Journal of Surgical Oncology Supplement 2:155-160 (1991)

local Recurrence After Curative Resection for Colorectal Cancer: Frequency, Risk Factors and Treatment ~~

SERGIO STIPA, MD, FACS, VIRGIL10 NICOLANTI, MD, CLAUD10 BOTTI, MD, MAURlZlO COSIMELLI, MD, E R N E S T 0 MANNELLA, MD, FRANCESCO STIPA, MD, DIANA GIANNARELLI, PhD, CATERINA BANGRAZI, MD, AND RENATO CAVALIERE, MD From the First Department of Surgery, The University of Rome, ”La Sapienra,” Rome (S.S., V.N., F.S.), Regina Elena Cancer Institute, Rome (C/.B., M.C., E.M., D.C., R.C.), and ENEA C.R.E., Caraccia, Rome (Ca.B.), Italy

Analysis of 498 patients with colorectal carcinoma was retrospectively reviewed to evaluate the incidence, risk factors and therapy of local recurrent carcinoma following curative resection. Complete follow-up information was obtained in all but four patients (99.2%). After a median follow up of 42 months, 64 out of 469 (13.6%) patients developed local recurrence (LR). The incidence of LR was higher in rectal than in colon cancer patients (18.3% vs 8.9%) ( P < 0.005). Separate univariate and Cox analyses for rectal patients showed tumor site ( P < 0.02). Dukes stage ( P < 0.002), and adjuvant radiotherapy ( P = 0.05) determined risk of LR. For colon cancer patients risk of LR was determined by histological tumor grade ( P < 0.01). Out of 64 patients, 5 (7.8%) underwent radical excision of LR. Forty percent of these survived at 5-year ( P < 0.08). Palliative treatment (radio-chemotherapy) obtained a 5-year survival of 15.3%, with no survivors in no-treatment group. These results suggest that local recurrent colorectal carcinoma remain a difficult treatment problem. More effective combinations of surgery and adjuvant therapy are therefore mandatory to reduce the incidence of local failure in high risk colorectal patients. KEYWORDS:colorectal cancer, local recurrence, risk factors, adjuvant radiotherapy, Dukes staging

INTRODUCTION Local recurrence (LR) occurs in 8-30% of patients with primary adenocarcinoma of the colon and rectum radically treated [ 1-51. Most of these recurrences appear within 2 years from surgery for the primary lesion [ 1,2]. Fifty to 70% of isolated LR are amenable to further resection [6]. Radical excision, however, is possible in 25% of these cases with an expected 5-year survival rate of 20-50% [2,7-91. These figures are not improved by radiotherapy and chemotherapy [lo]. Moreover, locally recurrent colorectal cancer is often a painful and debiliting condition that badly influences the quality of life. Patients at high risk of local relapse should be identified and treated in a multidisciplinary fashion in order to favorably modify their natural history. 0 1991 Wiley-Liss, Inc.

In this study we report a retrospective analysis of 498 patients whose colorectal cancer was resected with curative intent. The impact of some clinico-pathological and treatment related variables on locoregional control of disease and survival after local relapse were investigated.

PATIENTS AND METHODS From 1970 to 1990, 498 patients affected with large bowel adenocarcinoma who were referred to the two senior authors (S.S., R.C.) have been treated with Accepted for publication May 30, 1991. Address reprint requests to Dr. Sergio Stipa, The First Institute of Clinical Surgery, Policlinico Umberto I, Viale del Policlinico, 00161, Rome, Italy.

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curative surgery. For the purpose of this study curative resection meant that the surgeon found no evidence of hepatic or peritoneal metastases and resected all grossly visible and palpable tumor without evidence of tumor infiltration at the resection line. Age, sex, tumor site, type of resection, histological grade, Dukes stage, and adjuvant radiotherapy were recorded for each patient in a computerized data base. LR was defined as tumor growth at the suture line, regional nodes, adjoining structures, pelvis and perineum. Relapses occurring in the latter four sites were grouped as “tumor bed recurrences.” Physical examination and hematological controls (including serum levels of carcinoembryonic antigen (CEA) in the last 10 years) were performed every 3 months for 2 years, every 6 months for 3 years, and every year starting from the fifth year after surgical resection. Colonoscopy, abdominal and pelvic ultrasonography , computed tomography (CT) scan, and more recently, magnetic resonance imaging were employed every year or when required in order to achieve an early diagnosis of tumor recurrence. Complete follow-up information was obtained in all but four patients (99.2%). Median observation time was 42 months (range 12-213). The influence of each clinicopathologic and treatment variable on LR free interval after surgery was first examined. For the statistical analysis the Kaplan Meier method was used [ 1 11. Information obtained from the univariate analysis was applied to local disease free survival analysis with covariate using the Cox model of proportional hazard [ 121. Twenty-five patients dying within 30 days from operation (5%) and four patients with incomplete follow-up information were excluded from analysis.

TABLE I. Resection Modality in Colon Cancer Procedure Anterior resection Right colectomy Left colectomy Segmental resection Transverse colectomy Sub-total colectomy Hartmann Abdominoperineal resection Others

No. patients (%)

96 (39.6) 64 (26.3) 45 (18.1) 14 (5.8) 12 (4.9) 5 (2.1) 4 (1.6) 1 (0.4) 2 (0.8)

patients received post-surgical radiotherapy, namely in right colon localizations. One hundred forty-six out of 469 patients (3 1.1%) developed tumor relapse. Sixty-four patients (13.6%) experienced LR and 25% (16/64) of these patients also had evidence of distant synchronous or metachronous metastases. The incidence of LR was higher in rectal cancer patients (43/235) (18.3%) than in the colon cancer group (21/234) (8.9%) (P < 0.005). Table VI outlines the detailed incidence of local relapse according to primary site within the large bowel. The median time to LR was 18 months and only 33% of local failure were diagnosed 2 years after resection of the primary tumor. Univariate analysis demonstrated that in rectal patients local relapse occurred more frequently in: a) tumors located below the peritoneal reflection ( P < 0.007); b) abdominoperineal resection ( P < 0.002); c) advanced stage of disease ( P < 0.002); and d) no adjuvant radiotherapy ( P < 0.05) (Table VII). The Cox multivariate analysis identified the tumor site ( P < 0.02), Dukes stage ( P < 0.002) and adjuvant radiotherapy ( P = 0.05) as independent predicting factors RESULTS of local relapse for rectal cancer patients (Table VII). These findings induced us to stratify patients according Primary tumor was located in the colon in 234 cases and in the rectum (1 8 cm from anal verge, evaluated by to stage of disease and tumor site. Six classes of patients proctosigmoidoscopy) in 235 cases (95 above and 140 with different incidence of LR rates were therefore obtained (Fig. 1). The most favorable prognosis was below peritoneal reflection). The mean & SD age of the patients was 62 11, showed by patients with tumor located above the peritoranging from 20 to 79 years. Two hundred forty-eight neal reflection with Dukes stage A (0%of LR rate) while patients were male (52.8%) and 221 patients were female the highest incidence of local relapse was observed in (47.2%). patients with low rectal tumors with lymph node meColonic and rectal surgical resection modalities are tastases (43.5%). Only in patients with Dukes stage B shown in Tables I and 11. In 8.3% of cases (39/469) it was lower rectal tumors the LR rate was significantly reduced necessary to resect additional adjacent viscera firmly by adjuvant radiotherapy (7.6% vs 31.7%) ( P = 0.05). adhering to the primary tumor; resected organs are Separate mono and multifactorial analyses for colonic reported in Table 111. Pathological staging of neoplasia patients identified tumor grade as the only predictor of was performed according to Dukes’ classification (13) LR (Tab VIII) ( P < 0.01). Local recurrence rate ranged (Table IV). In 83 out of 235 rectal patients (35.3%) from 0% for well-differentiated tumors to 15.1% for surgical treatment was followed by radiotherapy (modal- poorly differentiated or undifferentiated tumors. ities are shown in Table V), while only a few colonic The overall 5-year survival rate from diagnosis of

*

Local Recurrence in Colorectal Cancer

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TABLE 11. Resection Modalitv in Rectal Cancer ~

~~~

Tumor location ~~

Procedure

Extraperitoneal No. of patients (%)

Intraperitoneal No. of patients (%)

41 (27.0) 100 (65.8)

85 (89.5) 2 (2.1) 2 (2.1) 2 (2.1) l(1.0) 3 (3.2)

Anterior resection Abdominoperineal resection Hartmann Sub-total colectomy Segmental resection Others

-

-

11 (7.2)

TABLE 111. Adjacent Organs Resected No. of patients Vagina Uterus and/or ovary and fallopian tube Partial cystectomy Abdominal wall Stomach Spleen Small bowel

12 11 5 4 3 2 2

TABLE IV. Stage of Disease According to Dukes’ Classification Stage A B C

Rectum

Colon

No. of patients (%)

No. of patients (%)

69 (27.1) 120 (47.0) 66 (25.9)

45 (18.5) 131 (53.9) 67 (27.6)

recurrence (residual survival) was 12.3% (median 15 months). Residual median survival was slightly better in the absence of distant metastases (19 months) than in the presence of systemic disease ( I 1 months). Selected treatment options for local recurrent colonic and rectal carcinoma in 64 evaluable patients are reported in Table IX. Surgery was performed in 28.1% (1 8/64) of patients with local failure. No operative mortality was observed. Further details on surgical modalities of treatment for LR are outlined in Table X. Resectability rates for anastomotic and tumor bed recurrence were 66.7% (8/12) and 19.2% (10/52) respectively (P < 0.002). The cumulative 5-year residual survival rate after surgical treatment was 14.5%. The corresponding percentages after radio-chemotherapy and after no treatment were 15.3 and 0. Resection with curative intent of the LR was performed in 5 out of 18 patients (27.7%). Four of these recurrences were anastomotic (50%) and 1 tumor bed (10%) (P < 0.08). The cumulative 5-year residual survival of the radically re-resected patients was 40%

TABLE V. Adjuvant Radiotherapy in 235 Rectal Cancer Patients Stage A

B C Overall

No. of patients 63 111 61 235

Radiotherapy Preoperative

Postoperative

Sandwiches

10

0 31 17 48

0 13 7 20

3 2 15

TABLE VI. Location of Recurrence Colon (234 patients)

Anastomosis Tumor bed Overall (%)

6 15 21 (8.9)

No. of patients Rectum (235 patients) 6 37 43 (1 8.3)

Overall (%)

12 (2.5) 52 ( I 1.0) 64 (13.6)

(median 30 months). No patients survived at 5 years after non curative re-resection (median 18 months). All these results are summarized in Figure 2.

DISCUSSION In this study we tried to identify by means of univariate and multivariate analysis clinico-pathological variables that were independently associated with a higher risk of the LR after curative surgery for cancer of the colon and rectum. Separate Cox analysis for rectal cancer patients identified tumor site, Dukes stage of disease and adjuvant radiotherapy as independent predictors of LR. These findings are in keeping with other reports [1,5,14]. Tumor site seems to heavily increase the risk of LR within each Dukes stage rectal cancers. This poses the problem whether rectal tumors originating below the peritoneal reflection, including those apparently confined within the bowel wall, should be considered candidates for adjuvant radio-chemotherapy or more aggressive

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Stipa et al. TABLE VII. Univariate and Multivariate Analvsis in Rectal Cancer ~~

Variable

No. of patients

Local recurrence (%)

P Value*

P Value**

14 87 134

25.9 22.9 20.8

NS

NS

133 102

20.0 24.5

NS

NS

95 140

11.7 32.2

0.007

0.019

137 98

13.5 34.0

0.002

NS

30 150 45 10

6.7 19.5 36.8 33.3

0.07

NS

63 111 61

8.8 19.7 43.6

0.002

0.002

69 103

17.4 33.0

0.05

0.052

Age 60 Sex male female Tumor site above peritoneal reflection below peritoneal reflection Type of resection Anterior resection Abdominoperineal resection Grade GI G2 G3 Gx Dukes stage A B C Radiotherapya Yes No

*Value derived from univariate analysis. **Value derived from multivariate analysis. aB and C Dukes stage rectal cancers.

43.5% BELOW

E401 J

0 W

20 -I

a

g

10

-J

0

B

A DUKES'

C

STAGE

Local recurrence rate in rectal cancer according to Dukes stage and tumor rate (peritoneal reflection). Fig. 1.

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Local Recurrence in Colorectal Cancer TABLE VIII. Univariate and Multivariate Analysis in Colon Cancer Variable Age 60 Sex Male Female Tumor site Ascending colon Transverse colon Descending colon Grade G1 G2 G3 Gx Dukes stage A B C

No. of patients

Local recurrence (%)

P Value*

P Value**

17 85 132

23.8 9.5 8.9

NS

NS

115 119

7.0 13.3

NS

NS

59 18 157

4.8 12.0 12.5

NS

NS

30 130 44 30

0.0 8.9 15.1 9.2

0.03

0.0 1

45 125 64

7.3 12.2 9.1

NS

NS

*Value derived from univariate analysis. **Value derived from multivariate analysis.

TABLE X. Surgical Treatment of Local Recurrence

TABLE IX. Treatment of Local Recurrence Modalitv of treatment Surgery Radio and or chemotherapy No treatment

No. of Datients (%) 18 (28.1) 21 (32.8) 25 (39.1)

surgery. Tumor foci have been demonstrated at a distance of 4 cm or more within the lateral and posterior aspects of perirectal soft tissue [15]. En bloc dissection of the mesorectum along with a wide pelvic lymphadenectomy has been associated with a lower LR rate [4] when compared with conventional resections. This therapeutical advantage was seen in both early and late stages of disease [ 161. At univariate analysis, abdominoperineal resections showed a higher 5-year rate of LR when compared to anterior resections (36.9% vs 10.5%). This difference probably was not real because of the higher number of lower rectal cancers in the Miles group. When controlling for Dukes stage and tumor site no difference in terms of local relapse was observed in abdominoperineal vs. anterior resections. These findings agree with other large series [2,4,14]. Radiotherapy was mostly effective in reducing LR rate in Dukes B stage tumors originating below the peritoneal reflection. The benefit of radiotherapy was negligible in

No. of patients

ODerative Drocedure Abdominoperineal resection Hartmann Resection and reanastomoses Perineal extirpation Transanal diatermocoagulation Laparotomy Overall (%)

Potentially curative

3 0 2 0 0 0 5 (27.7)

Palliative or honerable

3 3 2 1 1 3 13 (72.3)

Dukes C stage group. This observation is however biased by the insufficient number of patients analyzed and by the different quality of irradiation given in this subgroup. Recent randomized studies found adjuvant radiotherapy and radio-chemotherapy effective in reducing the LR rate in Dukes B and C low rectal tumors [17,18]. However, in spite of reduction of LR by 30% or more, the risk of developing local relapse was not completely eliminated. It should be interesting to examine in controlled studies the impact of the so called “aggressive surgery” (radical excision of mesorectum, wide ileopelvic lymphadenectomy and total proctectomy with or without coloanal reconstruction) in association with adjuvant therapy on local control of high risk low rectal cancer patients.

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1 7 L O C A L RECURRENCE

I

I

1

SURGERY I I

1

qP CURATIVE

5-YRS.

PALLIATIVE

H OVERAL

Fig. 2. Five-year survival after treatment for local recurrent colorectal carcinoma.

For colon cancer patients the risk of local tumor recurrence was determined by histological grade. Unlike reported by others [ 1,191 Dukes stage and site were not confirmed as statistically significant prognostic factors. It is unclear whether these findings are to ascribe to a different etiopathogenesis of LR in colon carcinoma or merely represent a reflection of statistical variation. The results of our analysis are not so impressive as to identify a group of colon cancer patients at high risk of LR for whom adjuvant treatment is desirable. In our experience, surgical control of LR was possible in 28% of patients with no operative mortality. In accordance with other authors [6,9,20,2 11, anastomotic recurrences had higher resectability and curability rates. Isolated LR were associated with a 5-year survival of 40% when radically resected. Unfortunately, only 10.4% of patients (348) benefitted such treatment. When local recurrent carcinoma could not be completely extirpated as it was in the majority of tumor bed recurrences, 5 year survival dramatically dropped to 0%, with a median survival of 18 months. Radio-chemotherapy palliative treatment gave similar results. Our experience, therefore, confirm the limited role of surgical and medical treatment in the management of locoregional recurrent colorectal carcinoma. Since aggressive follow-up and early detection of LR has not yet demonstrated a prognostic advantage in these patients,

the best treatment of local relapse from colorectal cancer remains its prevention by a correct preoperative staging and an adequate combination of radical surgery and adjuvant therapy.

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