Lars Påhlman

Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial.

BACKGROUND The safety and short-term benefits of laparoscopic colectomy for cancer remain debatable. The multicentre COLOR (COlon cancer Laparoscopic or Open Resection) trial was done to assess the safety and benefit of laparoscopic resection compared with open resection for curative treatment of patients with cancer of the right or left colon. METHODS 627 patients were randomly assigned to laparoscopic surgery and 621 patients to open surgery. The primary endpoint was cancer-free survival 3 years after surgery. Secondary outcomes were short-term morbidity and mortality, number of positive resection margins, local recurrence, port-site or wound-site recurrence, metastasis, overall survival, and blood loss during surgery. Analysis was by intention to treat. Here, clinical characteristics, operative findings, and postoperative outcome are reported. FINDINGS Patients assigned laparoscopic resection had less blood loss compared with those assigned open resection (median 100 mL [range 0-2700] vs 175 mL [0-2000], p<0.0001), although laparoscopic surgery lasted 30 min longer than did open surgery (p<0.0001). Conversion to open surgery was needed for 91 (17%) patients undergoing the laparoscopic procedure. Radicality of resection as assessed by number of removed lymph nodes and length of resected oral and aboral bowel did not differ between groups. Laparoscopic colectomy was associated with earlier recovery of bowel function (p<0.0001), need for fewer analgesics, and with a shorter hospital stay (p<0.0001) compared with open colectomy. Morbidity and mortality 28 days after colectomy did not differ between groups. INTERPRETATION Laparoscopic surgery can be used for safe and radical resection of cancer in the right, left, and sigmoid colon.

The TME trial after a median follow-up of 6 years - Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma

Objective:To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery. Summary Background Data:Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years. Methods:One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 × 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control. Results:Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins. Conclusions:With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.

Survival after laparoscopic surgery versus open surgery for colon cancer : long-term outcome of a randomised clinical trial

BACKGROUND Laparoscopic surgery for colon cancer has been proven safe, but debate continues over whether the available long-term survival data justify implementation of laparoscopic techniques in surgery for colon cancer. The aim of the COlon cancer Laparoscopic or Open Resection (COLOR) trial was to compare 3-year disease-free survival and overall survival after laparoscopic and open resection of solitary colon cancer. METHODS Between March 7, 1997, and March 6, 2003, patients recruited from 29 European hospitals with a solitary cancer of the right or left colon and a body-mass index up to 30 kg/m(2) were randomly assigned to either laparoscopic or open surgery as curative treatment in this non-inferiority randomised trial. Disease-free survival at 3 years after surgery was the primary outcome, with a prespecified non-inferiority boundary at 7% difference between groups. Secondary outcomes were short-term morbidity and mortality, number of positive resection margins, local recurrence, port-site or wound-site recurrence, and blood loss during surgery. Neither patients nor health-care providers were blinded to patient groupings. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00387842. FINDINGS During the recruitment period, 1248 patients were randomly assigned to either open surgery (n=621) or laparoscopic surgery (n=627). 172 were excluded after randomisation, mainly because of the presence of distant metastases or benign disease, leaving 1076 patients eligible for analysis (542 assigned open surgery and 534 assigned laparoscopic surgery). Median follow-up was 53 months (range 0.03-60). Positive resection margins, number of lymph nodes removed, and morbidity and mortality were similar in both groups. The combined 3-year disease-free survival for all stages was 74.2% (95% CI 70.4-78.0) in the laparoscopic group and 76.2% (72.6-79.8) in the open-surgery group (p=0.70 by log-rank test); the difference in disease-free survival after 3 years was 2.0% (95% CI -3.2 to 7.2). The hazard ratio (HR) for disease-free survival (open vs laparoscopic surgery) was 0.92 (95% CI 0.74-1.15). The combined 3-year overall survival for all stages was 81.8% (78.4-85.1) in the laparoscopic group and 84.2% (81.1-87.3) in the open-surgery group (p=0.45 by log-rank test); the difference in overall survival after 3 years was 2.4% (95% CI -2.1 to 7.0; HR 0.95 [0.74-1.22]). INTERPRETATION Our trial could not rule out a difference in disease-free survival at 3 years in favour of open colectomy because the upper limit of the 95% CI for the difference just exceeded the predetermined non-inferiority boundary of 7%. However, the difference in disease-free survival between groups was small and, we believe, clinically acceptable, justifying the implementation of laparoscopic surgery into daily practice. Further studies should address whether laparoscopic surgery is superior to open surgery in this setting.

Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial

BACKGROUND The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years. METHODS Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 × 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. FINDINGS 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0·0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0·032). INTERPRETATION For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains. FUNDING The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society.

Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma : report from a randomized multicenter trial

Between October 1980 and December 1985, 471 patients with a resectable rectal carcinoma entered a randomized multicenter trial for comparison of pre- and postoperative irradiation. Two hundred thirty-six patients were allocated to receive high-dose fractionated preoperative irradiation (total dosage, 25.5 Gy in five to seven days) and 235 patients to receive postoperative irradiation to a very high dosage level with conventional fractionation (60 Gy in a total 8 weeks). The postoperative treatment was delivered only to a high-risk group of patients (Astler-Coller stages B2, C1, and C2). The preoperative irradiation was well tolerated, with no immediate irradiation-related complications and no increased postoperative mortality (3%, 7 of 217 patients, compared to 5%, 10 of 215 patients in the postoperatively irradiated group). More patients in the preoperative irradiation group had perineal wound sepsis after abdominoperineal resection and this prolonged the stay in hospital after surgery. In 50% of the patients the postoperative treatment could not be commenced until more than 6 weeks after surgery. The postoperative treatment was not as well tolerated as the preoperative one. The local recurrence rate was statistically significantly lower after preoperative than after postoperative radiotherapy (12% versus 21%; p = 0.02). In both groups more patients developed a local recurrence if the bowel was perforated at surgery or if the resection line was microscopically close to the tumor. To date, with a minimum follow-up of 3 years and a mean follow-up of 6 years, there is no difference in survival rates between the two groups.

Swedish Rectal Cancer Trial: Long Lasting Benefits From Radiotherapy on Survival and Local Recurrence Rate

PURPOSE To evaluate the long-term effects on survival and recurrence rates of preoperative radiotherapy in the treatment of curatively operated rectal cancer patients. PATIENTS AND METHODS Of 1,168 randomly assigned patients in the Swedish Rectal Cancer Trial between 1987 and 1990, 908 had curative surgery; 454 of these patients had surgery alone, and 454 were administered preoperative radiotherapy (25 Gy in 5 days) followed by surgery within 1 week. Follow-up was performed by matching against three Swedish nationwide registries (the Swedish Cancer Register, the Hospital Discharge Register, and the Cause of Death Register). RESULTS Median follow-up time was 13 years (range, 3 to 15 years). The overall survival rate in the irradiated group was 38% v 30% in the nonirradiated group (P = .008). The cancer-specific survival rate in the irradiated group was 72% v 62% in the nonirradiated group (P = .03), and the local recurrence rate was 9% v 26% (P < .001), respectively. The reduction of local recurrence rates was observed at all tumor heights, although it was not statistically significant for tumors greater than 10 cm from the anal verge. CONCLUSION Preoperative radiotherapy with 25 Gy in 1 week before curative surgery for rectal cancer is beneficial for overall and cancer-specific survival and local recurrence rates after long-term follow-up.

Preoperative or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and an evaluation of late secondary effects

From 1980 to 1985, 471 patients with resectable rectal and rectosigmoid cancer were randomly allocated to receive either preoperative short-term high-dose irradiation (25.5 Gy in one week) for all patients or prolonged postoperative radiotherapy (60 Gy in seven to eight weeks) only for patients with a Dukes B or C lesion. After a minimum follow-up of five years, the local recurrence rate was statistically significantly lower after preoperative than after postoperative radiotherapy (13 percentvs.22 percent;P=0.02). No difference in overall survival was noted (P=0.5). To evaluate possible late side effects on the bowel, urinary bladder, or skin after surgery and additional preoperative or postoperative radiotherapy, all patients included in the randomized trial, together with 58 patients from a preceding pilot study with the same preoperative regimen, were studied in a prolonged follow-up program. The hospital files of all patients were re-examined. Of the patients who were carefully examined, 176 had a survival exceeding five years and 19 had a survival exceeding 10 years. Overall, 7 percent (33/ 464) either were operated upon or have had a radiologic diagnosis of small bowel obstruction: 14/255 (5 percent) after preoperative irradiation, 14/127 (11 percent) after postoperative irradiation, and 5/82 (6 percent) after surgery alone. The cumulative risk of developing a bowel obstruction was significantly increased after postoperative radiotherapy. Among the 98 patients alive after preoperative irradiation, significant morbidity from the bowel was noted in 11 patients, from the urinary bladder in two, and from the skin in six. In the postoperatively treated group of 34 patients, the bowel, urinary bladder, and skin morbidity were significant in five, two, and five patients, respectively. Corresponding morbidity in 44 nonirradiated patients was seen in five, one, and two patients, respectively. It is concluded that preoperative, short-term, high-dose radiotherapy decreases the local recurrence rate relative to postoperative radiotherapy, with no indications of increased late morbidity after a follow-up of 5 to 10 years.

Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study

PURPOSE: The Swedish Rectal Cancer Trial has unequivocally demonstrated that preoperative high-dose (5 × 5 Gy) radiotherapy reduces local failure rates and improves overall survival. This will have an impact on the primary treatment of rectal cancer. This study investigates the effect of preoperative high-dose radiotherapy on long-term bowel function in patients treated with anterior resection. METHODS: A questionnaire was answered by 92 percent (203/220) of patients who were included in the Swedish Rectal Cancer Trial and who were alive after a minimum of five years. Thirty-two patients were excluded, mainly because of postoperative stomas and dementia, which left 171 for analysis. RESULTS: Median bowel frequency per week was 20 in the irradiated group (n=84) and 10 in the surgery-alone group (n=87;P<0.001). Incontinence for loose stools (P<0.001), urgency (P<0.001), and emptying difficulties (P<0.05) were all more common after irradiation. Sensory functions such as “discrimination between gas and stool” and “ability to safely release flatus” did not, however, differ between groups. Thirty percent of the irradiated group stated that they had an impaired social life because of bowel dysfunction, compared with 10 percent of the surgery-alone group (P<0.01). CONCLUSIONS: The study indicates that high-dose radiotherapy influences long-term bowel function, thus emphasizing the need for finding predictive factors for local recurrence to exclude patients with a very high probability for cure with surgery alone and to use optimized radiation techniques.

Randomized comparison of straight and colonic J pouch anastomosis after low anterior resection.

OBJECTIVE The authors compared clinical bowel function and complications of a low anterior resection with either a straight or colonic J pouch anastomosis. SUMMARY BACKGROUND DATA Urgency and frequent bowel movements after rectal resection with a low anastomosis have been related to the loss of rectal reservoir function. Reconstruction with a colonic J pouch possibly can obviate some of this dysfunction. Earlier reports have been favorable, but they must be verified in randomized trials. METHOD One hundred patients with rectal cancer in whom a sphincter-saving procedure was appropriate were randomized to reconstruction with either a straight or a colonic J pouch anastomosis. RESULTS The incidence of symptomatic anastomotic leakage was lower in the pouch group (2% vs. 15%, p = 0.03). Eighty-nine patients could be evaluated after 1 year. The pouch patients had significantly fewer bowel movements per 24 hours, and less nocturnal evacuations, urgency, and incontinence. Overall well-being owing to the bowel function was rated significantly higher by the pouch patients. CONCLUSION Reconstruction with a colonic J pouch was associated with a lower incidence of anastomotic leakage and better clinical bowel function when compared with the traditional straight anastomosis. Functional superiority was especially evident during the first 2 months.

Randomized Phase III Study Comparing Preoperative Radiotherapy With Chemoradiotherapy in Nonresectable Rectal Cancer

PURPOSE Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. PATIENTS AND METHODS The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). RESULTS The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. CONCLUSION CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.