Anna Martling

Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer

To address issues regarding the fractionation of radiotherapy (RT) and timing of surgery for rectal cancer, a multicentre trial has randomized patients to preoperative short‐course RT with two different intervals to surgery, or long‐course RT with delayed surgery. The present interim analysis assessed feasibility, compliance and complications after RT and surgery.

Impact of a surgical training programme on rectal cancer outcomes in Stockholm

Total mesorectal excision (TME) and use of adjuvant radiotherapy are major advances in the treatment of rectal cancer that have emerged in the past 20 years. The aim of this study was to evaluate the effects of an initiative to teach the TME technique on outcomes at 5 years after surgery.

The Stockholm II trial on preoperative radiotherapy in rectal carcinoma

The Stockholm II trial is a population‐based prospective randomized trial on preoperative radiotherapy in rectal carcinoma.

Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer

This was a population‐based cohort study to determine the incidence, prevalence and risk factors for peritoneal carcinomatosis (PC) from colorectal cancer.

A Population-Based Study on the Management and Outcome in Patients with Locally Recurrent Rectal Cancer

BackgroundAlthough outcome in patients with rectal cancer has improved with preoperative radiotherapy and total mesorectal excision, local recurrence still remains a problem. The condition is difficult to cure and little is known on whether the prognosis for patients with locally recurrent tumours has changed over time. Few population-based studies have been performed.MethodTwo thousand three hundred and eighteen patients in Stockholm, Sweden had a potentially curative resection for rectal cancer between 1995 and 2003. Until 2005, 141 (6%) developed a local recurrence. Management and outcome for these patients were studied and compared to a previously analysed cohort of 156 patients with local recurrence, treated 1980–1991.ResultsOf the 141 patients, 57 (40%) had surgery with a curative intent, 48 (34%) radio- and/or chemotherapy and 36 (26%) symptomatic palliation only. The total 5-year survival was 9%. Twenty-five patients had a potentially curative resection, with a 5-year survival of 57%. The corresponding figures for the 156 patients in the earlier cohort were 4 and 42%.ConclusionAlthough outcome for patients with local recurrence of rectal cancer is dismal, the prognosis has improved slightly over time. A radical resection is a prerequisite for cure and the proportion having a potentially curative resection has increased. Multidisciplinary management, including optimised preoperative staging and patient selection for surgery, radical surgical approach and more effective adjuvant treatments are necessary to further improve the prognosis.

Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression

Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth.

Preoperative short-course radiotherapy with delayed surgery in primary rectal cancer.

Short‐course radiotherapy (SRT) with immediate surgery and long‐course chemoradiotherapy (CRT) are currently the standard preoperative treatment options for rectal cancer. SRT with surgery delayed for 4–8 weeks (SRT‐delay) is an option described for patients with locally advanced tumours who are not fit for CRT. This study examined early toxicity, response to radiotherapy (RT) and short‐term outcomes of SRT‐delay.

Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer

The Stockholm III Trial randomized patients with primary operable rectal cancers to either short‐course radiotherapy (RT) with immediate surgery (SRT), short‐course RT with surgery delayed 4–8 weeks (SRT‐delay) or long‐course RT with surgery delayed 4–8 weeks. This preplanned interim analysis examined the pathological outcome of delaying surgery.

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.

Prognostic value of preoperative magnetic resonance imaging of the pelvis in rectal cancer

Despite radiotherapy and improved surgical techniques, local recurrence rates after treatment of rectal cancer still vary between 3 and 30 per cent. Tumour involvement of the circumferential resection margin (CRM) predicts a high risk of local recurrence. Magnetic resonance imaging (MRI) allows accurate description of the tumour and its spread within the mesorectum. The aim of this study was to assess the prognostic impact of an involved CRM identified at preoperative MRI in patients with rectal cancer.