• rectal cancer, neoadjuvant therapy, adjuvant therapy, chemotherapy, Surveillance, Epidemiology, and End Results (SEER);
  • SEER-Medicare


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  2. Abstract


Neoadjuvant chemoradiotherapy followed by tumor resection and postoperative chemotherapy is the standard of care for patients with clinical stage II or III adenocarcinoma of the rectum. Significant variation exists in the receipt of postoperative chemotherapy after resection in this population. The objective of this study was to determine the demographic and clinicopathologic factors associated with the initiation of postoperative chemotherapy in elderly patients with rectal cancer and to identify potential targets for reducing treatment variation.


A retrospective cohort study was performed of patients with rectal cancer ages 66 to 80 years who received neoadjuvant chemoradiotherapy and underwent radical resection in the Surveillance, Epidemiology, and End Results-linked Medicare database (1998-2007). Multivariate logistic regression was used to assess chemotherapy use in relation to patient, tumor, and treatment response characteristics.


Among 1492 patients who met the study criteria, 61.5% received adjuvant therapy with 5-fluorouracil. Pathologic stage was the strongest determinant of whether patients received postoperative chemotherapy (48.3% of patients with stage I disease, 59.6% of patients with stage II disease, and 77.6% of patients with stage III disease). Increasing age and postoperative readmission also were associated significantly with a decreased rate of adjuvant therapy initiation.


Although standard treatment guidelines for locally advanced rectal cancer include postoperative chemotherapy for all patients after neoadjuvant chemoradiotherapy and radical resection, greater than 1 in 3 patients failed to receive adjuvant therapy. Despite the absence of established evidence, treatment decisions appear to be influenced by the findings at surgical pathology. Cancer 2014;120:1162–1170. © 2014 American Cancer Society.


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  2. Abstract

It is estimated that rectal cancer will affect 42,820 individuals in 2013 and will account for approximately 66% of the 50,830 colorectal cancer deaths.[1] Adherence to evidence-based colorectal cancer treatment guidelines is variable, and previous studies have demonstrated that patients frequently do not receive adjuvant therapy for cancer of the colon and rectum.[2] Reasons for omission of adjuvant therapy are not always apparent but may include nonclinical factors, such as patient preference, provider beliefs, and access to care, in addition to clinical factors, such as patient comorbidity, surgical complications, and prolonged postoperative recovery.

The current standard of care for stage II and III rectal adenocarcinoma is neoadjuvant chemoradiotherapy followed by radical resection and adjuvant chemotherapy. Multiple clinical trials have demonstrated a benefit to local control using this approach with a potential for survival benefit as well.[3, 4] Although this course of therapy often results in substantial tumor regression, current recommendations are based on clinical staging, not post-therapy pathologic staging. However, it is increasingly becoming recognized that response to neoadjuvant chemoradiotherapy may signal tumor chemosensitivity and is an important biomarker for long-term outcome.[5, 6] Clinical guidelines, like those from the National Comprehensive Cancer Network, recommend that all patients who receive neoadjuvant chemoradiation also receive adjuvant chemotherapy after resection, yet it is clear that not all patients do so, even in specialty cancer centers.[7, 8] The factors that contribute to the omission of chemotherapy after tumor resection are not well understood, but variability in treatment and outcomes has been linked to socioeconomic status (SES), race, age, and other factors.[9-13] However, in patients who receive neoadjuvant therapy, poor access to care is unlikely to be a major contributor to nonreceipt of adjuvant chemotherapy, because they have established relationships with a medical oncologist. We sought to understand the factors associated with receipt of adjuvant therapy in patients with rectal cancer after neoadjuvant chemoradiation and radical resection. In addition, we examined temporal trends in the administration of adjuvant therapy, including the use of multiagent regimens.


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  2. Abstract

For this study, we used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database 2009 release, including all Medicare-eligible patients who appeared in the SEER data set from 1991 to 2007 and their Medicare claims through December 2009. The National Cancer Institute's SEER Program is a comprehensive source of population-based information on cancer incidence and patient survival data from designated cancer registries in the United States, representing approximately 26% of the US population.[14]

Medicare provides health insurance to 97% of individuals aged ≥65 years in the United States and is comprised of Part A, which covers inpatient and home health care, and Part B, which provides more comprehensive benefits, including outpatient care and physician services.[15] The Medicare database complements SEER with treatment and diagnosis details and dates of service.

Approximately 93% of patients aged ≥65 years in the SEER files were successfully linked to the Medicare enrollment file.[16] The linked SEER-Medicare data are contained in a series of files, including the Patient Entitlement and Diagnosis Summary File (SES and Medicare and health maintenance organization enrollment information), the Medicare Provider Analysis and Review (MEDPAR) file (Part A claims), the National Claims History (NCH) file (Part B claims), and the Outpatient Standard Analytic File (SAF) (Part B claims).

Patients ages 66 to 80 years with pathologic stage I through III rectal (SEER site recode 26) adenocarcinoma (SEER histology codes 8140, 8210-8211, 8220-8221, 8260-8263, 8480-8481, and 8490) in from 1998 to 2007 were selected for inclusion. Disease stage was based on the American Joint Committee on Cancer Cancer Staging Manual, seventh edition. Patients who had stage I disease after neoadjuvant treatment were included, because these patients are expected to have had clinical stage II or III cancers before neoadjuvant treatment. Patients aged 65 years were excluded because lack of claims preceding diagnosis precluded comorbidity index estimation. Because chemotherapy and radiation were principally delivered in noninstitutional settings, continuous enrollment in both Medicare Parts A and B was required from 12 months before diagnosis (to allow the measurement of prior comorbidity) through the earliest of 24 months after diagnosis, death, or December 31, 2009. Medicare beneficiaries who participated in health maintenance organizations were excluded to ensure completeness of claims. Other exclusion criteria included undocumented month of diagnosis; a second primary cancer diagnosis within 24 months; or diagnosis initially noted on nursing/convalescent home/hospice summary, death certificate, or autopsy report.

Patients who underwent primary tumor resection (PTR) within 6 months after diagnosis were identified. We searched the MEDPAR, NCH, and SAF files to identify the earliest claim indicating PTR.[17] Local excision and ostomy were not considered definitive surgery. We used the first day of the month of diagnosis to estimate the interval to the date of service. We then identified patients who received both neoadjuvant pelvic radiation and 5-fluorouracil (5-FU) chemotherapy before PTR; patients who had claims consistent with radiotherapy[18] and chemotherapy[19] in the MEDPAR, NCH, or SAF files were considered recipients of neoadjuvant chemoradiation.

The primary outcome of interest in this study was the initiation of adjuvant chemotherapy among patients with stage I through III rectal cancer who received neoadjuvant chemoradiation. After chemoradiation and PTR, patients who had claims indicating the receipt of 5-FU–based chemotherapy in the MEDPAR, NCH, or SAF files at any point within the 6-month postoperative period were considered as having received adjuvant chemotherapy. After 2004, claims indicating the use of oxaliplatin could be identified.

Patient age at diagnosis, sex, race, marital status, SES, diagnosis year, tumor stage, tumor grade, SEER-based geographic location, and residence were obtained from the Patient Entitlement and Diagnosis Summary File. SES was determined based on median annual household income, the percentage of individuals aged ≥25 years with <12 years education, and the percentage of individuals living below the poverty line based on Census 1990 and 2000 data. Because these variables were highly correlated with each other, they were standardized and equally weighted to create a composite SES variable for analysis, which was then categorized into quartiles.

We calculated comorbidity scores according to the methodology described by Charlson et al and Romano et al.[20, 21] We searched both the MEDPAR file and the NCH file for 19 predefined noncancer illnesses that were coded from 1 year before to 1 month after the date of diagnosis to create comorbidity scores that were categorized into 0, 1, or ≥2 comorbid conditions according to the National Cancer Institute-provided SAS macro (available at: Postoperative readmissions were defined as occurring within 30 days of operation and identified from the MEDPAR file.

Socioeconomic and clinical variables for all patients and their relation to adjuvant chemotherapy initiation were assessed using chi-square tests. Multivariate logistic regression analysis was used to assess the relation of these variables to the initiation of adjuvant chemotherapy while controlling for potential confounding effects of patient demographics, tumor factors, and treatment-related variables. Odds ratios (OR) and 95% confidence intervals (CIs) were derived. All reported P values are 2-sided and considered significant at the .05 level. We used SAS (version 9.1.3; SAS Institute, Cary, NC) for data processing and Stata MP (version 11.0; StataCorp, College Station, Tex) for statistical analyses.


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  2. Abstract

We identified 1492 patients who received chemoradiation before undergoing rectal resection from the SEER-Medicare–linked database and met our inclusion criteria in the years from 1998 to 2007 (Table 1). Patient characteristics are provided in Table 2. Greater than 33% of patients were between ages 66 and 70 years (n = 567; 38%), and a similar proportion were between ages 71 and 75 years (n = 555; 37.2%). The majority of patients were men (n = 879; 58.9%), white (n = 1340; 89.8%), and resided in large metropolitan or metropolitan areas (n = 782 [52.4%] and n = 423 [28.4%], respectively). A slightly larger proportion of patients underwent low anterior resection (n = 658; 44.1%) versus abdominoperineal resection (n = 596; 39.9%).

Table 1. Patient Selection and Exclusion Criteria
CriteriaNo. of PatientsPercentage of Initially Identified Patients Remaining in the Analytic Cohort
  1. Abbreviations: SES, socioeconomic status.

Patients with stage I-III rectal adenocarcinoma who received chemoradiation during 1998 to 2007 (n = 1982)1982100
Excluding patients who had a second primary cancer diagnosis within 24 mo (n = 133)184993
Excluding patients who survived <6 mo after primary tumor resection (n = 114)173588
Excluding patients with unconfirmed diagnosis or diagnosis noted on nursing/convalescent home/hospice, death certificate, or autopsy report (n = 4)173187
Excluding patients aged >80 y (n = 229)150276
Excluding patients with missing SES (n = 10)149275
Table 2. Baseline Characteristics of Neoadjuvant Chemoradiation-Treated Stage I-III Rectal Cancer Patients and the Proportion That Initiated Adjuvant Chemotherapy (N = 1492)
CharacteristicNo. of Patients (%)Proportion Initiating Adjuvant Chemotherapy Within 6 Mo After Surgery, %P
  1. Abbreviations: APR, abdominoperineal resection; LAR, low anterior resection; Metro, metropolitan area; SEER; Surveillance, Epidemiology, and End Results; SES, socioeconomic status.

  2. a

    Other surgery indicates unspecified resection of the large intestine.

Overall1492 (100)61.5 
Age at diagnosis, y  .001
66-70567 (38)67.4 
71-75555 (37.2)58.9 
76-80370 (24.8)56.5 
Sex  .652
Men879 (58.9)62 
Women613 (41.1)60.8 
Race/ethnicity  .461
White1340 (89.8)61.1 
Black65 (4.4)61.5 
Other/unknown87 (5.8)67.8 
Composite SES quartile  .039
Top373 (25)67.8 
Second373 (25)59.5 
Third373 (25)59.8 
Bottom373 (25)59 
Residence  .246
Big metro782 (52.4)64.1 
Metro423 (28.4)59.1 
Urban99 (6.6)55.6 
Less urban136 (9.1)58.1 
Rural52 (3.5)63.5 
Post-therapy pathologic stage  < .001
I294 (19.7)48.3 
II502 (33.6)59.6 
III366 (24.5)77.6 
Unknown330 (22.1)58.5 
Grade  .160
Well and moderately differentiated1069 (71.6)61.5 
Poorly differentiated and undifferentiated226 (15.1)65.9 
Unknown197 (13.2)56.9 
Comorbidity index  .169
01037 (69.5)63 
1341 (22.9)59.2 
>2114 (7.6)55.3 
Postoperative readmission  < .001
No1310 (87.8)63.9 
Yes182 (12.2)43.9 
Year of diagnosis  .044
1998-1999142 (9.5)57.7 
2000-2001296 (19.8)56.4 
2002-2003343 (23)59.8 
2004-2005361 (24.2)63.4 
2006-2007350 (23.5)67.1 
Type of surgery  .010
APR596 (39.9)58.9 
LAR658 (44.1)63.5 
Other surgerya238 (16)51.1 
SEER region  .075
West589 (39.5)59.4 
Midwest225 (15.1)60.4 
Northeast345 (23.1)67.5 
South333 (22.3)59.8 

Overall, 61.5% of patients who underwent rectal resection after neoadjuvant chemoradiation subsequently received adjuvant chemotherapy. On univariate analysis, older patients were less likely to initiate adjuvant therapy; although 67.4% of patients ages 66 to 70 years initiated adjuvant treatment, only 56.5% of those ages 76 to 80 years did so (P = .001). Patients with higher SES initiated adjuvant chemotherapy more often than those from lower SES strata (67.8% in the highest quartile vs 59% in the lowest quartile; P = .039) as did those who were diagnosed more recently (67.1% of those diagnosed during 2006-2007 vs 57.7% of those diagnosed during 1998-1999; P = .044). Readmission within 30 days of operation occurred for 12.2% of patients. Readmission was associated with a decreased rate of initiating adjuvant chemotherapy on univariate analysis (43.9% vs 63.9% for those without readmission; P < .001) Patients with higher post-treatment pathologic stage tumors were more likely to receive adjuvant treatment (77.6% of patients with stage III disease vs 48.3% of patients with stage I disease; P < .001), as were patients who underwent low anterior resection (63.5%; P = .010). Sex, race, marital status, patient comorbidity, tumor grade, and SEER region were not associated with a significant difference in adjuvant therapy initiation rates on univariate analysis.

Figure 1 illustrates the effect size by hypothesis tests for each of the individual variables in the model. The horizontal bar (Wald chi-square statistic) represents the strength of association with the outcome. Post-treatment pathologic tumor stage was strongly associated with chemotherapy initiation; patients who had pathologic stage III tumors had an OR of 3.87 (95% CI, 2.72-5.51) for initiating adjuvant therapy compared with those who had stage I tumors (Table 3). Patients who had stage II or unknown post-treatment stage had intermediate odds (OR, 1.57 [95% CI, 1.16-2.14] and OR 1.56 [95% CI, 1.11-2.18], respectively). Postoperative readmission was associated with decreased odds of initiating adjuvant therapy (OR, 0.4; 95% CI, 0.28-0.56), as was increasing age at diagnosis (OR, 0.58; 95% CI, 0.43-0.78 for ages 75-79 years). A more recent year of diagnosis also was associated with higher odds of initiating adjuvant therapy (OR, 1.64; 95% CI, 1.06-2.56 for the years 2006-2007).


Figure 1. This chart illustrates a type 3 analysis of effect derived from multivariate logistic regression. AJCC indicates American Joint Committee on Cancer; SEER, Surveillance, Epidemiology, and End Results Program.

Download figure to PowerPoint

Table 3. Factors Associated With Initiation of Adjuvant Chemotherapy After Rectal Resection With Preoperative Chemoradiation and With the Use of an Oxaliplatin-Containing Regimen Among Those Who Initiated Chemotherapya
 Association With Chemotherapy InitiationAssociation With the Use of an Oxaliplatin-Containing Regimenb
VariableOR95% CIOR95% CI
  1. Abbreviations: CI, confidence interval; OR, odds ratio; Ref, reference category.

  2. a

    The model also was adjusted for Surveillance, Epidemiology, and End Results region; marital status; residence; comorbidity index; socioeconomic status; type of primary surgery received; race; tumor grade; and sex.

  3. b

    The model was unadjusted for year of diagnosis, because approval of oxaliplatin was obtained in November 2004.

Post-therapy pathologic stage   
Postoperative readmission  
Age at diagnosis, y  
Year of diagnosis   

Temporal changes in both the proportion of patients undergoing adjuvant chemotherapy and the type of agents were noted. No patients received oxaliplatin before 2002. Beginning in 2003, an increasing proportion of patients received combination therapy. (Fig. 2) In 2004 (the year the US Food and Drug Administration approved oxaliplatin for colorectal cancer), only 18.1% of patients who underwent adjuvant therapy received an oxaliplatin-containing regimen. In 2007, this proportion increased to 39%. The multivariate analysis depicted in Table 3 indicates that older patients were less likely to receive a regimen that included oxaliplatin (OR, 0.57; 95% CI, 0.38-0.84 for patients ages 75-79 years), whereas patients with pathologic stage III tumors were more likely to have oxaliplatin included in their regimen (OR, 1.78; 95% CI, 1.10-2.88).


Figure 2. This chart illustrates the type of chemotherapy received over time from 1998 to 2007 (N = 1492).

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  1. Top of page
  2. Abstract

Current guidelines for the treatment of stage II and III rectal adenocarcinoma recommend neoadjuvant chemoradiation followed by surgical resection and adjuvant chemotherapy. In this study of patients from the SEER-Medicare–linked database, a large number of patients who underwent neoadjuvant therapy and subsequent resection did not receive adjuvant chemotherapy. This is unlikely to be explained by issues of access, especially because all patients in this cohort received preoperative chemoradiation and, thus, we can assume that they were connected to a medical oncologist. In addition, treatment with neoadjuvant therapy is a marker for commitment to a multimodality strategy of care and coordination of teams to provide this care. Instead, patient and provider preferences and beliefs are likely to play a large role in decisions regarding adjuvant therapy in this setting.

The strongest predictor of the initiation of adjuvant chemotherapy in this patient cohort was pathologic tumor stage; patients who had post-treatment pathologic (yp) stage III tumors were nearly 4 times as likely as those with stage ypI tumors to receive adjuvant therapy. However, there are not good data to support using high post-treatment stage to determine need for further chemotherapy. In fact, some data suggest that those patients who have no or limited response to 5-FU–based neoadjuvant therapy (ie, those with high pathologic stage) benefit least from adjuvant 5-FU chemotherapy, whereas those who have a better response (eg, a pathologic complete or partial response) benefit more.[22] The data presented here suggest that current practice patterns do not reflect this and that further study is necessary to understand which patients gain a meaningful survival advantage from adjuvant therapy after neoadjuvant treatment and resection. Although it is acknowledged that additional data regarding the benefits of adjuvant chemotherapy among patients with rectal cancer are needed, given the existing data, efforts should be made to educate patients and health care providers on criteria for pursuing adjuvant therapy after rectal resection.

Surgical complications can lead to a delay in the initiation of adjuvant chemotherapy. However, prolonged postoperative recovery cannot fully explain gaps in adjuvant therapy administration. Although patients in the SEER-Medicare cohort were less likely to receive adjuvant therapy if they were readmitted, nearly half still did, whereas <66% of those without readmission initiated postoperative chemotherapy. These findings are consistent with previous studies, which demonstrated that complications were a significant factor in the omission of postoperative chemotherapy but only explained a minority of such omissions.[23] The inclusion of readmission in our model did not substantially affect the strong association between post-treatment stage and the receipt of adjuvant chemotherapy.

Age also was associated with the receipt of adjuvant therapy. Patients in the oldest group in this cohort (ages 75-79 years) had <66 the odds of the youngest group (ages 66-69 years) of initiating postoperative chemotherapy. This finding did not seem to be measurably mediated by comorbidity, because all patients in this cohort were deemed fit enough to withstand chemoradiation followed by surgery, and noncancer comorbidity (eg, Charlson comorbidity score) was not a significant predictor in multivariate analysis. It is not possible to know the reasons for the decreased rate of adjuvant therapy use in older patients in this cohort, but this is similar to findings from a recent study of patients who were treated within the National Cancer Institute.[8] A prior study of patients from the California Cancer Registry also indicated a strong association between advanced age and decreased receipt of chemotherapy, a relation that held true even for older patients without significant comorbidities.[12] These and our results are in contrast to data from randomized trials in rectal cancer that have reported adjuvant chemotherapy completion rates from 79% to 94%.[24, 25] Thus, this variation in receipt by age is likely reflective of both patient preferences and provider biases. Careful examination of these practices is necessary, especially because available data suggest that fit elderly patients receive a similar advantage from adjuvant therapy as other groups.[26-30]

We observed several notable temporal trends. The rate of initiating adjuvant therapy after a neoadjuvant approach to rectal cancer has increased significantly from 1998 to 2007. This suggests that adherence to treatment guidelines is improving. Although there still remains a large group of patients who do not receive adjuvant chemotherapy, the 62% overall adjuvant chemotherapy initiation rate is similar to the 42% to 75% adjuvant chemotherapy administration rate reported for elderly patients with stage III colon cancer in clinical practice, although it is considerably lower than the rates achieved in randomized study.[31] It is notable, however, that the population of rectal cancer patients in this study is biased toward a treatment-eligible cohort based on receipt of neoadjuvant chemoradiation therapy. In addition, the rate at which oxaliplatin-containing regimens were used has steadily increased since approval of this agent in 2004. However, these data also demonstrate that single-agent, fluorouracil-based chemotherapy remains a common treatment choice for elderly patients undergoing rectal resection. Indeed, there may be a group of patients who may not derive significant added benefit with the addition of oxaliplatin; however, currently, there are insufficient data for routine chemotherapy treatment stratification.

There are several limitations to this study. Because it is a retrospective database study, it is difficult to ascertain the precise reasons for the omission of adjuvant therapy for individuals. Patients may defer further treatment after surgery, especially if their postoperative recovery is prolonged, however, this issue would not be expected to disproportionately affect patients with early yp stage, and the inclusion of readmission in the model did not diminish the strength of the association with chemotherapy use. Difficulty with preoperative therapy may also influence decisions about postoperative treatment. However, although patient preference may contribute to this decision, the data here suggest that other factors may contribute substantially, especially postoperative stage. Although the impulse to omit chemotherapy based on a good treatment response, on the surface, is understandable, data do not exist to support this approach. In fact, data from the European Organization for Research and Treatment of Cancer 22921 randomized trial suggests that those patients who have a good response to neoadjuvant therapy (ie, lower pathologic stage) derive the greatest benefit from adjuvant chemotherapy.[22] It is possible that the lack of response to 5-FU during concurrent chemoradiotherapy indicates resistance to 5-FU in the adjuvant setting and the need for combination chemotherapy. Thus, the rational selection of the postoperative regimen (ie, the decision to include oxaliplatin) may be possible based on the patient's response to neoadjuvant therapy, although additional study will be necessary to determine this. However, whatever the rationale for individual treatment decisions, our analysis suggests that this is already occurring, because patients with pathologic stage III tumors were more likely to receive oxaliplatin as part of their postoperative therapy. Another limitation of this data set is the lack of coding to consistently identify pathologic complete responders; these patients may have been classified as unstaged (Tx, Nx). However, this is likely to represent <15% of patients after neoadjuvant chemoradiotherapy, and any error introduced by these issues is unlikely to systematically influence the findings. Moreover, patients with metastatic disease were excluded, and all patients in this cohort received preoperative chemoradiation; thus, it is likely that they had clinical stage II or III disease.

Our findings suggest that there is substantial variability in the administration of adjuvant chemotherapy after neoadjuvant chemoradiation and resection for rectal cancer. Although the precise etiology of this variability is not clear, it is notable that the patterns of care do not reflect the best available evidence; however, they also serve to highlight the need for better evidence. Further study is necessary to illuminate the reasons for the observed deviation from guideline-based therapy in approximately 1 of 3 patients who undergo a neoadjuvant approach to adenocarcinoma of the rectum, let alone in those patients who do not undergo neoadjuvant treatment and are outside the scope of this study. Investigation of patient and provider decision-making will assist in ensuring that truly informed decisions are being made and that patients are receiving the full benefit of a multimodality approach to rectal cancer therapy.


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  2. Abstract

This work was supported in part by grants from the National Cancer Institute (grant K07CA133187 to G.J.C. and Cancer Center Support Grant CA016672 to MD Anderson).


  1. Top of page
  2. Abstract

Dr. Rodriguez-Bigas reports lecture fees from Genomic Health.


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  2. Abstract
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