Johan N. Wiig

A national strategic change in treatment policy for rectal cancer--implementation of total mesorectal excision as routine treatment in Norway. A national audit.

AbstractINTRODUCTION: Rectal cancer surgery has been characterized by a high incidence of local recurrence, an occurrence which influences survival negatively. In Norway there was a growing recognition that local recurrence rates were related to surgeon performance and that surgeons applying a standardized surgical technique in the form of total mesorectal excision could achieve better results. This contrasts with the prevailing argument voiced by many opinion leaders that local recurrence rates and possibly survival rates can only be improved by adjuvant or neoadjuvant treatment strategies. The Norwegian Rectal Cancer Project—initiated in 1993—aimed at improving the outcome of patients with rectal cancer by implementing total mesorectal excision as the standard rectal resection technique. METHODS: This observational national cohort study covers all new patients (3,319) with rectal cancer from a population of 4.5 million treated between November 1993 and August 1997. The main outcome measures were local recurrence, survival, and postoperative mortality and morbidity rates. The technique of total mesorectal excision was compared with conventional surgery. RESULTS: The proportion of patients undergoing total mesorectal excision was 78 percent in 1994, increasing to 92 percent in 1997. The observed local recurrence rate for patients undergoing a curative resection was 6 percent in the group treated by total mesorectal excision and 12 percent in the conventional surgery group. Four-year survival rate was 73 percent after total mesorectal excision and 60 percent after conventional surgery. Postoperative mortality rate was 3 percent and the anastomotic dehiscence rate was 10 percent. Radiotherapy was given to 5 percent and chemotherapy to 3 percent of the patients in the curative resection group. CONCLUSION: A refinement of the surgical resection technique for rectal cancer can be achieved on a national level, the technique of total mesorectal excision can be widely distributed, and surgery alone can give good results.

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.

Anastomotic leakage following routine mesorectal excision for rectal cancer in a national cohort of patients

Objective  Mesorectal excision is successfully implemented as the standard surgical technique for rectal cancer resections in Norway. This technique has been associated with higher rates of anastomotic leakage (AL) and the purpose of this study was to examine AL in a large national cohort of patients.

Esophageal and gastric carcinoma in Norway 1958-1992: Incidence time trend variability according to morphological subtypes and organ subsites

The occurrence of adenocarcinoma (AC) of the esophagus and gastric cardia has shown large increases in many but not all examined populations. This trend is in contrast with a decrease in distal gastric AC and a relative stability of esophageal squamous cell carcinoma. Our study aimed to describe esophageal and gastric carcinoma time trends in the Norwegian population between 1958 and 1992 based on data from the Cancer Registry of Norway. Estimated esophageal AC rates have accelerated over the study period, reaching average annual increases of 17% in men and 14% in women between 1983 and 1992. The occurrence of esophageal squamous cell carcinoma was relatively stable in both sexes. Proximal gastric cancer rates were stable in males and decreased somewhat in females. Distal gastric tumors showed decreases in both sexes, but were more pronounced in females. The strong increase in esophageal AC incidence parallels similar increases in the United States and some other countries. Although the observed increase may be explained to some extent by a shift in the classification of esophago‐cardial adenocarcinomas, the figures are compatible with a real increase. AC of the esophagus, the proximal stomach and the distal stomach exhibit different epidemiological features, both in terms of sex ratios and time trends, suggesting risk factor differences between the subsites. Int. J. Cancer 71:340‐344, 1997.

Inadvertent perforation during rectal cancer resection in Norway

Inadvertent perforation of the bowel or tumour is a relatively common complication during resection of rectal cancer. The purpose of this study was to examine intraoperative perforation following the introduction of mesorectal excision as a standard surgical technique in Norway.

Preoperative irradiation and surgery for recurrent rectal cancer. Will intraoperative radiotherapy (IORT) be of additional benefit? A prospective study

BACKGROUND The therapeutic gain of surgery for recurrent rectal cancer is not clear, particularly with regard to the addition of intraoperative radiotherapy (IORT). METHODS Patients (107) with isolated pelvic recurrence of rectal cancer received preoperative external radiotherapy of 46-50 in 2 Gy fractions. At surgery 59 patients had IORT 12-18 Gy. Survival and local recurrence was analysed with regard to surgical resection stages and IORT. RESULTS Patients (44) had R0- and 39 R1-resections, 24 R2-resections or exploratory laparotomy. IORT was given most often after R1-resections, least in R0-patients. Estimated 5-year survival was overall around 30%, around 60% in the R0-, around 25% for R1- and 0% in R2-patients. Local recurrence was around 30% in the R0- and around 65% in R1-stage patients. R0-/R1-stage patients survived statistically significantly longer than the R2-group otherwise there was no statistical significant difference between IORT and non-IORT groups in any R-stages regarding overall survival or local recurrence. CONCLUSIONS Macroscopic removal of the recurrence improves survival. Whether R0- is better than R1-resections is not clear. The effect of IORT is not a major one. IORT need be evaluated in randomised controlled trials.

Total pelvic exenteration with preoperative irradiation for advanced primary and recurrent rectal cancer

OBJECTIVE To study the complication rate, local recurrence rate, and survival after total pelvic exenteration for primary advanced and recurrent rectal cancer. DESIGN Prospective study. SETTING Tertiary referral university hospital, Norway. SUBJECTS 25 patients who were operated on for primary advanced and 22 for recurrent rectal cancer since 1991; 42 men and 5 women, mean age 64 years (range 44-78). All had preoperative irradiation of 46-50 Gy. MAIN OUTCOME MEASURES Incidence of major complications, and actuarial 5-year survival and local recurrence rate. RESULTS Twenty patients had RO resection in the primary group versus seven in the recurrent group. No R2 resections were done in the primary group compared with four in the recurrent group. Half the primary cases (n = 13) had abdominoperineal resections. Hartmanns procedures were common in both groups (n = 8 in each). Postoperative mortality at 30 days was 4% (n = 2) and in-hospital 13% (n = 6). 18 patients had major complications and 12 were reoperated on. Overall 5-year actuarial survival for 43 patients without distant metastases was 28%-those with primary tumours 36%, and those with recurrent tumours 18%-similar to the figures for RO and R1 resections. Actuarial local recurrence at 5 years for primary cancers was 18% compared with 68% for recurrent cancers, again nearly identical to the figures for R0/R1 operations (p = 0.008 and p = 0.03). CONCLUSION Some patients with advanced rectal cancer either primary or recurrent may benefit from simultaneous en-bloc cystectomy. The higher postoperative morbidity and mortality indicate the need for well-defined indications for this procedure and the necessity for thorough preoperative staging.

Nationwide quality assurance of rectal cancer treatment

Objective  The purpose of this prospective study was to examine the influence of the efforts for nationwide quality assurance of rectal cancer treatment. The study focuses on local recurrence and overall survival.

Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group

Background. The recommendation of adjuvant chemotherapy for colon cancer with lymph node metastases, based on two studies from USA, was reluctantly accepted by Norwegian medical doctors. It was therefore decided to assess the role of adjuvant therapy with 5fluorouracil (5-FU) combined with levamisole (Lev) in a confirmatory randomised study. Material and methods. Four hundred and twenty five patients with operable colon and rectum cancer, Stage II and III (Dukes’ stage B and C), were from January 1993 to October 1996, included in a randomised multicentre trial in Norway. The age limits were 18–75 years. Therapy started with a loading course of bolus i.v. 5-FU (450 mg/m2) daily for 5 days and p.o. doses of Lev (50 mg x 3) for 3 days. From day 28 a weekly i.v. 5-FU dose (450 mg/m2) were administered for 48 weeks. From day 28 also p.o. doses of Lev (50 mg x 3) for 3 days were given every 14 days. In total 214 patients were randomised to 5FU/Lev and 211 were included in the control group with surgery alone. Some did not comply with the inclusion and exclusion criteria, thus leaving 206 evaluable patients in each group. Results. There was no significant survival difference between the two groups at 5 years: Disease-free survival (DFS) was 73% after chemotherapy, 68% (p=0.24) in the control group, and corresponding cancer specific survival (CSS) 75% and 71%, respectively (p=0.69). There was no difference between the two groups when analysed for colon and rectum separately. However, the subgroup of colon cancer with stage III exhibited a statistically significant difference both for DFS, 58% vs. 37% (p=0.012) and CSS, 65% vs. 47% (p=0.032) in favour of adjuvant chemotherapy. The benefit was further statistically significant for women but not for men. Toxicity was generally mild and acceptable with no drug related fatalities. Conclusions. Colon cancer patients with lymph node metastases benefit from adjuvant chemotherapy with 5-FU/Lev with acceptable toxicity. In a subgroup analysis females did better than males. Rectal cancer does not benefit from this regimen.

Combined modality treatment including intraoperative radiotherapy in locally advanced and recurrent rectal cancer

BACKGROUND Treatment of locally advanced and recurrent rectal cancer usually has a high local recurrence rate and poor survival. Promising results have been reported by combined external radiotherapy, extensive surgery and intraoperative radiotherapy (IORT). METHODS One hundred fifteen patients with locally advanced rectal cancers fixed to the pelvic wall or locally recurrent rectal cancers underwent preoperative external radiotherapy with 46-50 Gy. Six to 8 weeks later radical pelvic surgery was attempted, and was combined with intraoperative electron beam radiotherapy (15-20 Gy) in 66 patients. The patients were followed closely to evaluate complication rate, local and distant recurrence rate and survival. RESULTS Surgery with no macroscopic tumour remaining was obtained in 65% of the patients with no postoperative deaths. Pelvic infection was the major complication (21%). Although the observation time is short (3-60 months), the local recurrence rate seems low (22%) and survival seems promising (about 60% at 4 years) in patients with complete tumour resection, in contrast to patients with residual tumour (none living at 4 years). CONCLUSIONS The combined modality treatment with preoperative external radiotherapy and extensive pelvic surgery with IORT is sufficiently promising to start a randomized trial on the clinical value of IORT as a boost treatment in the multidisciplinary approach to this disease.