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  Volume 95
Numero 6
novembre-dicembre 2009 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
Retrospective long-term results and prognostic factors of postoperative treatment for UICC stages II and III rectal cancer

Domenico Genovesi, Giampiero Ausili Cèfaro, Annamaria Vinciguerra, Antonietta Augurio, Marco D’Alessandro, Valentina Borzillo, Rita Marchese, Marta Di Nicola
1Radiation Oncology Department, and 2Laboratory of Biostatistics, Department of Biomedical Science, “G. d’Annunzio University”, Chieti, Italy

Key words: adjuvant treatment, prognostic factors, radiochemotherapy, rectal cancer.

abstract

Aims. To retrospectively evaluate 5-year local control, disease-free survival, cancer-specific survival and overall survival rates in patients with UICC stages II and III rectal cancer treated with adjuvant therapy and especially to analyze the impact of some prognostic factors on clinical outcome at univariate and multivariate analyses.
Methods and materials. We retrospectively reviewed 306 patients treated with postoperative 5-fluorouracil-based chemoradiation (278 patients) or radiotherapy alone (28 patients) after curative surgery. The following prognostic factors were considered at univariate and multivariate analyses: age, sex, tumor location, surgery procedure, pathological stage, histology, tumor grade, surgical margins and radiotherapy technique.
Results. The 5-year actuarial rates for local control, disease-free survival, cancer-specific survival and overall survival were respectively 89.7%, 59.7%, 68.6% and 61.4% for the 278 patients (91%) treated with postoperative chemoradiation. Univariate analysis showed that abdominal-perineal resection impacted disease-free survival and that the T4 variable had an impact on cancer-specific survival and disease-free survival. Instead, age ≥70, N2, IIIB (p T3 p N1) and IIIC (p T3 p N2) stage impacted cancer-specific survival, disease-free survival and rate of distant metastases. Multivariate analysis showed as significant variables age ≥70 years, pN1 and pN2 and extraperitoneal tumor location.
Conclusions. Our retrospective study showed a good 5-year local control. Factors such as individual pT4, pN1, pN2, age ≥70 years, abdominal-perineal resection, stages IIIB-IIIC versus II-IIIA and extraperitoneal tumor location negatively influenced disease-free survival, distant metastases and cancer-specific survival. Differences exist between stages II and III rectal cancer and treatment modulation and intensification are required in order to offer the most appropriate and effective adjuvant treatment and to improve survival of rectal cancer patients.

Introduction
A randomized German trial showed a benefit in local control (LC), acute and late toxicity and sphincter-saving rate for preoperative chemoradiation compared with postoperative chemoradiation1,2 in locally advanced rectal cancer (International Union Against Cancer UICC Stages II and III)3. Nevertheless, postoperative chemoradiation remains a valid option for locally advanced rectal cancer patients, and it still represents a treatment of choice at the moment.
Several important randomized studies have shown improved LC and demonstrated a survival benefit in terms of overall survival (OS) and disease-free survival (DFS) after postoperative 5-fluorouracil (5-FU)-based radiochemotherapy versus surgery alone or surgery followed by adjuvant therapy with radiotherapy or chemotherapy alone4-13. Therefore, combined chemoradiation improves LC, rate of distant metastases and OS with a satisfactory overall gastrointestinal and hematological acute toxicity14-16. The beneficial effect of adjuvant treatment was only achieved by combined chemoradiation with radiation doses >45-50 Gy/reference point in daily fractions of 1.8-2.0 Gy4,8.
In 1990, a US NIH Consensus Conference recommended postoperative 5-FU-based radiochemotherapy as standard treatment for stages II and III rectal cancer17, and some retrospective studies reviewed clinical outcome (LC, DFS and OS) referred to a mean 5-year follow-up18-21. Moreover, many factors could influence local recurrence, DFS and OS18,21-39.
Although with all the limitations of a retrospective study, the aim of the present analysis was to determine 5-year LC rates, DFS, cancer-specific survival (CSS) and OS of 278 patients with UICC stages II and III rectal cancer treated with postoperative chemoradiation. Particularly, it analyzed the impact of some factors on DFS, CSS and distant metastases at univariate and multivariate analyses.

Methods and materials
We retrospectively reviewed 306 patients (217 male and 89 female) with UICC stages II and III rectal cancer treated between 1993 and 2003 at the Radiation Oncology Department of Chieti with postoperative radiotherapy with or without concomitant 5-FU chemotherapy schedules. Selection criteria were: postoperative 5-FU-based chemoradiation (278 patients), no exclusion according to the drugs and performed surgery between 1993-2003.
Tumor site was defined as low for tumors located within 5 cm of the anal verge, middle for tumors located between 6 and 10 cm, and high (or rectosigmoid junction tumors) for tumors between 11 and 15 cm. Tumor site was identified by endoscopy, preoperative computerized tomography (CT) and surgical clips. Local recurrence was defined as pelvic relapse after surgery, and it was histologically or radiologically proven. The following variables were considered: age (<70 and ≥70 years), sex, tumor site, surgery procedure, pathologic stage, histology, tumor grade, surgical margins and radiotherapy technique.
All patients were surgically treated with anterior rectal (ARR) or abdominal-perineal resection (APR). A total of 278 patients was treated with postoperative concomitant radiotherapy and 5-FU, and 28 patients were treated with postoperative radiotherapy alone. The UICC-TNM system was used for tumor staging3.
Radiotherapy was delivered with a total dose of 50 Gy (1.8-2.0 Gy/die for five days a week) and a mean time interval of 16 weeks from surgery. A 2D radiotherapy technique was used from 1993 to 2000, whereas a 3D technique was used from 2001 to 2003 according to International Commission on Radiation Units and Measurements (ICRU) recommendations40-41.
All patients were treated in prone position with a 10 MV photon linear accelerator: target volume included surgical clips suggesting tumor bed, internal iliac nodes, obturator nodes, presacral and perirectal spaces; for T4 tumors, external iliac nodes were also included. After abdominal-perineal amputation (Miles’amputation), the perineal scar was also included in the target volume.
Six cycles of 5-FU-based chemotherapy were administered to 278 patients. The treatment consisted of two cycles of an endovenous bolus infusion of 5-FU (500 mg/m2/die for five consecutive days followed by an interval of four weeks) and then another two cycles of 5-FU (endovenous bolus of 500 mg/m2/die for three consecutive days) administered during the first and the last week of the radiotherapy treatment. Another two cycles of chemotherapy (endovenous bolus of 400 and 500 mg/m2/die respectively, for five consecutive days) were administered four weeks after the end of the radiochemotherapy treatment. Acute and late toxicity were assessed using the Radiation Therapy Oncology Group (RTOG) scale42.
Patients were followed every four months the first year, every six months from the second to the fifth year, and then once a year. Follow-up evaluation started after the completion of adjuvant treatment. During the follow-up, physical examination, performance status evaluation, complete blood count, serum chemistry, tumor markers (CEA and CA 19-9 levels), chest radiography and colonoscopy were performed every four months for the first year. Moreover, chest-abdominal-pelvic CT scan was performed at the fourth and twelfth month for the first year. All these studies were repeated every six months for the subsequent 5 years. After 5 years, a colonoscopy and chest-abdominal-pelvic CT scan were performed every 12 months.

Statistical analysis
All qualitative factors were summarized as frequency and percentage and all quantitative factors as mean and standard deviation or median and range. The Kaplan-Meier method was used to analyze LC, DFS and CSS and also to estimate CSS, DFS and distant metastases rate and the standard error at 60 months of follow-up. Statistical significance between curves was evaluated using the logrank test. Multivariate analysis was performed using the Cox proportional hazards model. Covariates were: age, gender, T and N stage, margin status, grading, tumor location and radiation therapy technique. Calculating the exponential of regression coefficients from the Cox model provided an estimate of the hazard ratio and the 95% confidence interval 43.
Follow-up was defined as the interval between surgery and death or as the time between surgery and the first verified event or the last follow-up. P ≤0.05 was considered statistically significant. All statistical analyses were performed using SPSS® software 11.0 (SPSS Inc, Chicago, IL, USA).

Results
Median follow-up was 53 months (range, 6-194), and the median age was 62 years (range, 28-86). Characteristics of patients are shown in Table 1. At surgery, 240 patients (78.4%) were <70 years and 66 (21.6%) were ≥70 years. A total of 203 of 306 patients (66.3%) were treated with ARR and 103 of 306 patients (33.7%) with APR.

Table 1 - Demographic, histologic and treatment characteristics of patients

Variable

 

No. of patients

%

 

 

 

 

Overall no.

 

306

 

Age at surgery (yr)

 

 

 

 

<70

240

78.4

 

≥70

66

21.6

Gender

 

 

 

 

Male

217

70.9

 

Female

89

29.1

Tumor location

 

 

 

 

Low rectum

74

24.2

 

Middle rectum

80

26.1

 

High rectum-rectosigmoid

103

33.7

 

Junction unknown

49

16.0

Pathologic stage

 

 

 

 

II

132

43.1

 

III

174

56.9

Margin status

 

 

 

 

Negative

228

74.5

 

Positive

5

1.6

 

Unknown

73

23.9

Surgery

 

 

 

 

ARR

203

66.3

 

APR

103

33.7

Radiation therapy technique

 

 

 

 

3-field

25

8.2

 

4-field

71

23.2

 

AP/PA technique

210

68.6

Tumor grading

 

 

 

 

1

35

11.4

 

2

223

72.9

 

3

23

7.5

 

Not evaluated

25

8.2

Chemotherapy

 

 

 

 

Yes

278

90.8

 

No

28

9.2

Histology

 

 

 

 

Adenocarcinoma

302

98.7

 

Mucinous

4

1.3

Months of follow-up, median, range

 

53

6-194

 

 

 

 

ARR, anterior rectal resection; APR, abdominal-perineal resection; AP/PA, anterior-posterior/posterior-anterior.

Table 2 - Distribution of pathological staging (pTN)

T

N0

N1

N2

 

 

 

 

1

-

 1 (0.3)

-

2

-

19 (6.2)

5 (1.6)

3

125 (40.9)

 80 (26.2)

59 (19.3)

4

 7 (2.3)

    5 (1.6)

5 (1.6)


Chemotherapy was contraindicated in 28 of 306 patients (9.2%) because of comorbidities. Distribution of pathological staging (T and N) is shown in Table 2. The 28 patients (9.2%) treated with adjuvant radiotherapy alone had no local recurrence, whereas 2 of them (7.1%) were alive with systemic disease at the last follow-up and 11 patients (39.3%) died because of metastatic disease. No local or distant recurrence was observed in 15 patients (53.6%).
For the 278 patients (91%) treated with postoperative chemoradiation, LC was 89.7%, DFS was 59.7%, CSS was 68.6%, and OS was 61.4% at 5 years, respectively. LC seemed to be constant for patients with a longer follow-up, whereas DFS and CSS seemed to be worse for patients with a longer follow-up (Figure 1). Twenty-six patients treated with postoperative chemoradiation experienced local recurrence, and 14 of them, who had distant metastases, died for disease-related causes.



Table 3 - Univariate analysis of impact of T stage, N stage and TN stage on cancer-specific survival, disease-free survival and distant metastases at 60 months of follow-up

Variable

Cancer-specific survival

Disease-free survival

Distant metastases

 

 

 

 

 

 

 

 

 

 

60 mo rate ± SE*

P§

60 mo rate ± SE*

P§

60 mo rate ± SE*

P§

 

 

 

 

 

 

 

 

T-stage

 

 

 

 

 

 

 

T1-2

76.8 ± 9.2

-

67.4 ± 9.5

-

68.8 ± 9.8

-

 

T3

69.4 ± 3.1

ns

60.5 ± 3.2

ns

64.7 ± 3.2

ns

 

T4

41.7 ± 12.7

<0.01

36.8 ± 12.3

<0.05

46.2 ± 13.5

ns

N-stage

 

 

 

 

 

 

 

N0

78.0 ± 4.0

-

68.9 ± 4.3

-

72.8 ± 4.2

-

 

N1

66.1 ± 4.9

ns

60.7 ± 5.0

ns

64.5 ± 5.0

ns

 

N2

53.9 ± 6.5

<0.001

40.3 ± 6.5

<0.001

45.9 ± 6.9

<0.001

TN stage

 

 

 

 

 

 

 

IIIA (pT1-2 pN1)

75.7 ± 10.8

-

69.3 ± 10.5

-

73.0±10.4

-

 

IIIC (pT1 pN2)

80.0±17.9

ns

60.0 ± 21.9

ns

40.0 ± 21.9

ns

 

IIA (pT3 pN0)

79.2 ± 4.0

-

74.0 ± 4.1

-

74.7 ± 4.2

-

 

IIIB (pT3 pN1)

65.5 ± 5.7

<0.05

60.0 ± 5.8

<0.05

63.1 ± 5.8

<0.05

 

IIIC (pT3 pN2)

54.0 ± 7.0

<0.001

39.8 ± 7.1

<0.001

44.8 ± 7.4

<0.001

 

IIB (pT4 pN0)

57.1 ± 18.7

-

42.9 ± 18.7

-

42.9 ± 18.7

-

 

IIIB (pT4 pN1)

40.0 ± 21.9

ns

40.0 ± 21.9

ns

50.0 ± 25.0

ns

 

IIIC (pT4 pN2)

30.0 ± 22.3

ns

26.7 ± 22.6

ns

53.3 ± 24.8

ns

 

 

 

 

 

 

 

 

*Unadjusted Kaplan-Meier estimates expressed as percentage.

§Logrank test versus the first category.

ns, not significant.


The individual evaluation of pT and pN characteristics showed that the pT4 variable had a statistically significant impact on CSS and DFS (P <0.01 and P <0.05, respectively) and that the pN2 variable had a statistically significant impact on distant metastases, CSS and DFS (P <0.001).
Pathologic stages IIIB (pT3pN1) and IIIC (pT3pN2) had a statistically significant impact on CSS, DFS and distant metastases (P <0.05 and P <0.001, respectively) (Table 3).
The 5-year univariate analysis showed that pathologic stages IIIB (pT3pN1) and IIIC (pT3pN2) compared with stages IIIA and II had a statistically significant impact on CSS, DFS and distant metastases. Age ≥70 years and pathologic III stage also had a statistically significant impact on CSS, DFS and distant metastases.
The APR surgical procedure and tumor location had an impact on DFS and distant metastases, respectively (Table 4).
Multivariate analysis of factors influencing CSS, DFS and distant metastases showed that age ≥70 years was a statistically significant factor for DFS (P <0.05) and distant metastases (P <0.01).
The N1 variable was a statistically significant factor only for CSS (P <0.05), whereas the N2 variable was a statistically significant factor for CSS (P <0.001), DFS (P<0.001) and distant metastases (P <0.01).
An intraperitoneal tumor location (high rectum and rectosigmoid junction) was better than other extraperitonal locations as a prognostic factor for CSS (P <0.05) and DFS (P <0.01) (Table 5).
Grades 3 and 4 acute gastrointestinal toxicity occurred in 6% of patients and acute hematologic toxicity in 8%. Twenty-three patients experienced grades 3-4 gastrointestinal late toxicity and 12 patients experienced grade 4 late toxicity in terms of intestinal obstruction.

Table 4 - Univariate analysis of impact of clinical characteristics on cancer-specific survival, disease-free survival and distant metastases at 60 months of follow-up

Variable

Cancer-specific survival

Disease-free survival

Distant metastases

 

 

 

 

 

 

 

 

 

 

60 mo rate ± SE*

P§

60 mo rate ± SE*

P§

60 mo rate ± SE*

P§

 

 

 

 

 

 

 

 

Gender

 

 

 

 

 

 

 

Male

65.0 ± 3.5

-

56.5 ± 3.6

-

60.8 ± 3.6

-

 

Female

77.4 ± 4.7

ns

69.7 ± 5.1

ns

72.5 ± 5.1

ns

Age at surgery (yr)

 

 

 

 

 

 

 

<70

70.4 ± 3.1

-

66.1 ± 3.2

-

67.5 ± 3.3

-

 

≥70

60.8 ± 6.9

<0.05

46.1 ± 6.9

<0.05

51.0 ± 7.0

<0.05

Tumor location

 

 

 

 

 

 

 

Low rectum

66.2 ± 6.0

-

56.6 ± 6.1

-

60.3 ± 6.1

-

 

Medium rectum

72.6 ± 5.3

ns

65.7 ± 5.5

ns

71.6 ± 5.3

<0.05

 

High rectum-rectosigmoid junction

70.8 ± 4.9

ns

68.5 ± 4.8

ns

72.4 ± 4.7

ns

Pathologic staging

 

 

 

 

 

 

 

II

78.0 ± 4.0

-

68.9 ± 4.3

-

72.8 ± 4.2

-

 

III

61.3 ± 4.0

<0.001

52.9 ± 4.0

<0.01

57.5 ± 4.1

<0.01

Margin status

 

 

 

 

 

 

 

Negative

69.1 ± 3.4

-

60.0 ± 3.5

-

66.1 ± 3.4

-

 

Positive

80.0 ± 17.9

ns

80.0 ± 17.9

ns

100.0

ns

Surgery

 

 

 

 

 

 

 

ARR

71.2 ± 3.5

-

63.3 ± 3.7

-

67.5 ± 3.6

-

 

APR

63.2 ± 5.0

ns

53.8 ± 5.1

<0.05

57.5 ± 5.2

ns

Technique

 

 

 

 

 

 

 

3-4 field

72.4 ± 5.6

-

55.1 ± 7.6

-

56.7 ± 7.6

-

 

AP/PA

67.1 ± 3.3

ns

60.2 ± 3.4

ns

65.9 ± 3.4

ns

Tumor grading

 

 

 

 

 

 

 

G1 or G2

68.6 ± 3.1

-

61.5 ± 3.2

-

66.5 ± 3.2

-

 

G3

66.0 ± 10.6

ns

54.5 ± 10.9

ns

57.6 ± 10.9

ns

 

 

 

 

 

 

 

 

*Unadjusted Kaplan-Meier estimates expressed as percentage.

§Logrank test versus the first category.

ARR, anterior rectal resection; APR, abdominal-perineal resection; AP/PA, anterior-posterior/posterior-anterior; ns, not significant.

Table 5 - Multivariate analysis of factors influencing cancer-specific survival, disease-free survival and distant metastases

Variable

Cancer-specific survival

Disease-free survival

 

Distant metastases

 

 

 

 

 

 

 

 

 

 

 

HR (95% CI)

P

HR (95% CI)

P

HR (95% CI)

P

 

 

 

 

 

 

 

 

Age at surgery (yr)

 

 

 

 

 

 

 

<70

1

-

1

-

1

-

 

≥70

1.57 (0.97-2.76)

ns

1.61 (1.08-2.52)

<0.05

2.07 (1.26-3.39)

<0.01

N-stage

 

 

 

 

 

 

 

 

N0

1

-

1

-

1

-

 

N1

1.70 (1.08-3.13)

<0.05

1.57 (0.98-2.54)

ns

1.54 (0.90-2.63)

ns

 

N2

3.42 (2.10-6.29)

<0.001

3.01 (1.90-4.95)

<0.001

2.40 (1.35-4.27)

<0.01

Tumor location

 

 

 

 

 

 

 

Low rectum

1

-

1

-

1

-

 

Middle rectum

0.68 (0.41-1.16)

ns

0.65 (0.41-1.11)

ns

0.64 (0.34-1.21)

ns

 

High rectum-rectosigmoid junction

0.57 (0.34-0.95)

<0.05

0.53 (0.33-0.85)

<0.01

0.62 (0.32-1.17)

ns

Technique

 

 

 

 

 

 

 

3-4  field

1

-

1

-

1

-

 

AP/PA

1.64 (0.96-2.88)

ns

1.09 (0.69-1.72)

ns

0.89 (0.41-1.92)

ns

 

 

 

 

 

 

 

 

HR, hazard ratio estimated by Cox proportional hazards model adjusted for T-stage, gender, margin status, surgery and grading.

AP/PA, anterior-posterior/posterior-anterior; ns, not significant.



Discussion
The historical combined randomized postoperative 5-FU-based chemoradiation trials demonstrated an improvement of LC ranging from 83% to 92%, with a mean survival rate of 60%9-12,44. Although with all limitations of a retrospective analysis, with a long period of collection and some differences in technologies, radiotherapy and surgery procedures, we confirmed the importance of some factors which explain the heterogeneity within stages II and III regarding prognosis.
In the present study, for the postoperative chemoradiation group (278 patients), the 5-year results showed that LC was 89.7%, and this seems to remain the same for patients with a longer follow-up. DFS was 59.7% and CSS was 68.6% at 5-years, with worse results for patients with a longer follow-up. OS was 61.4% at 5-years.
Wulf et al.18, in their retrospective surveillance study of 198 patients with stages II-III rectal cancer, observed a 5-year LC of 75%, a DFS of 53% and a CSS of 53%. Bagatzounis et al.19 retrospectively analyzed 112 stage II-III patients treated with radiotherapy (44 patients) and adjuvant 5-FU-based radiochemotherapy (68 patients) and reported a 5-year LC rate of 67% (radiotherapy group) and 69% (chemoradiation group), DFS of 50%-52% for the two groups, and OS of 53% (radiotherapy group) and 63% (chemoradiation group).
In our study, univariate analysis showed that the most important factors significantly influencing DFS, distant metastases and CSS were age ≥70, the APR surgical procedure, individual factors pT4 and pN2, IIIB and IIIC stage. Multivariate analysis confirmed the impact of age ≥70, N1-2 factors and extraperitoneal site on survival. The most important historical studies showed that prognostic factors influencing local recurrences and survival in stages II-III/TNM (UICC) rectal cancer were primary tumor extension and positive nodes 9-11,18,20-39.
As regards tumor stage, Gunderson et al.28, in their pooled analysis of 2551 patients, analyzed the influence of individual factors T and N and pathological stage on LC, DFS and OS. They demonstrated a negative influence of T and N factors because a locally advanced tumor (T3-T4, N plus) had a worse prognostic evolution than others with a single factor alone (T3N0 or T1-2 N1). Therefore, stages II (T3-4 N0) and IIIA (T1-2 N1) had a better prognosis than stages IIIB (T3N1) and IIIC (T3-4 N2).
Greene et al.29 analyzed data entered in a National Cancer Data Base for 5,987 stage III patients with rectal cancer between 1991 and 1993. Stage IIIA patients had an observed 60% 5-year survival, IIIB patients 41%, and IIIC patients 29%, with significant differences in all stages.
Our data confirmed these evaluations: univariate analysis confirmed that factors such as pT4, pN2, IIIB and IIIC stage influenced DFS, distant metastases and CSS, whereas multivariate analysis identified N1 and N2 as factors that influenced DFS, distant metastases and CSS.
In the retrospective study of Bagatzounis et al.19, they revealed that positive lymph node stage and high tumor differentiation were independently statistically significant for DFS and OS. Other studies evidenced the importance of number of removed nodes (≥12) and the negative prognostic impact on clinical outcome of node-positive number ≥318,21,45-46. Mean number of removed nodes was 14 (range, 5-43) in our study, and we showed the importance of N1 and N2 factors at multivariate analysis.
Factors such as tumor grade have been shown to influence survival, LC and metastasis rate18-19,24. However, in our analysis such a factor was not statistically significant.
Jatzko et al.34 found that age was not a significant factor at univariate analysis, but it became significant at multivariate analysis because age ≥65 years influenced DFS. Other studies have demonstrated the influence of age on survival47-48, but Myerson et al.24 did not find an influence of age on LC and DFS. Our study showed an impact of age (≥70 years) on DFS both at univariate and multivariate analysis and also an influence on CSS and metastasis rate at multivariate analysis.
Other variables have also been considered as factors that influence LC, metastasis rate, DFS and OS, such as negative surgical margins18, lymphatic vascular invasion19, tumor fixation at surgery, gender49 and intraperitoneal versus extraperitoneal rectal cancer location50. In our analysis, surgical margins and tumor grade were not statistically significant variables, probably due to the few number of patients with positive or unknown margins and to the few number of G3 cases or with an unknown tumor grade.
As regards tumor location, Benzoni et al.50 examined clinical outcome in patients enrolled in a neoadjuvant chemoradiation followed by surgery protocol for rectal cancer, distinguishing between intraperitoneal and extraperitoneal cancer. The DFS and OS were worse for extraperitoneal than for intraperitoneal rectal cancer. Our data confirmed these evaluations in the multivariate analysis, with a negative influence of extraperitoneal tumor location on DFS and CSS. This could be explained by either an incomplete lymphatic resection or inappropriate application of chemoradiation protocols. It could be that extraperitoneal tumors are more aggressive than intraperitoneal tumors, spreading precociously or less responsive to adjuvant chemoradiation because of their localization, rather than differences in biological characteristics.

Conclusions
Even though the standard of therapy for locally advanced rectal cancer (stages II and III) is preoperative chemoradiation, the postoperative chemoradiation regimen represents a valid treatment option and is still a treatment choice for locally advanced rectal cancer in Italy at the moment. Although there are important differences between stages II and III in terms of biological aspects and prognosis, patients with stages II or III rectal cancer are often treated with similar adjuvant chemoradiation schedules in terms of radiation doses and drugs. Although with all limitations of a retrospective study, our results confirmed those of larger retrospective analyses. We pointed out the importance of prognostic factors in treatment modulation and intensification based on clinicopathologic characteristics, especially with regard to T and N substages 51,52.

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