Open Access

What does absence of lymph node in resected specimen mean after neoadjuvant chemoradiation for rectal cancer

Radiation Oncology20138:202

https://doi.org/10.1186/1748-717X-8-202

Received: 21 August 2012

Accepted: 12 August 2013

Published: 19 August 2013

Abstract

Background

The effect of insufficient node sampling in patients with rectal cancer managed by neoadjuvant chemoradiation followed by surgery has not been clearly determined. We evalulated the impact of insufficient sampling or even abscence of lymph nodes in the specimen on survival in patients at high-risk (T3, T4 or node positive) for rectal cancer.

Methods

We conducted a single institution, retrospective analysis of all patients who underwent surgical rectal resection following neoadjuvant chemoradiation for treatment of mid to lower rectal cancer between 1997 and 2009. ypNX was defined as the absence of lymph nodes retrieved in the resected specimen.

Results

A total of 132 patients underwent resection for treatment of rectal cancer following neoadjuvant chemoradiation. Ninety four patients (71.2%) were considered as having node-negative disease, including ypNx and ypN0. In 38 patients (28.8%), the primary tumor was associated with regional lymph node metastases (ypNpos). The mean number of retrieved nodes per specimen was 14.2, respectively. The five-year overall survival from initial operation for the ypNx group was 100%, respectively. The estimated five-year overall survival for ypN0 and ypNpos was 84.0% and 60.3%, respectively (P =0.001). No significant differences in overall survival were observed between the ypNx and ypN0 group (P =0.302).

Conclusion

Absence of recovered LN in resected specimens after neoadjuvant chemoradiation was observed in 7.6% of specimens. Absence of LN should not be regarded as a risk factor for poor survival or as a sign of less radical surgery.

Keywords

Rectal neoplasm Surgery Neoadjuvant chemoradiation

Introduction

It is estimated that approximately 50 ~ 60% of rectal cancers are considered to be locally advanced tumors with clinical stage T3 or T4 or node positive disease, characterized by poor prognosis due to increased incidence of systemic and local recurrence and decreased long-term survival [1]. The preferred strategy for management of locally advanced mid to distal rectal cancer is multimodality treatment that includes radical surgery, chemotherapy, and radiation therapy. Radical surgery should be performed according to established surgical principles, which include en bloc resection of the tumor-bearing rectum and the adjacent lymphovascular pedicle, commonly referred to as total mesorectal excision [2].

The lymph node (LN) status remains one of the independant prognostic factors in rectal cancer. Patients without LN metastses have significantly better survival, compared to node positive patients, in the abscence of distant metastasis. However, a mininum number of LNs retrieved from the resected specimen is prerequisite to ensuring both adequate nodal sampling and surgical radicality [3]. Several studies have demonstrated a significant survival benefit of patients with node negative disease with an increased number of recovered nodes [46]. Chemoradiation exerts effects not only on tumor down staging and rate of metastatic LN but also on the overall number of retrieved nodes [7, 8]. The number of LNs assessed pathologically is a combination of the aggressiveness of the surgeon in resecting widely around the primary tumor and of the didicated pathologist in searching the specimen for additional nodes. Inadequate retrieval of LNs is considered unacceptable for patients who have not undergone pretreatment and went straight to surgery. However, the effect of this finding in patients with rectal cancer managed by neoadjuvant chemoradiation followed by surgery has not yet been determined.

In an attempt to determine the impact of insufficient sampling (i.e. ypN ≤ 12) or even abscence of lymph nodes in the specimen (i.e. ypNx) on survival in these patients, we evaluated a cohort of patients who enrolled in our neoadjuvant chemoradiation protocol for patients with high-risk (T3, T4 or node positive) rectal cancer.

Patients and methods

Eligibility

Between September 1997 and September 2009, 720 patients with rectal cancer underwent treatment at Gachon Medical Center. The inclusion criteria for the study were as follows: 1) lesion located no more than 10 cm from the anal verge; 2) clinical TNM stage II and III (T2-T4, or N positive and M0) on abdominopelvic computated tomography; 3) patients with histologically proven rectal carcinoma; 4) age ≥18 years; 5) patients who underwent preoperative chemoradiation; 6) mid (anal verge 6 cm to 10 cm) and lower (anal verge 1 cm to 5 cm) rectal cancer patients. Of the 720 patients screened for rectal resection, 132 patients fulfilled the inclusion criteria and were included in this retrospective analysis.

Pretreatment staging

Initial staging included complete physical examination, digital rectal examination, colonoscopy, serum CEA (carcino-embryonic antigen) abdominal and pelvic spiral CT scans, and endorectal ultrasonography or rectal magnetic resonance imaging in selected patient chest X-ray.

Treatment

All patients received two initial cycles of chemotherapy followed by pelvic radiation therapy plus chemotherapy. The concurrent chemotherapy was performed at the first and fifth week of radiation with bolus intravenous 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 for five days per week. All patients received external beam radiation therapy (median dose, 50.40 Gy; range 48.4 to 55.8 Gy), according the previously published techniques [9, 10]. Using 6 to 10 Mv photons, a 3- or 4-field technique was used.

Surgery was attempted at 6–8 weeks after completion of neoadjuvant chemoradiotherapy. All patients underwent low anterior resection or abdominoperineal resection and total mesorectal excision (TME) according to the surgical technique described by Heald et al. [11] as well as high ligation inferior mesenteric artery and en bloc resection of any suspected adjacent organ invasion. Four cycles of postoperative adjuvant chemotherapy with 5-fluorouracil 500 mg/m2 for five days was added.

Staging

Two pathologists performed meticulous dissection and retrieval of mesorectal lymph nodes. A rigorous search of the mesorectum was performed in order to identify as many lymph nodes as possible. Each lymph node was analyzed in its entirety in separate blocks. When fewer than 12 lymph nodes were found, an additional 24-hour surfixation in Bouin’s fluid was performed in order to facilitate recovery of residual lymph nodes. No clearing technique was performed. Patients were staged according to the American Joint Committee on Cancer recommendations [12]. ypNX was defined as the absence of lymph nodes recovered in the resected specimen.

Surveillance

Surveillance for recurrence following surgery was outlined as follows: physical examination, serum CEA, chest X-ray, and spiral abdominal CT scan were performed every six months for three years, and annually thereafter.

Statistical methods

The primary endpoint of the study was overall survival. Overall survival (OS) was estimated using the Kaplan-Meier method. OS was measured from the date of diagnosis to the date of death or the last follow-up visit. Survival rates were compared for statistical differences using log-rank analysis. Chi squared and ANOVA were used for categorical and numeral variables between groups. Multivariate analysis was performed using stepwise Cox proportional hazards regression modeling. P values less than .05 were considered statistically significant and all P values correspond to two-sided significance tests.

Results

Patient characteristics

There were 95 men and 37 women enrolled in the study. The median age of subjects was 59 years (39-77). The median follow up from primary surgery was 54.2 months (range, 12.1-128.5 months). Primary lesions were found above 6 cm or more from the anal verge in 82 patients (62.1%) and below 5 cm in 50 patients (37.9%) (Table 1).
Table 1

Patient characteristics (n = 132)

Variables

Number of patients

%

Median age

59.0(39-77)

 

  ≤ 60

61

46.2

  > 60

71

53.8

Sex: M/F

95:37

 

Primary tumor location

  

  Mid

109

47.0

  Lower

23

53.0

Pretreatment CEA, ng/mL*

  

  Median

5.32(0.1-83.3)

 

  ≤ 5.0

112

84.8

  > 5.0

20

15.2

ypT stage

  

  Tx

9

6.8

  T1

1

0.8

  T2

29

22.0

  T3

92

69.7

  T4

1

0.8

ypN stage

  

  x

11

8.3

  0

83

62.9

  positive

38

28.8

Retrieved nodes

  

  Mean

14.2(0-31)

 

Lymphovascular invasion

  

  Positive

30

77.3

  Negative

102

22.7

Perineural invasion

  

  Positive

13

9.8

  Negative

119

90.2

Cell differentiation

  

  Well

12

9.1

  Moderately

104

78.8

  Poorly or mucinous

16

12.1

Body mass index

  

  ≤ 22

39

29.5

  > 22

93

70.5

*CEA, carcinoembryonic antigen (normal range 0-7 ng/mL).

Numbers in parenthesis indicate ranges.

The median interval time between completion of preoperative chemoradiation and surgery was 6.2 weeks (range, 4.4-8.6 weeks). Among the 132 patients, 52 (39.4%) underwent low anterior resections with or without protective ileostomy; 39 (29.5%) underwent ultralow low anterior resections with or without protective ileostomy; 22 (16.7%) underwent Hartmann’s procedure and 19 patients (14.3%) underwent abdominoperineal resections. A summary of patient characteristics is shown in Table 1. In this study, 92 patients (69.7%) underwent a sphincter saving operation without permanent colostomy.

A total of 94 patients (71.2%) were considered as having node-negative disease, including ypNx and ypN0. In 38 patients (28.8%), the primary tumor was associated with regional lymph node metastases (ypNpos). The mean number of retrieved nodes per specimen was 14.2, respectively. The rate of complete sterilization, i.e., staged ypTxN0 and ypTxNx, was 6.8% (nine patients). Of the 130 patients with clinical stage III, 92 patients (69.7%) (9 + 2 + 28 + 53 patients) were downstaged after chemoradiation (Table 2). All of the ypNx patients (n = 11) had clinically significant lymph node enlargement(s).
Table 2

TNM downstaging in a series of 132 rectal cancer patients treated with preoperative chemoradiotherapy

 

CR

0

I

II

III

Total

cII*

0

0

1

1

0

2

cIII*

9

2

28

53

38

130

Total

9

2

29

54

38

132

* Clinical stage II or stage III.

Lymph node status

Pathologist A evaluated 74 patients and retrieved an average of 13 (range, 0-24) lymph nodes and Pathologist B evaluated 58 patients and retrieved 15 (range, 0-31) lymph nodes, respectively. There were 11 patients (8.3%) with absence of lymph nodes recovered in the resected specimen, i.e., ypNx (0 out of 0). The overall pathologic characteristics of ypT stage and ypN stage are shown in Table 3. In comparison of patients with ypNx and those with ypN0, no significant differences were observed in terms of gender, age, CEA, cell type, and body mass index. However, significantly lower risk of lymphovascular invasion was observed in the ypNx group, compared with the ypNpos group (P = 0.001) (Table 4).
Table 3

Correlation of ypT stage and ypN stage (n = 132)

ypT stage

yp Nx(%)

ypN0(%)

ypNpos(%)

Total

ypTx

3(2.3)

6(4.5)

0(0.0)

9(6.8)

ypT1

0(0.0)

1(0.8)

0(0.0)

1(0.8)

ypT2

4(3.0)

23(17.4)

2(1.5)

29(21.9)

ypT3

4(3.0)

52(39.4)

36(27.3)

92(69.7)

ypT4

0(0.0)

1(0.8)

0(0.0)

1(0.8)

Total

11(8.3)

83(62.9)

38(28.8)

132(100.0)

Table 4

Clinicopathological characteristics of patients according to ypN status (n = 132)

Parameter

ypNx,%

ypN0,%

ypNpos,%

P-value

P-value, ypNx vs ypN0

Number of patients

11(8.3)

83(62.9)

38(28.8)

  

Mean age(yr) ± STD

66.9 ± 9.13

59.5 ± 8.80

58.5 ± 11.4

0.434

0.725

Primary tumor location

   

0.514

0.680

  Mid

11(100.0)

70(84.3)

28(73.7)

  

  Lower

0(0.0)

13(15.7)

10(26.3)

  

Pretreatment CEA(ng/mL)

5.59 ± 5.98

4.02 ± 5.67

7.36 ± 17.73

0.229

0.926

Cell differentiation

   

0.765

0.443

  Well

0(0.0)

7(8.4)

5(13.2)

  

  Moderate

8(72.7)

69(83.1)

27(71.1)

  

  Poorly

3(27.3)

7(8.5)

6(15.7)

  

Perineural invasion

3(27.3)

3(3.6)

7(18.4)

0.102

0.288

Lymphovascular invasion

3(27.3)

9(10.8)

18(47.4)

0.001

0.435

Body mass index

22.18 ± 1.57

23.39 ± 3.14

22.86 ± 2.61

0.723

0.091

Retrieved nodes

-

13.45 ± 7.59

17.9 ± 6.87

0.720

0.047

CEA Carcinoembryonic antigen, STD Standard deviation.

Risk factor analyses

In univariate analyses, CEA greater than 5, primary node status, and lymphovascular invasion had a statistically significant adverse influence on survival (Table 5). Although the results of multivariate analysis are limited by the small number of patients, results of stepwise Cox multivariate regression analysis revealed lymph node metastasis as a single independent prognostic factor affecting overall survival (P = 0.029; relative risk, 2.233; 95% Confidence Interval = 1.087-4.587).
Table 5

Univariate predictors of adverse outcome (n = 132)

Variables(N)

5-year survival,%

P-value

Age

 

0.053

  ≤ 60

85.9

 

  > 60

77.0

 

Primary tumor location

 

0.004

  Mid

80.1

 

  Lower

70.7

 

CEA, ng/mL*

 

0.001

  ≤ 5.0

84.3

 

  > 5.0

45.2

 

Pathologic N stage

 

0.003

  yNx

100

 

  yN0

85.0

 

  yNpos

60.3

 

Lymphovascular invasion

 

0.642

  Positive

70.8

 

  Negative

78.8

 

Perineural invasion

 

0.951

  Positive

75.0

 

  Negative

79.7

 

Cell differentiation

 

0.709

  Well

75.0

 

  Moderately poorly

79.7

 

Body mass index

 

0.838

  ≤ 22

73.4

 

  > 22

77.1

 

CEA Carcinoembryonic antigen (normal range 0-7 ng/mL), N Number.

Disease recurrence and survival

The overall recurrence rate was 18.3% (25 patients) and overall cancer-related mortality was 17.4% (23 patients). No recurrences were observed among the ypNx group. Comparison of recurrences and cancer-related deaths showed significant differences between the ypNx and ypN0 group (P =0.032) (Table 6). Five-year overall survival for patients with ypNx group 100%. The estimated five-year overall survival for ypN0 and ypNpos was 84.0% and 60.3%, respectively (Figure 1). The estimated five-year disease free survival for ypN0 and ypNpos was 82.8% and 58.9%, respectively (Figure 2). No significant difference in overall survival was observed between the ypNx and ypN0 group (P = 0.302). However, the ypNpos group showed significantly worse five-year survival than the ypNx and ypN0 groups (P = 0.002).
Figure 1

Overall survival according to according to ypN status (n = 132) (p = 0.003).

Figure 2

Disease free survival (DFS) according to ypNx status (n = 132) (p = 0.022).

Table 6

Recurrence according to ypN status (n = 132)

Parameter

ypNx

ypN0

ypNpos

P-value

Recurrence

0

11

14

0.032

Cancer related mortality

0

10

13

0.002

Discussion

Neoadjuvant chemotherapy and radiation therapy for treatment of locally advanced rectal cancer is a widely accepted treatment before surgical operation. Although it was initially used to improve rates of sphincter preservation and to optimize patient tolerance, the ideal number of nodes for rectal cancer surgery has been an issue of controversy. Many studies have demonstrated that the number of lymph nodes involved with a tumor has a strong impact on outcome for patients treated for rectal cancer [3]. Indeed, the TNM staging system is based on whether one to three nodes are involved or four or more [12]. An apparent increase in the number of retrieved nodes in patients with N1 or N2 disease, when compared to N0 disease, has been reported [3, 6]. Although there is no clear agreement on the absolute number of total retrieved nodes, [3, 1315] the American Joint Committee on Cancer (AJCC) has recommended at least 12 lymph nodes as the standard for adequate staging of colon and rectal disease [12, 16]. The AJCC staging does not include an exception criteria for pretreated rectal cancer, which in fact may have several factors that interfere with lymph node retrieval after rectal cancer surgery. In addition, the impact of absence of lymph nodes in the resected specimen after radical surgery for treatment of mid to distal rectal cancer after neoadjuvant chemoradiation has not been clearly defined in terms of overall survival.

In this study, the mean number of lymph nodes recovered after neoadjuvant chemoradiation followed by radical surgery was 14.2 LN per specimen, whereas the rate of ypNx was 7.6%. Findings of this series showed a statistically significant higher number of nodes in node positive patients, compared with node negative patients. For example, Wong et al. [17] reported that a mean of 14 nodes was found in node negative patients, as compared with 20 nodes in node positive patients. Unlike the study reported by Gorog et al. [18] and Kuo et al. [19], in this study, body surface area did not affect the number of LN retrieved. The major weakness of this study is that the results are based on 11 patients with no recurrent disease after ypNx. The retrospective nature and small sample size might actually have affected statistical analysis.

In a population-based study, including 5000 patients with rectal cancer from the SEER (Surveillance, Epidemiology, and End Results) database, results of multivariate analysis showed that patients who underwent preoperative radiation had significantly fewer recovered nodes, as compared with patients treated by adjuvant therapy [20]. The main reason for more retrieved nodes in this study may have resulted from complete total mesorectal excision with high ligation of inferior mesenteric vessels; however, a more likely explanation is the pathologist’s determination to retrieve as many nodes as possible.

The clinical impact of decreased retrieval of LN after neoadjuvant chemoradiation has not yet been clearly defined. It is generally believed that examining a greater number of nodes increases the likelihood of proper staging and thus might benefit from adjuvant therapy. Is survival in the ypNx population worse than that in the ypN0 population? In our series, the answer is no. The ypNx group exhibited a tendency toward better overall survival than the ypN0 group. The ypNx group may reflect an increased sensitivity to chemoradiation, which ultimately results in downstaging, as suggested by Habr-Gama et al. [5]. In fact, some of patients with ypNx could have been node positive patients before neoadjuvant chemoradiation. The results of the current series should be interpreted with caution. Due to the retrospective nature of this study, the analysis of disease free survival, local recurrence free survival and overall survival lack significant variables having a major impact on the outcome. Based on our results, the authors of this study suggest that the current recommendation of minimum requirement for LN retrieved (i.e. more than 12 nodes) for proper staging in these subsets of patients may be inappropriate and that conduct of more larger studies comparing the therapeutic outcome of ypNx and ypN0 is definitely warranted.

A wide range of tumor responses after preoperative chemoradiation therapy have been reported [2, 6, 9, 21, 22]. The reason for this wide variability in tumor responses is unclear. The results of studies reporting predictive clinicopathologic factors of tumor response are controversial and patients in the ypNx group may be associated with increased sensitivity toward chemoradiation therapy, and, thus, toward better survival. Some molecular biomarkers and various enzymes that may predict tumor response to chemotherapy have been suggested [19, 2325]. Neoadjuvant chemoradiation therapy has played a critical role in improving resectability and downstaging tumors. A variety of neoadjuvant chemoradiation regimens and radiosentisizers should be investigated for improvement of tumor response after chemoradiation and further prediction of tumor response.

In conclusion, absence of recovered LN in a resected specimen after neoadjuvant chemoradiation is rare and was observed in 7.6% in this series. Patients with ypNx after neoadjuvant chemoradiation and radical surgery may not be considered as patients at high risk for development of recurrence.

Declarations

Authors’ Affiliations

(1)
Department of Surgery, Gil Medical Center, School of MedicineGachon University
(2)
Department of Radiation Oncology Gil Medical Center, School of MedicineGachon University
(3)
Department of Pathology, Gil Medical CenterSchool of MedicineGachon University,

References

  1. Jessup JM, Stewart AK, Menck HR: The national cancer data base report on patterns of care for adenocarcinoma of the rectum, 1985-95. Cancer 1998,83(11):2408-2418. 10.1002/(SICI)1097-0142(19981201)83:11<2408::AID-CNCR22>3.0.CO;2-GView ArticlePubMedGoogle Scholar
  2. Lee WS, Yun SH, Roh YN, Yun HR, Lee WY, Cho YB, Chun HK: Risk factors and clinical outcome for anastomotic leakage after total mesorectal excision for rectal cancer. World J Surg 2008,32(6):1124-1129. 10.1007/s00268-007-9451-2View ArticlePubMedGoogle Scholar
  3. Tepper JE, O’Connell MJ, Niedzwiecki D, Hollis D, Compton C, Benson AB 3rd, Cummings B, Gunderson L, Macdonald JS, Mayer RJ: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 2001,19(1):157-163.PubMedGoogle Scholar
  4. Prandi M, Lionetto R, Bini A, Francioni G, Accarpio G, Anfossi A, Ballario E, Becchi G, Bonilauri S, Carobbi A, et al.: Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 2002,235(4):458-463. 10.1097/00000658-200204000-00002View ArticlePubMedPubMed CentralGoogle Scholar
  5. Habr-Gama A, Perez RO, Proscurshim I, Rawet V, Pereira DD, Sousa AH, Kiss D, Cecconello I: Absence of lymph nodes in the resected specimen after radical surgery for distal rectal cancer and neoadjuvant chemoradiation therapy: what does it mean? Dis Colon Rectum 2008,51(3):277-283. 10.1007/s10350-007-9148-5View ArticlePubMedGoogle Scholar
  6. Kim NK, Baik SH, Seong JS, Kim H, Roh JK, Lee KY, Sohn SK, Cho CH: Oncologic outcomes after neoadjuvant chemoradiation followed by curative resection with tumor-specific mesorectal excision for fixed locally advanced rectal cancer: Impact of postirradiated pathologic downstaging on local recurrence and survival. Ann Surg 2006,244(6):1024-1030. 10.1097/01.sla.0000225360.99257.73View ArticlePubMedPubMed CentralGoogle Scholar
  7. Wichmann MW, Muller C, Meyer G, Strauss T, Hornung HM, Lau-Werner U, Angele MK, Schildberg FW: Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer. Arch Surg 2002,137(2):206-210. 10.1001/archsurg.137.2.206View ArticlePubMedGoogle Scholar
  8. Wijesuriya RE, Deen KI, Hewavisenthi J, Balawardana J, Perera M: Neoadjuvant therapy for rectal cancer down-stages the tumor but reduces lymph node harvest significantly. Surg Today 2005,35(6):442-445. 10.1007/s00595-004-2956-5View ArticlePubMedGoogle Scholar
  9. Lee SH, Lee KC, Choi JH, Oh JH, Baek JH, Park SH, Shin DB: Chemoradiotherapy followed by surgery in rectal cancer: improved local control using a moderately high pelvic radiation dose. Jpn J Clin Oncol 2008,38(2):112-121. 10.1093/jjco/hym164View ArticlePubMedGoogle Scholar
  10. Medich D, McGinty J, Parda D, Karlovits S, Davis C, Caushaj P, Lembersky B: Preoperative chemoradiotherapy and radical surgery for locally advanced distal rectal adenocarcinoma: pathologic findings and clinical implications. Dis Colon Rectum 2001,44(8):1123-1128. 10.1007/BF02234632View ArticlePubMedGoogle Scholar
  11. Heald RJ, Husband EM, Ryall RD: The mesorectum in rectal cancer surgery–the clue to pelvic recurrence? Br J Surg 1982,69(10):613-616. 10.1002/bjs.1800691019View ArticlePubMedGoogle Scholar
  12. Greene FL, Page DL, Fleming ID, et al.: AJCC cancer staging manual. 6th edition. New York: Springer-Verlag; 2002.View ArticleGoogle Scholar
  13. Scabini S, Ferrando V: Number of lymph nodes after neoadjuvant therapy for rectal cancer: How many are needed? World J Gastrointest Surg 2012,4(2):32-35. 10.4240/wjgs.v4.i2.32View ArticlePubMedPubMed CentralGoogle Scholar
  14. Perez RO, Habr-Gama A, Nishida Arazawa ST, Rawet V, Coelho Siqueira SA, Kiss DR, Gama-Rodrigues JJ: Lymph node micrometastasis in stage II distal rectal cancer following neoadjuvant chemoradiation therapy. Int J Colorectal Dis 2005,20(5):434-439. 10.1007/s00384-004-0712-3View ArticlePubMedGoogle Scholar
  15. Hughes R, Glynne-Jones R, Grainger J, Richman P, Makris A, Harrison M, Ashford R, Harrison RA, Livingstone JI, McDonald PJ, et al.: Can pathological complete response in the primary tumour following pre-operative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision? Int J Colorectal Dis 2006,21(1):11-17. 10.1007/s00384-005-0749-yView ArticlePubMedGoogle Scholar
  16. Edge SB, Compton CC: The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010,17(6):1471-1474. 10.1245/s10434-010-0985-4View ArticlePubMedGoogle Scholar
  17. Wong JH, Severino R, Honnebier MB, Tom P, Namiki TS: Number of nodes examined and staging accuracy in colorectal carcinoma. J Clin Oncol 1999,17(9):2896-2900.PubMedGoogle Scholar
  18. Gorog D, Nagy P, Peter A, Perner F: Influence of obesity on lymph node recovery from rectal resection specimens. Pathol Oncol Res 2003,9(3):180-183. 10.1007/BF03033734View ArticlePubMedGoogle Scholar
  19. Kuo LJ, Chiou JF, Tai CJ, Chang CC, Kung CH, Lin SE, Hung CS, Wang W, Tam KW, Lee HC, et al.: Can we predict pathologic complete response before surgery for locally advanced rectal cancer treated with preoperative chemoradiation therapy? Int J Colorectal Dis 2012,27(5):613-621. 10.1007/s00384-011-1348-8View ArticlePubMedGoogle Scholar
  20. Baxter NN, Virnig DJ, Rothenberger DA, Morris AM, Jessurun J, Virnig BA: Lymph node evaluation in colorectal cancer patients: a population-based study. J Natl Cancer Inst 2005,97(3):219-225. 10.1093/jnci/dji020View ArticlePubMedGoogle Scholar
  21. Ahmad NR, Nagle D: Long-term results of preoperative radiation therapy alone for stage T3 and T4 rectal cancer. Br J Surg 1997,84(10):1445-1448. 10.1002/bjs.1800841029View ArticlePubMedGoogle Scholar
  22. Minsky BD, Cohen AM, Kemeny N, Enker WE, Kelsen DP, Reichman B, Saltz L, Sigurdson ER, Frankel J: Combined modality therapy of rectal cancer: decreased acute toxicity with the preoperative approach. J Clin Oncol 1992,10(8):1218-1224.PubMedGoogle Scholar
  23. Fu CG, Tominaga O, Nagawa H, Nita ME, Masaki T, Ishimaru G, Higuchi Y, Tsuruo T, Muto T: Role of p53 and p21/WAF1 detection in patient selection for preoperative radiotherapy in rectal cancer patients. Dis Colon Rectum 1998,41(1):68-74. 10.1007/BF02236898View ArticlePubMedGoogle Scholar
  24. Palazzo JP, Kafka NJ, Grasso L, Chakrani F, Hanau C, Cuesta KH, Mercer WE: The role of p53, p21WAF1/C1PI, and bcl-2 in radioresistant colorectal carcinoma. Hum Pathol 1997,28(10):1189-1195. 10.1016/S0046-8177(97)90257-4View ArticlePubMedGoogle Scholar
  25. Villafranca E, Okruzhnov Y, Dominguez MA, Garcia-Foncillas J, Azinovic I, Martinez E, Illarramendi JJ, Arias F, Martinez Monge R, Salgado E, et al.: Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001,19(6):1779-1786.PubMedGoogle Scholar

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© Lee et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.