peritoneal cavity, pelvis, or abdominal wall.6 According to a number of reports, LRR is ... were treated for primary colorectal cancer in the. Colorectal Cancer Unit ...
Surg Today (2004) 34:907–912 DOI 10.1007/s00595-004-2816-3
Potentially Curative Resection for Locoregional Recurrence of Colorectal Cancer Mehmet Fuzun1, Cem Terzi1, Selman Sokmen1, Tarkan Unek1, and Mehmet Haciyanli2 1 2
Department of Surgery, Colorectal Surgery Unit, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey Second Department of Surgery, Izmir Atatürk Training and Research Hospital, Izmir, Turkey
Abstract Purpose. Local recurrence after curative surgery for colorectal cancer may be treated by potentially curative surgery, defined as resection of all macroscopic disease. We conducted this retrospective study to show the effectiveness of potentially curative resection for patients with locoregional recurrence (LRR). Methods. We reviewed the records of 242 patients who underwent curative resection of colorectal cancer in our unit between 1988 and 2000. Locoregional recurrence developed in 50 (20.6%) patients, and was treated by R0 resection in 10 (20%) patients (group R0), by R1 resection in 8 (16%) patients (group R1), by R2 resection in 13 (26%) patients (group R2), and by surgery without resection in 12 (24%) patients (group NR). Seven (15%) patients did not undergo surgery (group NS). Results. The mean survival periods were 48, 36, 10, 5.6, and 5 months in groups R0, R1, R2, NR, and NS, respectively. There was no significant difference in survival between groups R0 and R1 (P ⫽ 0.5), but survival was significantly longer in groups R0 and R1 than in groups R2, NR, and NS (P ⫽ 0.001). Conclusion. These findings show that surgeons should aim to achieve at least macroscopic clearance of the recurrent tumor. Potentially curative surgery improves survival in selected patients with LRR after curative resection of colorectal cancer. Key words Colorectal cancer · Recurrence · Curative resection
Reprint requests to: M. Fuzun, Dokuz Eylul University Hospital, General Surgery, Inciralti, 35340 Izmir, Turkey Received: December 2, 2002 / Accepted: July 8, 2003
Introduction The prognosis and long-term survival of patients with colorectal carcinoma is dependent on two factors: the nature of the malignancy and the stage of the disease. Up to one third of patients have locally advanced or metastatic disease at the time of diagnosis, which precludes surgical cure. The remaining two thirds undergo potentially curative resection, but nearly half of these patients will suffer recurrence and die within 5 years.1 The most common sites of recurrence are the liver (25%), lungs (20%), and abdomen or pelvis (25%–30%).2,3–5 Locoregional recurrence (LRR), which is defined as recurrence in the tumor bed, regional nodes, adjoining structures, anastomosis, pelvis, perineum, and surgical scars, is responsible for about 30% of deaths.3 Locoregional recurrence can range from small isolated failures in the anastomosis to diffuse involvement of the peritoneal cavity, pelvis, or abdominal wall.6 According to a number of reports, LRR is associated with peritoneal, metastatic, or plurimetastatic deposits in 70%–90% of patients.3,4,7 There is no standard treatment for LRR of colorectal cancer, but depending on the primary treatment, many treatments, including surgery, external beam radiotherapy, intraoperative radiotherapy, systemic chemotherapy, locoregional chemotherapy, or combinations of these have been used. Chemotherapy alone or combined with radiotherapy can provide temporary relief of symptoms.8–10 Similarly, surgical resection, although not always curative, can provide good palliation of pain, obstruction, perforation, bleeding, and sepsis. For patients with recurrence after curative surgery for colorectal cancer, the choice of therapy is between nonsurgical palliative modalities and radical surgery.2,3,5,11,12 Active reoperation with grossly complete resection is indicated for recurrence of colorectal cancer, to achieve prolonged survival.
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We evaluated the outcome and survival of 50 patients who underwent potentially curative resection for LRR.
Table 1. Clinical features of the 242 patients who underwent curative resection of colorectal cancer
Patients and Methods
Sex Men Women Primary site Rectum Colon Stage of the primary tumor I II III Recurrence sites Locoregional Total Isolated Liver Total Isolated Lung Total Isolated Other Total Isolated
Between March 1988 and March 2000, 358 patients were treated for primary colorectal cancer in the Colorectal Cancer Unit, Dokuz Eylul University Hospital. The medical team included oncologists, radiation oncologists, pathologists, radiologists, and gastroenterologists. Most of the patients were operated on by the same surgeon (M.F.). After the exclusion of 90 (25%) patients found to have stage IV disease at presentation, 268 patients with potentially curable disease (stage I, II, III) underwent curative surgery (R0 resection).13 Six (2.2%) of these patients died postoperatively, 11 (4.1%) were lost to follow-up, and 9 (3.3%) died of causes other than colorectal cancer. Therefore, this retrospective study included 242 patients who underwent curative resection. The extent of resection for curative surgery encompassed the tumor with a wide local lateral margin and a distal margin of at least 5 cm. It also encompassed the mesentery to the origin of the major vessels. If the tumor was attached to the adjacent structures or viscera, en bloc excision was performed.14 We performed high ligation of the inferior mesenteric artery for all patients undergoing surgery with curative intent for rectal cancer. The entire mesorectum was mobilized to the pelvic floor using sharp dissection and the mesorectum distal to the tumor was completely excised when the tumor was less than 10 cm from the anal verge. For high rectal cancers the mesorectum was divided 5 cm distal to the tumor. Locally advanced tumors with adjacent organ involvement or wall fixation were resected en bloc. The clinical features of these patients are shown in Table 1. Patients with stage II or III colon cancer received postoperative chemotherapy, as 5-fluorouracil 400 mg/ m2 per day i.v. bolus ⫹ leucoverin 200 mg/m2 per day i.v. given over 2 h followed by 5-fluorouracil 600 mg/m2 per day as a 22-h infusion for 2 days. This regimen was given every 2 weeks, and repeated for 12 cycles. Patients with stage II or III rectal cancer received either pre- or postoperative chemotherapy plus radiotherapy, as 1.8 Gy per day, 5 days per week giving 25 fractions over a period of 5 weeks to a total dose of 4 500 cGy, as well as an infusion of 5-fluorouracil 225 mg/m2 per day given for 5 days/week for 5 weeks. Patients older than 75 years and those with concomitant cardiac disease did not receive any adjuvant treatment. All of the patients were followed up by clinical examination, carcinoembryonic antigen (CEA) assessment,
Mean age in years (range) Mean follow-up in years (range)
a b
56 (16–86) 4.2 (1–12) n 119 (49)a 123 (51) 97 (40) 145 (60) 35 (14) 119 (49) 88 (36) 50 (20.6) 33 (13.6)b 29 (12) 10 (4.1) 18 (7.4) 8 (3.3) 6 (2) 0
Values in parentheses are percentages Including five patients with peritoneal carcinomatosis
rigid rectosigmoidoscope, and abdominal ultrasonography every 3 months for the first 2 years, then every 6 months for the next 3 years and thereafter annually for 5 years. Patients also had an annual chest X-ray and abdominopelvic computerized tomography (CT), and a colonoscopy was performed every 2 years. Locoregional recurrence was defined as any tumor recurrence in the abdomen, excluding the liver, with or without concomitant distant metastases. Therefore, LRR included tumors in the operative field, adjacent structures, anastomosis, operative incisions, and peritoneal seeding or serosal involvement of the peritoneal structures. Recurrence developed in 75 (31%) of 242 patients and the sites of recurrence are shown in Table 1. Of these 75 patients, 50 (66%) had LRR, 18 of whom underwent potentially curative resection, whereas the remaining 32 underwent either a palliative (R2) resection or no resection. Potentially curative resection was defined as surgery for recurrent disease in which no macroscopic tumor was left behind. Potentially curative resection was classified as R0 postoperatively by histopathological examination as (resection with no residual tumor) or as R1 (resection with microscopic residual tumor).13 All of these 50 patients were in relatively good health and the magnitude of the re-resection was clearly explained. None of the patients had American Society
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M. Fuzun et al.: Locoregional Recurrence of Colorectal Cancer Table 2. Features of the 50 patients with locoregional recurrence Mean age in years (range) Period between primary surgery and recurrence in months (range) Mean follow-up after recurrence in months (range) Sex Men Women Primary site of the recurrence Rectum Colon Stage of the primary tumor (in number) Stage I Stage II Stage III Asymptomatic patients Treatment Potentially curative resections R0 resection R1 resection Noncurative procedures R2 resection No resection No surgery a
49 (16–76) 18 (3–56) 19.4 (2–76) n 28 (56)a 22 (44) 22 (44) 28 (56) 2 (4) 11 (22) 37 (74) 8 (16) 10 (20) 8 (16) 13 (36) 12 (24) 7 (14)
Values in parentheses are percentages
of Anesthesiology classification IV–V disease. The primary goal of surgery was to achieve gross and microscopic total resection. Patients with peritoneal carcinomatosis were carefully selected. Low-risk patients with few peritoneal surface metastases were selected for cytoreductive surgery and intraperitoneal chemotherapy. This issue was discussed elsewhere.15 When LRR was detected, all patients were considered as potential candidates for surgery. After clinical and radiological evaluation, resection with curative intent was planned for 27 patients. Resection of all macroscopic disease was achieved in 18 patients, as R0 in ten patients and as R1 in eight patients. However, in the remaining nine patients only R2 resection was achieved due to either anatomical constraints or more widespread disease than expected. Potentially curative surgery ranged from limited local resection to extensive surgery, including pelvic exenteration and peritonectomy procedures.15–17 The characteristics and type of surgery performed in these 50 patients are summarized in Tables 2 and 3. Eighteen (36%) patients who underwent potentially curative surgery (groups R0, R1) were given systemic chemotherapy postoperatively. Five patients (2 R0, 2 R1, 1 R2) who underwent peritonectomy procedures were also given early postoperative intraperitoneal chemotherapy.15 The other |32 (64%) patients were only given chemotherapy if their health status was amenable to cytotoxic treatment. All of the patients who underwent potentially curative surgery for recurrence were closely followed
Table 3. Operations performed for locoregional recurrence in 43 patients Type of surgery
n
Colectomy Rectal resection Local tumor resection Abdominal wall resection Resection of small bowel Peritonectomy procedures Oophorectomy Hysterectomy Resection of bladder Total pelvic exenteration Splenectomy Laparotomy only Biopsy only Colostomy Ileostomy Gastrointestinal bypass
15 8 9 4 4 5 5 2 3 1 1 1 1 2 1 5
up according to the above-mentioned protocol. Four (40%) of these patients who had previously undergone R0 resection underwent a second resection and 1 (10%) underwent a third resection for a third time. All of the resections were R1 resections. Statistical Analysis A two-sided chi-squared or Fisher exact test was used to assess differences in proportions. The probability of treatment failure locoregional control, and overall survival were calculated by the Kaplan-Meier produce
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Table 4. Complications after surgery for recurrence in 11 patients Complication Pleuropulmopathy Postoperative hemorrhage Prolonged ileus Urinary fistula Anastomotic dehiscence Bile leakage Intra-abdominal abscess Evisceration Septicemia Wound infection Total
n 3 1 2 1 1 1 1 1 1 4 16a
Reoperation
Type of surgery R0, R0, R2 R0 R1, R1 R0 R0 R1 R1 NR R1 R1, R2, NR, NR
Yes Yes Yes Yes 4
R0, R0 resected; R1, R1 resected; R2, R2 resected; NR, no resection a Some patients had more than one complication
limit method. The Log-rank test was used for comparison and all time estimates were done using the date of surgery as the initial value. The level of statistical significance was set at 5%.
Results Patient Characteristics Locoregional recurrence developed in 22 (22.6%) of 97 patients with rectal cancer and in 28 (19.3%) of 145 patients with colon cancer. The recurrence rate was not significantly different between the two groups (P ⫽ 0.5). Locoregional recurrence developed in 28 (23.5%) of 119 men and 22 (17.9%) of 123 women, without a significant difference (P ⫽ 0.1). Locoregional recurrence was seen in 2 (5.7%) of 35 patients with stage I disease, in 11 (9.2%) of 119 patients with stage II disease, and in 37 (42%) of 88 patients with stage III disease. The incidence of recurrence was significantly higher in patients with stage III disease than in those with stage I and II disease (P ⫽ 0.001), but the difference between patients with stage I and those with stage II disease was not significant (P ⫽ 0.5). Symptoms at the Time of Recurrence Of the 50 patients with LRR, 8 (16%) were asymptomatic when recurrence was diagnosed, all of whom (100%) underwent potentially curative surgery. Only 10 (23.8%) of the remaining 42 patients with symptoms underwent potentially curative resection (P ⫽ 0.001). The mean survival of the asymptomatic patients was 41 months, whereas that of the symptomatic patients was only 13.3 months (P ⫽ 0.001).
Table 5. Survival of each group Survival (months) Group
n
R0 R1 R2 NR NS
10 8 13 12 7
Mean ⫾ SE 48 ⫾ 36 ⫾ 10 ⫾ 6⫾ 5⫾
7.0 5.0 1.0 1.5 0.6
Median, range 41.5, 15–76 25.5, 15–52 10, 6–14 4, 2–22 4, 3–7
R0, R0 resected; R1, R1 resected; R2, R2 resected; NR, surgery without resection; NS, no surgery
Mortality and Morbidity There was no postoperative 30-day mortality in the series of 43 patients who underwent surgery, although 11 (25%) suffered one or more postoperative complications (Table 4), 4 of whom required reoperation. The mean hospital stay was 26 days (range 7–54 days). Survival The mean survival for the entire series of 50 patients was 18 months (range 2–76 months). The mean survival times for each group are summarized in Table 5 and Fig. 1. The mean survival of the R0 group was 48 months and that of the R1 group was 36 months (P ⫽ 0.5). The mean survival of the R2, NR, and NS groups was 10, 5.6, and 5.0 months, respectively. The 5-year survival of the 18 patients who underwent potentially curative resection was 29%, versus 0% for the 32 patients who underwent noncurative procedures (P ⫽ 0.001). The mean survival of the four surviving patients, all of whom underwent curative resection, was 50.5 months (range 28–76 months). Discussion The findings of this study showed that the LRR rate was strongly related to the stage of the primary tumor, being
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Fig. 1. Kaplan-Meier survival curves for all groups. R1 versus R2, log-rank P ⫽ 0.0001
significantly higher in patients with stage III disease than in those with stage I or II disease (P ⫽ 0.001). The goals of treatment for recurrent colorectal cancer are to relieve symptoms, to enhance quality of life, and if possible, to achieve cure with a low rate of treatmentrelated complications. The indications for potentially curative surgery depend on several factors, including the extent of disease, the presence of concomitant illness, and the experience of the surgeon. Systemic disease, systemic disease with peritoneal implants, multiple hepatic metastases, or extensive pelvic involvement preclude surgical treatment for cure.8 We were able to perform potentially curative resections with an acceptable complication rate in 18 (36%) patients. The resection rate for LRR is reported to range from 25% to 75%.2,8,12 In our series, the R0 and R1 resection rate was 36%. The ability to perform curative resection for recurrent colorectal cancer is the only factor that has been shown consistently to have an impact on overall survival.2,18 The median survival of patients who undergo curative resection ranges from 21 to 36 months,2,18 whereas that of patients who undergo noncurative procedures or nonoperative patients ranges from 6 to 10 months.2,6 The median survival in our series, of 35 months, versus 6 months for patients who underwent potentially curative surgery and those who received palliative treatment only, respectively, was in agreement with these findings. The 5-year overall survival of patients who underwent potentially curative surgery was 29%, but there was no difference in survival between patients who underwent an R0 resection and those who underwent an R1 resection, probably because of the small number of patients studied. However, there was a highly significant difference in median survival between patients who underwent potentially curative resection (R0 or R1) and to those who underwent noncurative procedures. Our results suggest that the most important objective of potentially curative surgery is to remove all
macroscopic disease, followed by adjuvant therapy. Similar results (71 R0 resections vs 14 R1 resections: P ⫽ 0.56) were reported by Salo et al. from a referral institution; the Memorial Sloan-Kettering Cancer Center.19 They also attributed their results to the small number of patients in the R1 resection group. Detecting recurrence in an early asymptomatic phase provides a greater chance for potentially curative surgery than when the recurrence is symptomatic. The St. Mark’s group found that longer survival was associated with the absence of severe symptoms.20 Our series clearly showed the importance of detecting recurrent disease at an early asymptomatic phase when it can still be treated by either R0 or R1 resection, justifying an aggressive follow-up policy. The management of locally recurrent colorectal cancer depends on the site and extent of disease. Recurrent colorectal cancer may involve adjacent organs, the abdominal wall, the lateral pelvic wall, the sacrum, or the wound. More extensive disease may involve peritoneal carcinomatosis. Our surgical management aimed to minimize residual tumor cells and avoid spillage. Our technical approach was to perform en bloc resection of the recurrence and adjacent structures. The result was R2 resection when the normal tissue plains had been obliterated by previous surgery, radiation, or both, making it impossible to obtain negative margins. In patients who had a nonresectable tumor, a stoma or bypass was done to palliate impending obstruction. In conclusion, the possibility of potentially curative resection is high for asymptomatic patients; therefore, close follow-up detect the LRR at an early stage should be done so that R0 or R1 resection can be performed successfully. Potentially curative surgery for LRR in selected patients who have undergone curative resection of colorectal cancer prolongs survival.
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M. Fuzun et al.: Locoregional Recurrence of Colorectal Cancer 14. Sökmen S, Terzi C, Ünek T, Alanyalı H, Füzün M. Multivisceral resections for primary advanced rectal cancer. Int J Colorectal Dis 1999;14:282–5. 15. Fuzun M, Sokmen S, Terzi C, Alakavuklar M, Hacıyanlı M. Cytoreductive approach to peritoneal carcinomatosis. J BUON 4 1999;189–92. 16. Sugarbaker PH. Management of peritoneal surface malignancy using intraperitoneal chemotherapy and cytoreductive surgery: a manual for physician and nurses. 3rd ed. Grand Rapids: Ludann; 1998. 17. Sagar PM, Pemberton JH. Surgical management of locally recurrent rectal cancer. Br J Surg 1996;83:293–304. 18. Cunningham JD, Warren E, Cohen A. Salvage therapy for pelvic recurrence following curative rectal cancer resection. Dis Colon Rectum 1997;40:393–400. 19. Salo JC, Paty PB, Guilem J, Minsky BD, Harrison LB, Cohen AM. Surgical salvage or recurrent rectal carcinoma after curative resection: a 10-year experience. Ann Surg Oncol 1999;6:171– 7. 20. Gagliardi G, Hawley PR, Hershman MJ, Arnott SJ. Prognostic factors in surgery for local recurrence of rectal cancer. Br J Surg 1995;82:1401–5.
