension into the levator ani muscles went on to have either an
unresectable tumor or recurrence. Therefore, this finding alone may
warrant additional preoperative evaluation.
The high likelihood of poor outcome with levator ani muscle
extension is likely related to its ability to lead to a positive CRM.
Nagtegaal and Quirke have shown that a positive CRM is the most
significant finding leading to recurrence [18]. In our study, five out of
six patients with positive CRM and levator ani muscle extension had a
poor outcome. If this finding remains present on repeat imaging after
neoadjuvant CRT, then additional considerations for management
should be made. This could include surgical planning for a wider
CRM, possibly necessitating en bloc resection of adjacent organs, or
additional systemic chemotherapy prior to operation.
Additionally, our study found that larger tumor size and
specifically tumors greater than 3 cm are associated with both an
unsuccessful outcome and recurrence. This indicates that tumor
size may be an important prognostic indicator in addition to the
AJCC clinical stage. While it may seem intuitive that a larger tumor
is associated with poor outcome, current staging of rectal cancer
includes depth of penetration only, and does not account for tumor
size [19]. The tumor size in our study was measured on gross pathology
after formalin fixation, however this value could be estimated on a
preoperative imaging study and used as a predictor of outcome.
The laboratory findings included a significantly lower albumin,
hemoglobin, and MCV at the time of diagnosis are predictive of
an unsuccessful outcome. Low albumin serves as a marker for
malnutrition, and low hemoglobin and MCV are markers for
microcytic anemia. Regarding malnutrition, this is likely due to
the more advanced disease state of the patients with unsuccessful
outcome. Regarding anemia, studies have reported increased
likelihood of local recurrence, decreased survival as well as reduced
effectiveness of neoadjuvant CRT in anemic patients [4-7]. It is
possible that this effect is due to the previously reported decreased
efficacy of radiotherapy in hypoxic tissue, leading to ineffective CRT
[5]. It is also possible these tumors are further along in the oncogenic
process, are more prone for blood loss, and the resulting anemia is just
an indicator for more advanced disease. Regardless, these laboratory
indicators show only that a lower value raises the likelihood of UO
without a definitive cut-point; studies have used multiple cutoffs for
hemoglobin measurements in showing prognostic significance and
there is no consensus value at this point [5,7]. Therefore, additional
studies are needed to determine a specific value relevant for predicting
a poor outcome.
Limitations of this study include the retrospective nature of the
chart review, and a small sample size. Given a larger sample size,
other factors may have been found to be predictive of UO. There
were also ten patients that were operated on for curative intent but
were unresectable. The authors of this study recognize this number
is high, and believe this is due to our patient populations’ advanced
disease and our lack of re-imaging these patients to detect adequacy
of response to neoadjuvant CRT. These patients represent the most
significant clinical application of this research. If these patients
were identified preoperatively as high risk for poor outcome and
had additional preoperative imaging, many may have avoided an
operation.
Conclusion
This study identified significant predictors of poor outcome. These high-risk patients represent a patient population that would benefit from re-staging CT, MRI, or EUS after neoadjuvant CRT. This additional information could help with advanced surgical planning to obtain better radial clearance, or it may warrant delaying surgery for administration of additional chemotherapy to further downstage the tumor.
References
- Szynglarewicz B, Matkowski R, Forgacz J, Pudelko M, Smorag Z, Dryl J, et al. Clinical factors in prediction of prognosis after anterior resection with total mesorectal excision for carcinoma of the rectum. Oncol Rep. 2007; 17: 471-475.
- Giessen C, Nagel D, Glas M, Spelsberg F, Lau-Werner U, Modest DP, et al. Evaluation of preoperative serum markers for individual patient prognosis in stage I-III rectal cancer. Tumour Biol. 2014; 35: 10237-10248.
- Jang NY, Kang S-B, Kim D-W, Kim JH, Lee K-W, Kim IA, et al. The role of carcinoembryonic antigen after neoadjuvant chemoradiotherapy in patients with rectal cancer. Dis Colon Rectum. 2011; 54: 245-252.
- van Halteren HK, Houterman S, Verheij CDGW, Lemmens VEPP, Coebergh JWW. Anaemia prior to operation is related with poorer longterm survival in patients with operable rectal cancer. Eur J Surg Oncol. 2004; 30: 628-632.
- Lee SD, Park JW, Park KS, Lim S-B, Chang HJ, Kim DY, et al. Influence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Colorectal Dis. 2009; 24: 1451-1418.
- Rades D, Kuhn H, Schultze J, Homann N, Brandenburg B, Schulte R, et al. Prognostic factors affecting locally recurrent rectal cancer and clinical significance of hemoglobin. Int J Radiat Oncol Biol Phys. 2008; 70: 1087- 1093.
- Khan AA, Klonizakis M, Shabaan A, Glynne-Jones R. Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long-term outcomes in patients with locally advanced rectal cancers. Colorectal Dis. 2013; 15: 1232-1237.
- Valentini V, van Stiphout RGPM, Lammering G, Gambacorta MA, Barba MC, Bebenek M, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol. 2011; 29: 3163-3172.
- Bown EJ, Lloyd GM, Boyle KM, Miller AS. Rectal cancer: prognostic indicators of long-term outcome in patients considered for surgery. Int J Colorectal Dis. 2014; 29: 147-155.
- Mirbagheri N, Kumar B, Deb S, Poh BR, Dark JG, Leow CC, et al. Lymph node status as a prognostic indicator after preoperative neoadjuvant chemoradiotherapy of rectal cancer. Colorectal Dis. 2014; 16: 339-346.
- Kraemer M, Wiratkapun S, Seow-Choen F, Ho YH, Eu KW, Nyam D. Stratifying risk factors for follow-up: a comparison of recurrent and nonrecurrent colorectal cancer. Dis Colon Rectum. 2001; 44: 815-821.
- Toiyama Y, Inoue Y, Saigusa S, Kawamura M, Kawamoto A, Okugawa Y, et al. C-reactive protein as predictor of recurrence in patients with rectal cancer undergoing chemoradiotherapy followed by surgery. Anticancer Res. 2013; 33: 5065-5074.
- Zhang L-N, OuYang P-Y, Xiao W-W, Yu X, You K-Y, Zeng Z-F, et al. Elevated CA19-9 as the Most Significant Prognostic Factor in Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiotherapy. Medicine (Baltimore). 2015; 94: e1793.
- Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004; 351: 1731-1740.
- Roh MS, Colangelo LH, O’Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009; 27: 5124-5130.
- Arredondo J, Baixauli J, Beorlegui C, Arbea L, Rodríguez J, Sola JJ, et al. Prognosis factors for recurrence in patients with locally advanced rectal cancer preoperatively treated with chemoradiotherapy and adjuvant chemotherapy. Dis Colon Rectum. 2013; 56: 416-421.
- Roses RE, Rodriguez-Bigas MA. The Management of Rectal Cancer. In: Current Surgical Therapy, 11th edn. Cameron JL, Cameron AM, editors. Elsevier Sanders: Philadelphia, PA. 2013; 218-224.
- Nagtegaal ID, Quirke P. What Is the Role for the Circumferential Margin in the Modern Treatment of Rectal Cancer? J Clin Oncol. 2008; 26: 303- 312.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. 2016.