Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial.

BACKGROUND: Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. METHODS: In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. FINDINGS: Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2-62·2) in the short-course radiotherapy group and 19·3 months (8·5-39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8-114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 [95% CI 0·41-5·11]; long-course radiotherapy with delay 2·24 [0·71-7·10]; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0·59 [95% CI 0·36-0·97], long-course radiotherapy with delay 0·63 [0·38-1·04], p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0·61 [95% CI 0·45-0·83] p=0·001). INTERPRETATION: Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. FUNDING: Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.

[Specialist referral with photography for faster diagnosis of skin tumor. Management can be better planned--and saves resources]. / Specialistremiss med fotografi ger snabbare diagnos av hudtumör - Omhändertagandet kan planeras bättre - och resurser sparas.

Adding a photograph of suspected skin cancer to the standard referral can shorten the time to the initial evaluation by a specialist department. The management of the patient can also be better planned and resources can be saved.

The impact of hospital volume on surgical outcome in patients with rectal cancer.

PURPOSE: This study was designed to investigate, in a population-based setting, the surgical outcome in patients with rectal cancer according to the hospital volume. METHODS: Since 1995 all patients with rectal cancer have been registered in the Swedish Rectal Cancer Registry. Hospitals were classified, according to number treated per year, as low-volume, intermediate-volume, or high-volume hospitals (<11, 11-25, or >25 procedures per year). Postoperative mortality, reoperation rate within 30 days, local recurrence rate, and overall five-year survival were studied. For postoperative morbidity and mortality the whole cohort from 1995 to 2003 (n = 10,425) was used. For cancer-related outcome only, those with five-year follow-ups, from 1995 to 1998, were used (n = 4,355). RESULTS: In this registry setting the postoperative mortality rate was 3.6% in low-volume hospitals, and 2.2% in intermediate-volume and high-volume hospitals (P = 0.002). The reoperation rate was 10%, with no differences according to volume. The overall local recurrence rates were 9.4%, 9.3%, and 7.5%, respectively (P = 0.06). Significant difference was found among the nonirradiated patients (P = 0.004), but not among the irradiated patients (P = 0.45). No differences were found according to volume in the absolute five-year survival. CONCLUSION: Postoperative mortality and local recurrence in nonirradiated patients were lower in high-volume hospitals. No difference was seen between volumes in reoperation rates, overall local recurrence, or absolute five-year survival.

Quality of life after potentially curative treatment for locally advanced rectal cancer.

BACKGROUND: Patients with locally advanced rectal cancer have a poor prognosis and the early and late postoperative morbidity is high. The aim of this study was to assess health-related quality of life (HRQL) in patients treated with extensive surgical resections for locally advanced rectal cancer and to compare the results with those in patients treated for primarily resectable rectal cancer. METHODS: Between 1991 and 2003, 142 patients with locally advanced rectal cancer had an extensive resection at the Karolinska Hospital in Stockholm, Sweden. A HRQL assessment with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR38 questionnaires was performed in patients alive and disease free in 2005. The results were compared with an age- and sex-matched reference group of patients with primarily resectable rectal cancer having had total mesorectal excision alone. RESULTS: The study group of 43 patients (81% of eligible) scored clinically and statistically significantly lower in global quality of life, role function, physical function, social function, and body image and reported a higher degree of pain and fatigue compared with the reference group of 80 patients. In the study group, men scored lower than women in global quality of life, role functioning and social functioning and reported more problems with fatigue. CONCLUSION: Several aspects of HRQL are impaired in disease-free patients treated for locally advanced rectal cancer. This knowledge may be useful in the preoperative counselling and postoperative support of these patients.

MRI after preoperative radiotherapy for rectal cancer; correlation with histopathology and the role of volumetry.

The objective is to assess if tumor size after radiotherapy in patients with rectal cancer can be assessed by a second magnetic resonance imaging (MRI), after radiotherapy prior to surgery and to correlate changes observed on MRI with findings at histopathology at surgery. Twenty-five patients with MRI before and after radiotherapy were included. Variables studied were changes in tumor size, T-staging and distance to the circumferential resection margin (CRM). RVs was measured as tumor volume at surgery (Vs) divided by tumor volume at the initial MRI (Vi) in percent. RVm was defined as the tumor volume at the second MRI (Vm) divided by Vi in percent. The ypT-stage was the same or more favorable than the initial MRI T-stage in 24 of 25 patients. The second MRI was not more accurately predictive than the initial MRI for ypT-staging or distance to CRM (p > 0.05). Vm correlated significantly to Vs, as did RVs to RVm, although the former was always smaller than the latter. Vm and RVm correlated well with ypT-stage (p < 0.001). Volumetry seems to correlate with ypT-stage after preoperative radiotherapy for resectable rectal cancer. The value of a second MRI after radiotherapy for assessment of distance to CRM and ypT-staging is, however, not apparent.

Loco-regional recurrence from colon cancer: a population-based study.

BACKGROUND: The survival after colon cancer surgery has not improved to the same extent as after rectal cancer treatment and studies on loco-regional recurrence after colon cancer surgery are scarce. The aim of this study was to assess the problem of loco-regional recurrence after potentially curative resections for colon cancer, regarding incidence, risk factors, management, and outcome. METHODS: All 1,856 patients submitted to potentially curative surgery for colon cancer in the Stockholm/Gotland region in Sweden between 1996 and 2000 were followed until January 2005 or until death. Follow-up data were prospectively collected. Risk factors for loco-regional recurrences were analyzed, treatment and outcome for patients with recurrence was studied. RESULTS: The cumulative 5-year incidence of loco-regional recurrence was 11.5%. Tumor locations in the right flexure and in the sigmoid colon, bowel perforation and emergent surgery were identified as independent risk factors for loco-regional recurrence. The risk also increased with increasing T- and N-stage. The median survival for all 192 patients with loco-regional recurrence was 9 months. Surgery was performed in 110 (57%) patients. In 23 (12%) patients a complete tumor clearance was achieved and the estimated 5-year survival in this group was 43%. CONCLUSION: Loco-regional recurrence from colon cancer is a significant clinical problem. A multidisciplinary treatment approach, including preoperative staging, a complete resection of the recurrence and more effective adjuvant treatments may improve the outcome.

Long-term effect of preoperative radiation therapy on anorectal function.

PURPOSE: Preoperative radiotherapy improves local control in rectal cancer treatment, but there are few reports on the influence of radiotherapy on anorectal function. The aim of the present study was to assess late effects of short-course, high-dose radiotherapy on anorectal function after low anterior resection for rectal cancer. METHODS: Sixty-four patients, randomized within the Stockholm Radiotherapy Trials and operated on with low anterior resection with or without preoperative radiotherapy (mean, 14 years), previously were followed up with quality-of-life questionnaires, clinical examination, anorectal manometry, and endoanal ultrasound. Twenty-one patients had received preoperative radiotherapy of the rectum and 43 patients had been treated with surgery alone. RESULTS: Impaired anorectal function was common after low anterior resection for rectal cancer and the risk was increased after radiotherapy. Irradiated patients had significantly more symptoms of fecal incontinence (57 vs. 26 percent, P = 0.01), soiling (38 vs. 16 percent, P = 0.04), and significantly more bowel movements per week (20 vs. 10, P = 0.02). At anorectal manometry, irradiated patients had significantly lower resting (35 mmHg vs. 62 mmHg, P < 0,001) and squeeze pressures (104 mmHg vs. 143 mmHg, P = 0.05). At endoanal ultrasound, irradiated patients had significantly more scarring of the anal sphincters (33 vs. 13 percent, P = 0.03). There were no significant differences in quality-of-life scores between irradiated and nonirradiated patients; however, patients with anal incontinence had significantly lower quality-of-life scores compared to continent patients. CONCLUSIONS: Short-course radiotherapy, including the anal sphincters, impairs anorectal function and increases gastrointestinal symptoms permanently when the anal sphincters are irradiated.

Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group.

Due to uncertainties regarding clinically meaningful gains from adjuvant chemotherapy after colorectal cancer surgery, several Nordic Groups in the early 1990s initiated randomised trials to prove or reject such gains. This report gives the joint analyses after a minimum 5-year follow-up. Between October 1991 and December 1997, 2 224 patients under 76 years of age with colorectal cancer stages II and III were randomised to surgery alone (n = 1 121) or adjuvant chemotherapy (n = 1 103) which varied between trials (5FU/levamisole for 12 months, n = 444; 5FU/leucovorin for 4-5 months according to either a modified Mayo Clinic schedule (n = 262) or the Nordic schedule (n = 397). Some centres also randomised patients treated with 5FU/leucovorin to+/-levamisole). A total of 812 patients had colon cancer stage II, 708 colon cancer stage III, 323 rectal cancer stage II and 368 rectal cancer stage III. All analyses were according to intention-to-treat. No statistically significant difference in overall survival, stratified for country or region, could be found in any group of patients according to stage or site. In colon cancer stage III, an absolute difference of 7% (p = 0.15), favouring chemotherapy, was seen. The present analyses corroborate a small but clinically meaningful survival gain from adjuvant chemotherapy in colon cancer stage III, but not in the other presentations.

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.

[Skills by training. Education and case volume are strong prognostic factors in rectal cancer surgery]. / Ovning gerfärdighet. Utbildning och operationsvolym är starka prognostiska faktorer vid rektalcancerkirurgi.

The TME project (TME = total mesorectal excision) demonstrated and probably enhanced a major shift in rectal cancer surgical practice in Stockholm with an increased centralisation and specialisation. As a result, local control and cancer-specific survival has been significantly improved. In addition, the frequency of APR (APR = abdominoperineal resection) declined. TME based surgery demands surgical skill, which can be achieved by participation in education programmes and increased by personal training and experience. Variability in patient outcome is seen also with TME based surgery and is mainly related to case volume, with better results obtained in patients treated by high-volume surgeons. A combined treatment modality approach, integrating the colorectalsurgeon, diagnostic radiologist, pathologist, medical and radiation oncologist is necessary to achieve optimal outcome.

Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.

Several types of endocrine tumors show frequent somatic deletions of the distal part of chromosome arm 11q, where the tumor-suppressor gene SDHD (succinate-ubiquinone oxidoreductase subunit D), constitutionally mutated in paragangliomas of the head and neck, is located. In this study, we screened 18 midgut carcinoids, 7 Merkel cell carcinomas, 46 adrenal pheochromocytomas (37 sporadic and 9 familial), and 7 abdominal paragangliomas for loss of heterozygosity (LOH) and/or mutations at the SDHD gene locus. LOH was detected in 5 out of 8 (62%) informative midgut carcinoids, in 9 out of 30 (30%) sporadic pheochromocytomas, in none of the familial pheochromocytomas (0%), and in 1 out of 6 (17%) abdominal paragangliomas. No sequence variants were detected in the pheochromocytomas or paragangliomas. However, two constitutional putative missense mutations, H50R and G12S, were detected in two midgut carcinoids, which were both associated with LOH of the other allele. The same sequence variants were also detected in two Merkel cell carcinomas. In addition, the S68S polymorphism was found to coexist with the G12S sequence variant in both cases. In conclusion, we show that alterations of the SDHD gene seem to be involved in the tumorigenesis of both midgut carcinoids and Merkel cell carcinomas.