Neoadjuvant Radiation Therapy in Locally Advanced Colon Cancer: a Cohort Analysis

  • Devi Mukkai Krishnamurty
  • Alexander T. Hawkins
  • Katerina O. Wells
  • Matthew G. Mutch
  • Mathew L. Silviera
  • Sean C. Glasgow
  • Steven R. Hunt
  • Sekhar Dharmarajan
Original Research
  • 80 Downloads

Abstract

Background

A paucity of data exists in the use of neoadjuvant chemoradiation therapy (NRT) for T4, non-metastatic colon cancer. This study was conducted to determine the effect of NRT on outcomes after resection for T4 colon cancer.

Methods

All patients with non-metastatic resected clinical T4 colon cancer from 2000 to 2012 at a tertiary care center were included. The cohort was divided into two groups—those that received NRT and those that did not (non-NRT). The primary outcomes were margin-negative resection and overall survival (OS).

Results

One hundred and thirty-one consecutive patients with non-metastatic clinical T4 colon cancer with a mean age of 65 years were included. NRT was used in 23 patients (17.4%). NRT group was noted to have non-statistically significant improvement in R0 resection rate (NRT 95.7% vs non-NRT 88.0%; p = 0.27) and local recurrence (NRT 4.3% vs non-NRT 15.7%; p = 0.15). There was a significant difference in T-stage downstaging between the two groups (NRT 30.4% vs non-NRT 6.5%; p = 0.007). In a bivariate analysis, NRT was associated with improved 5-year OS (NRT 76.4% vs non-NRT 51.5%; p = 0.03). This relationship did not persist in a Cox proportional hazard analysis that included age and comorbidity (HR 2.19; 95% CI 0.87–5.52; p = 0.09).

Conclusions

The use of NRT in locally advanced T4 colon cancer is safe and associated with increased downstaging. While there was a trend toward improvement in local recurrence and the ability to obtain margin-negative resections in the NRT group, this was not significant. Significantly improved overall survival was not observed in a multivariable analysis.

Keywords

Locally advanced colon cancer Radiotherapy Surgery Outcomes Adenocarcinoma 

Introduction

Resection of locally advanced colon cancer is associated with higher rates of positive surgical margins and local recurrence and reduced rates of overall and disease-free survival.1, 2, 3, 4 Radiation therapy, especially in the neoadjuvant setting, is an important strategy in rectal cancer for loco-regional control.5 The role of neoadjuvant radiation therapy (NRT) in locally advanced colon cancer is poorly defined. There are multiple theoretical advantages to preoperative radiation. Preserved tissue oxygenation and blood supply make native tissues more susceptible to radiation compared to postoperative tissues with poor blood flow and fibrosis. Downsizing and decreased risk of tumor cell shedding during the operation should make surgery more favorable technically. This may go on to improve resectability and local control. The toxicity of radiation therapy may be lower if it is administered in the neoadjuvant setting, where treatment can be better targeted and exposure of healthy tissues to radiation can be minimized. Finally, response to neoadjuvant therapy may be used to select patients for further surgical treatment and adjuvant therapy.

While a number of studies have evaluated the role of adjuvant radiation therapy in locally advanced colon cancer,6, 7, 8 only single-arm cohort studies and case series describe the use of radiation therapy in the neoadjuvant setting.9, 10, 11, 12, 13 Despite the lack of strong evidence to support its use, current NCCN guidelines recommend consideration of NRT for colon cancers attached to fixed structures.14

We hypothesized that the use of neoadjuvant chemoradiation therapy for locally advanced colon cancer would result in an increased rate of margin-negative resection, reduced local recurrence, and improved disease-free and overall survival. To evaluate this hypothesis, we retrospectively reviewed our institutional database of patients with non-metastatic clinical T4 colon cancers treated with or without NRT therapy and assessed the effect of NRT on outcomes including margin-negative resection, loco-regional control (LRC), disease-free survival (DFS), overall survival (OS), and postoperative complications.

Materials and Methods

Participants and Study Design

Consecutive adult (age > 18) patients undergoing colectomy for biopsy-proven adenocarcinoma with clinical T4 stage (AJCC 7th edition) between January 2000 and December 2012 at the Washington University in St. Louis were identified through a retrospective chart review.15 Colonic adenocarcinoma was defined as any tumor located in the colon 15 cm above the dentate line. Clinical T4 status was defined as pathologic or radiological evidence of tumor penetration of the visceral peritoneum (T4a) or direct tumor invasion or adhesion to other organs or structures (T4b). Exclusion criteria included neoplasia other than adenocarcinoma, rectal cancer, non-T4 colon cancers, and patients with distant metastasis at the time of presentation. Patients were selected to undergo neoadjuvant therapy on a case-by-case basis by the attending surgeon in conjunction with a radiation oncologist and medical oncologist. Local invasion in to the visceral peritoneum or direct tumor invasion or adhesion to other organs or structures was the primary reason for NRT. Radiotherapy was conducted at the discretion of the radiation oncologist. This study was reviewed and approved by the Washington University in St. Louis Institutional Review Board.

Patient files were retrospectively reviewed and pertinent demographic, oncological, and pathologic information was collected. To allow for risk adjustment, a Charlson comorbidity index score was generated for each patient. The Charlson comorbidity index predicts the 10-year mortality for a patient and is widely used to risk-adjust patient populations.16 For the group undergoing NRT, dosage, fractionation, adverse outcomes and concurrent chemotherapy use were recorded.

Outcome Measures

Primary events after surgery included the margin status of the pathologic specimen, local recurrence, overall survival, and disease-free survival. OS was calculated from initial diagnosis to death. DFS was calculated to the date of first recurrence or death. For DFS, patients were censored for death or last known follow-up. Secondary outcomes after surgery included postoperative complication and adjuvant chemotherapy and radiation therapy. Postoperative complications were defined as Clavien-Dindo grade III or greater and included intensive care unit admission, pulmonary embolus, bleeding requiring reoperation, ileus, anastomotic leak, pneumonia, respiratory failure, acute kidney injury, and superficial site infection requiring wound care.17 Complications were determined form a chart review.

Statistical Analysis

Continuous and categorical variables are expressed as mean ± standard deviation and proportions, respectively, throughout the manuscript with the exception of continuous variables with grossly skewed distributions that are reported as the median with the interquartile range. Bivariate analysis of continuous and categorical variables was performed with the Student t test and Chi-square test, respectively. For survival analysis, bivariate comparison was performed using the log-rank test. Factors significant for overall survival were compared using a multivariable Cox proportional hazard model. All variables judged not to be affected by radiation were considered using a stepwise procedure (backwards Wald) with a p value of 0.10 to enter and 0.05 to eliminate variables. All statistical analysis was performed using SAS statistical software (version 9.3; SAS Institutes Inc., Cary NC, USA). All tests were two-sided with an alpha level of 0.05.

Results

Patient Characteristics and Cohort Comparison

A total of 131 consecutive patients with non-metastatic T4 colon cancer were identified (Table 1). The mean age was 64.9 (range 22–92) and 68 (51.9% were female). Twenty-three patients (17.4%) underwent NRT. There was no significant difference between the two groups in mean age, gender, race, mean Charlson comorbidity index, clinical T status (T4a vs T4b), or tumor location. The NRT group had a much higher rate of neoadjuvant chemotherapy (NRT 91.3% vs non-NRT 2.8%; p < 0.001).
Table 1

Baseline demographics of all patients with T4 colon cancer from 2000 to 2012 treated with NRT

Characteristics

Entire cohort (n = 131)

NRT (n = 23)

No NRT (n = 108)

p value

Demographic

 Age, mean, year (range)

64.9 (22–92)

59.9 (22–77)

66.2 (26–92)

0.06

 Female

68 (51.9%)

9 (37.1%)

59 (54.6%)

0.18

 Caucasian

106 (80.9%)

19 (82.6%)

87 (80.6%)

0.82

 Charlson comorbidity index, mean (range)

2.6 (2–7)

2.3 (2–4)

2.7 (2–6)

0.09

Oncologic

 Clinical T4b

65 (49.6%)

14 (60.9%)

51 (47.2%)

0.23

 Proximal to splenic flexure

62 (47.3%)

13 (56.5%)

49 (45.4%)

0.33

 Neoadjuvant chemo

24 (18.3%)

21 (91.3%)

3 (2.8%)

< 0.01

In the 23 patients undergoing NRT, the majority of patients (n = 17; 73.9%) underwent 4500 cGy of radiation divided evenly between 25 fractions. The range of all radiation doses was 3900–5040 cGy. Concurrent chemotherapy with 5-FU and leucovorin was administered in 21 patients (91.3%). Two patients (8.7%) underwent neoadjuvant chemotherapy with FOLFOX. No major complications related to neoadjuvant therapy were noted in the cohort and none of the patients required termination of therapy or emergent surgery due to treatment-related complications. Surgery was performed 4–6 weeks following NRT.

Pathologic and Surgical Outcomes

Patients in the NRT group had a longer median time to surgery from diagnosis (NRT 123 days vs non-NRT 12 days; p < 0.0001). In the analysis of pathologic outcomes, the only significant difference was in nodal staging with NRT associated with higher rates of pN0 (NRT 78.3% vs non-NRT 39.8%; p = 0.0008), potentially due to the effects of NRT (Table 2). There were no significant differences between the two groups in mean size (NRT 66.4 mm vs non-NRT 64.8 mm; p = 0.84), R0 resection rate (NRT 95.7% vs non-NRT 88.0%; p = 0.27), and multivisceral resection (NRT 65.2% vs non-NRT 45.4%; p = 0.08). Complete pathologic response, with no residual tumor on final specimen, was achieved in 2 (8.3%) patients treated with NRT. There was a significant difference in T-stage downstaging between the two groups (NRT 30.4% vs non-NRT 6.5%; p = 0.007).
Table 2

Outcomes for all patients with T4 colon cancer from 2000 to 2012 treated with NRT

Outcomes

Entire cohort (n = 131)

NRT (n = 23)

No NRT (n = 108)

p value

Peri-operative

 Time to surgery, median, days (IQR)

18 (3–61)

123 (113–156)

12 (2–31)

< 0.0001

 Tumor size, mean, mm (range)

65.1 (11–250)

66.4 (21–150)

64.8 (19–250)

0.84

 Multivisceral resection

64 (48.8%)

15 (65.2%)

49 (45.4%)

0.08

 R0 resection

118 (89.3%)

22 (95.7%)

96 (88.0%)

0.27

 pT stage

 

0.008

  0

2 (1.5%)

2 (8.7%)

0 (0.0%)

 

  1

0 (0.0%)

0 (0.0%)

0 (0.0%)

  2

1 (0.7%)

0 (0.0%)

1 (0.7%)

  3

11 (8.4%)

5 (21.7%)

6 (5.5%)

  4

117 (89.3%)

16 (69.6%)

101 (93.5%)

 Tumor downstaged

14 (10.7%)

7 (30.4%)

7 (6.5%)

0.0007

 pN0 stage

61 (46.6%)

18 (78.3%)

43 (39.8%)

0.0008

Postoperative

 Postoperative complication

13 (9.9%)

4 (17.4%)

9 (8.3%)

0.18

  ICU transfer

1 (0.7%)

0 (0%)

1 (0.9%)

 

  Pulmonary embolus

1 (0.7%)

0 (0%)

1 (0.9%)

  Acute blood loss anemia

2 (1.5%)

1 (4.3%)

1 (0.9%)

  Dehydration

1 (0.7%)

1 (4.3%)

0 (0%)

  Ileus

1 (0.7%)

0 (0%)

1 (0.9%)

  Anastomotic leak

1 (0.7%)

0 (0%)

1 (0.9%)

  Pneumonia

1 (0.7%)

1 (4.3%)

0 (0%)

  Respiratory failure

2 (1.5%)

0 (0%)

2 (1.8%)

  Sepsis

1 (0.7%)

0 (0%)

1 (0.9%)

  Urinary tract infection

1 (0.7%)

1 (4.3%)

0 (0%)

  Surgical site infection

1 (0.7%)

0 (0%)

1 (0.9%)

 Adjuvant chemotherapy

68 (51.9%)

12 (52.2%)

56 (51.8%)

0.97

 Adjuvant radiotherapy

8 (6.1%)

0 (0%)

8 (7.4%)

0.18

Recurrence

 Local

18 (13.7%)

1 (4.3%)

17 (15.7%)

0.15

 Distant

30 (22.9%)

4 (17.4%)

26 (24.1%)

0.49

5-year overall survival

55.5%

76.4%

51.5%

0.03

5-year disease-free survival

51.3%

63.4%

49.3%

0.09

ICU intensive care unit

Postoperative Outcomes

There was no significant difference in rate of postoperative Clavien-Dindo grade III or greater complications between the NRT and non-NRT groups (17.4 vs 8.3% p = 0.18). Eight patients (7.4%) in the non-NRT group received adjuvant radiation therapy. No difference was noted in adjuvant chemotherapy utilization between the two groups (52.2 vs 51.8% p = 0.97).

Survival

Over a median follow-up of 52.6 months, the 5-year overall survival for the cohort was 55.6%. The administration of NRT was associated with improved 5-year overall survival (NRT 76.4% vs non-NRT 51.5%; p = 0.03) (Fig 1b). This relationship did not persist in a multivariate Cox proportional hazard analysis that included age and Charlson comorbidity index (HR 2.19; 95% CI 0.87–5.52; p = 0.09) (Table 3). Local recurrence was found in 18 patients overall (13.7%) with no significant difference between groups (NRT 4.3% vs non-NRT 15.7%; p = 0.15). A similar finding was made in distant recurrence, with an overall rate of 30 patients (22.9%) with no significant difference between groups (NRT 17.4% vs non-NRT 24.1%; p = 0.49). The cumulative disease-free survival for the cohort was 51.3%, and no significant association between NRT and disease-free survival was noted (NRT 63.4% vs non-NRT 49.3%; p = 0.09). (Fig. 1b).
Fig. 1

a Kaplan-Meier curve for overall survival stratified by neoadjuvant radiation therapy. b Kaplan-Meier curve for disease-free survival stratified by neoadjuvant radiation therapy

Table 3

Bivariate and multivariable cox proportional hazard model for overall survival

Overall survival

Bivariate

Multivariable

Variable

HR (95% CI)

p

HR (95% CI)

p

Neoadjuvant radiation

2.70 (1.08–6.73)

0.03

2.19 (0.87–5.52)

0.09

Age > 65

0.40 (0.24–0.67)

0.0005

0.48 (0.28–0.82)

0.007

Female

0.81 (0.50–1.33)

0.41

 

Charlson comorbidity index > 2

0.48 (0.30–0.79)

0.0004

0.59 (0.36–0.98)

0.04

Caucasian

0.88 (0.49–1.59)

0.67

 

Clinical T4b

1.63 (0.99–2.66)

0.05

NS

NS

Proximal to splenic flexure

1.41 (0.87–2.31)

0.16

 

Multivisceral resection

1.26 (0.76–2.03)

0.38

R0 resection

1.82 (0.92–3.61)

0.08

NS

NS

Tumor downstaged

2.17 (0.79–5.98)

0.13

 

Postoperative complication

0.44 (0.21–0.93)

0.03

NS

NS

Adjuvant chemotherapy

0.59 (0.36–0.96)

0.03

NS

NS

Adjuvant radiotherapy

2.36 (0.73–7.63)

0.15

 

Discussion

This study examined the role of neoadjuvant chemoradiotherapy in the management of non-metastatic T4 colon cancer. A cohort of patients with clinical T4 colon cancer who underwent NRT was compared with a group of clinical T4 patients who did not undergo NRT. The two groups were similar in pre-operative variables. Higher rates of R0 resection and lower rates of local recurrence were seen in the NRT group, but these were not statistically significant. The use of NRT was associated with significant downstaging and improved overall survival in a bivariate analysis. This relationship did not persist in a multivariable model nor in an analysis of disease-free survival.

Based on results from large population studies, the overall survival in patients with T4 disease varies based on extent of disease (T4a vs T4b) and lymph node involvement (N0–N2b) with 60.6% for T4aN0 to 17.5% for T4aN2b compared to 45.7% for T4b N0 to 12.9% for T4bN2b disease.18 Complete surgical resection with negative margins followed by adjuvant chemotherapy is the only potentially curative therapy for these patients. Patients with T4 disease, especially T4b, often require multivisceral resections to achieve clear margins with associated increased operative time. In addition, they have high rates of postoperative morbidity (11 to 44%) and mortality (2 to 7.5%).1,12,19,20 While superior efficacy of neoadjuvant therapy has been demonstrated in rectal cancer,5,21, 22, 23, 24, 25 neoadjuvant trials in colon cancer are limited and studies that exist have focused on the role of neoadjuvant chemotherapy. The FOxTROT collaborative group evaluating neoadjuvant chemotherapy in locally advanced (T3 or greater) colon cancers has demonstrated safety and feasibility, and a phase III trial to establish long-term oncologic outcomes is currently underway.26 Similar results were also demonstrated by a phase II Danish trial.27

Very few studies have looked at the role of chemoradiation therapy in colon cancer. A single-phase III randomized controlled study evaluating adjuvant radiation therapy in patients with locally advanced colon cancers (T3N1, T3N2, and T4anyN) showed similar overall survival in patients receiving chemotherapy and radiation compared to those treated with chemotherapy alone but with higher toxicity in patients receiving radiation therapy.7 This study was terminated early before the target sample size could be achieved because of slow accrual. There are 2 additional smaller case series describing the use of NRT in colon cancer, and both descriptive studies have smaller median follow-up and no comparison group. In a retrospective review of an institutional database, Cukier et al. reported a 100% R0 rate and a 3% complete pathologic response rate along with a 3-year OS and DFS rate of 85.9 and 73.7%, respectively, at a median follow-up of 36 months.9 Another study evaluating the role of neoadjuvant therapy in locally advanced sigmoid colon cancers with median follow-up of 42 months (range, 17–57 months) had a 95.2% R0 resection rate and a 38.1% pathologic complete response rate. Multivisceral resection was necessary in only 7 patients (33.3%). Two patients (9.5%) experienced grade 2 postoperative complications with no mortality and a cumulative probability of 3-year OS of 95.2%.28

Our study is the first to compare a cohort of patients treated with and without NRT. In our study, the two cohorts were similar in pre-operative variables such as mean age, gender, race, Charlson comorbidity index, clinical T4b status, and tumor location. Although statistical significance was not achieved, a higher rate of margin-negative resection (95.7 vs 88%) and lower rate of local recurrence (4.3 vs 15.7%) and the ability to obtain complete pathologic response in advanced T4 tumors (8 vs 0%) noted in our study are encouraging. A higher node negative rate was seen in our study in the NRT group, and similar results have been reported by other investigators evaluating NRT in colon cancer.9 As this is a retrospective study with the likelihood of severe selection bias, a multivariable analysis is crucial to account for potential biases. Improved overall survival was noted with the use of NRT in a bivariate analysis. This relationship, however, did not persist in a multivariable model and we are unable to conclude that NRT is associated with improvement in either overall or disease-free survival. No major complications were seen in our cohort during the pre-operative treatment phase and none of our patients in the NRT group required interruption of treatment or emergency surgery due to treatment-related complications.

There are several limitations of this study. The small sample size of our study makes it susceptible to type 2 error. We observed non-significant differences in both margin-negative resection and local recurrence. As this is a retrospective study, there is potential for selection bias. In our study, patient selection was based on the oncologist and surgeon’s clinical judgment and strict clinical or radiological criteria to select patients prior to neoadjuvant therapy were not established. It is possible that tumors that were selected for neoadjuvant therapy were more advanced compared to those treated with a surgery first approach. At the same time, one could argue that patients in the NRT group were those who did not have complications that would preclude the use of neoadjuvant therapy such as obstruction, perforation, or poor performance status. In our review of pre-treatment factors, the two cohorts were similar with respect to age, gender, race and mean Charlson comorbidity index, clinical T4 status, and tumor location. The primary exposure for the study, radiation technique/dose and the chemotherapy regimen, were not uniform in all patients. However, the range between radiation doses was narrow and all patients in the NRT cohort received comparable radiation dosing. One potential confounding factor in our study is the role of neoadjuvant chemotherapy. In our study, the NRT group had a significantly higher rate of neoadjuvant chemotherapy (91.3%) compared to the non-NRT group (2.8%; p < 0.001). But the chemotherapeutic regimens used in all but 2 patients were radio-sensitizing doses of 5-FU and leucovorin with the balance receiving FOLFOX. Data regarding tumor downsizing or conversion of inoperable tumors to operable was not available from our study and should be included in future studies.

Despite these limitations, the ability to achieve downstaging, pathologic complete response rate of 8.3% along with > 95% R0 resection rates with neoadjuvant therapy in patients with locally advanced colon cancers is encouraging. In this era of improved pre-operative imaging modalities, which allow accurate pre-operative staging and targeting of radiation therapy, and limited radiation related toxicity, there may be a role for radiation therapy in improving resectability and survival in locally advanced colon cancer.

Conclusion

The use of neoadjuvant chemoradiation therapy in locally advanced T4 colon cancer is safe. Improved overall survival was observed in an unadjusted analysis, but this did not persist in a multivariable analysis. Despite the limitations of small sample size and retrospective nature, our study is the first to compare the use of neoadjuvant chemoradiation therapy in locally advanced colon cancer with a control cohort. Further prospective studies with strict patient selection criteria and treatment parameters are needed to fully evaluate the role of neoadjuvant chemoradiation therapy in patients with locally advanced colon cancer.

Notes

Authors’ Contribution

All authors have provided substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work, drafted the work or revised it critically for important intellectual content, approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Compliance with Ethical Standards

Funding information

Departmental

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Copyright information

© The Society for Surgery of the Alimentary Tract 2018

Authors and Affiliations

  • Devi Mukkai Krishnamurty
    • 1
  • Alexander T. Hawkins
    • 1
  • Katerina O. Wells
    • 1
  • Matthew G. Mutch
    • 1
  • Mathew L. Silviera
    • 1
  • Sean C. Glasgow
    • 1
  • Steven R. Hunt
    • 1
  • Sekhar Dharmarajan
    • 2
  1. 1.Division of General Surgery, Section of Colon and Rectal Surgery, Washington University School of MedicineWashington University in St. LouisSt. LouisUSA
  2. 2.Division of General SurgeryMercy HospitalSt. LouisUSA

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